Clinical Effectiveness of Pre-incision Versus Post-incision Local Anesthetic During Laparoscopic/Robotic Sacrocolpopexy
Phase: PHASE4
Conditions: Pain, Postoperative
Sponsor: Northwell Health

Clinical effectiveness of pre-incision versus
post-incision local anesthetic during
laparoscopic/robotic sacrocolpopexy
(The CLAPPS Trial)
Protocol Number: 21-0422
National Clinical Trial (NCT) Identified Number: pending
Principal Investigator: Harvey Winkler, MD
Sponsor: not applicable
Funded by: not applicable
Version Number: v.1.0.
29 July 2021
Summary of Changes from Previous Version:
Affected
Section(s)
Summary of Revisions Made
Rationale

Table of Contents
1.
STATEMENT OF COMPLIANCE
1
1
PROTOCOL SUMMARY
1
1.1
Synopsis
1
1.2
Schema
2
1.3
Schedule of Activities (SoA)
3
2
INTRODUCTION
4
2.1
Study Rationale
4
2.2
Background
5
2.3
Risk/Benefit Assessment
5
2.3.1
Known Potential Risks
5
2.3.2
Known Potential Benefits
5
2.3.3
Assessment of Potential Risks and Benefits
5
3
OBJECTIVES AND ENDPOINTS
6
4
STUDY DESIGN
6
4.1
Overall Design
6
4.2
Scientific Rationale for Study Design
8
4.3
Justification for Dose
8
4.4
End of Study Definition
8
5
STUDY POPULATION
8
5.1
Inclusion Criteria
8
5.2
Exclusion Criteria
9
5.3
Lifestyle Considerations
9
5.4
Screen Failures
9
5.5
Strategies for Recruitment and Retention
9
6
STUDY INTERVENTION
10
6.1
Study Intervention(s) Administration
10
6.1.1
Study Intervention Description
10
6.1.2
Dosing and Administration
10
6.2
Preparation/Handling/Storage/Accountability
10
6.2.1
Acquisition and accountability
10
6.2.2
Formulation, Appearance, Packaging, and Labeling
11
6.2.3
Product Storage and Stability
11
6.2.4
Preparation
11
6.3
Measures to Minimize Bias: Randomization and Blinding
11
6.4
Study Intervention Compliance
11
6.5
Concomitant Therapy
12
6.5.1
Rescue Medicine
12
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
12
7.1
Discontinuation of Study Intervention
12
7.2
Participant Discontinuation/Withdrawal from the Study
12

7.3
Lost to Follow-Up
13
8
STUDY ASSESSMENTS AND PROCEDURES
13
8.1
Efficacy Assessments
13
8.2
Safety and Other Assessments
13
8.3
Adverse Events and Serious Adverse Events
14
8.3.1
Definition of Adverse Events (AE)
14
8.3.2
Definition of Serious Adverse Events (SAE)
14
8.3.3 Classification of an Adverse Event
14
8.3.3.1
Severity of Event
14
8.3.3.2
Relationship to Study INTERVENTION
15
8.3.3.3
Expectedness
15
8.3.4
Time Period and Frequency for Event Assessment and Follow-Up
15
8.3.5
Adverse Event ReportinG
16
8.3.6
Serious Adverse Event Reporting
16
8.3.7
Reporting Events to Participants
16
8.3.8
Events of Special Interest
16
8.3.9
Reporting of Pregnancy
17
8.4
Unanticipated Problems
17
8.4.1
Definition of Unanticipated Problems (UP)
17
8.4.2
Unanticipated Problem Reporting
17
8.4.3
Reporting Unanticipated Problems to Participants
18
8.4.4
Data and safety monitoring plan
18
Data and Safety Monitoring Plan (DSMP)
18
Risk Assessment
18
9. STATISTICAL CONSIDERATIONS
19
9.1
Statistical Hypotheses
19
9.2
9.2 Sample Size Determination
20
9.3
Populations for Analyses
20
9.4
Statistical Analyses
21
9.4.1
General Approach
21
9.4.2
Analysis of the Primary Efficacy Endpoint(s)
21
9.4.3
Analysis of the Secondary Endpoint(s)
21
9.4.4
9.4.4 Safety Analyses
22
9.4.5
Baseline Descriptive Statistics
22
9.4.6
Planned Interim Analyses
22
9.4.7 Sub-Group Analyses
22
9.4.7
Tabulation of Individual participant Data
23
9.4.9 Exploratory Analyses
23
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
23
10.1
Regulatory, Ethical, and Study Oversight Considerations
23
10.1.1
Informed Consent Process
23

10.1.1.1 Consent/assent and Other Informational Documents Provided to
participants
23
10.1.1.2 Consent Procedures and Documentation
23
10.1.2 Study Discontinuation and Closure
23
10.1.3 CONFIDENTIALITY and Privacy
24
10.1.4 FUTURE Use of Stored Specimens and Data
25
10.1.5 KEY Roles and Study Governance
25
10.1.6 Safety Oversight
25
10.1.7 Clinical Monitoring
25
10.1.8 Quality Assurance and Quality Control
26
10.1.9
Data Handling and Record Keeping
26
10.1.9.1 Data Collection and Management Responsibilities
26
10.1.9.2
Study Records Retention
26
10.1.10 Protocol Deviations
27
10.1.11 Publication and Data Sharing Policy
27
10.1.12 Conflict of Interest Policy
27
10.2 Additional Considerations
28
10.3 Abbreviations
29
10.4 Protocol Amendment History
30
10
11 REFERENCES
31

Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
1.
STATEMENT OF COMPLIANCE
The trial will be conducted in accordance with the International Conference on Harmonisation
Good Clinical Practice (ICH GCP), and applicable United States (US) Code of Federal Regulations
(CFR). The Principal Investigator will assure that no deviation from, or changes to the protocol
will take place without prior agreement from the documented approval from the Institutional
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial
participants. All personnel involved in the conduct of this study have completed Human Subjects
Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will
be submitted to the 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. 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.
1
PROTOCOL SUMMARY
1.1
SYNOPSIS
Title:
Clinical effectiveness of pre-incision versus post-incision local anesthetic
during laparoscopic/robotic sacrocolpopexy
Study Description:
To compare postoperative narcotic use and pain score with pre-incisional
versus post-incisional injection of local anesthetic at trocar sites in
robotic/laparoscopic-assisted sacrocolpopexy
Objectives:
●
Primary objective: Comparing postoperative Likert pain
scale between patients who received pre-incisional versus
post-incisional local anesthetic on postoperative day one
●
Secondary objectives: Total narcotic use over two weeks
between patients who received pre-incisional versus
post-incisional local anesthetic. To compare the pain levels
reported by patients on the brief pain inventory
questionnaire at POD14 between the two study groups
(pre-incisional vs post-incisional) by two sample t –test or
Wilcoxin rank-sum test, where appropriate.
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
Endpoints:
Primary Endpoint: comparing Likert-pain scale scores between
pre-incisional versus post-incisional local anesthetic on postoperative day
one
Secondary Endpoints: total narcotic use over two weeks between patients
who received pre-incisional versus post-incisional local anesthetic and to
compare brief pain inventory questionnaires at POD14 between the two
study groups.
Study Population:
Sample size – 64 per arm; Female gender, age ≥18 years old, general
health status healthy
Phase:
N/A
Description of
Sites/Facilities
Enrolling Participants:
Northwell Health sites (Lenox Hill Hospital, Southshore Hospital, Long
Island Jewish Hospital, Northshore Hospital, Huntington Hospital,
Plainview, Peconic, Mather). No hospital outside of the US.
Description of Study
Intervention:
Subcutaneous injection of 4-5mL of 0.25% Bupivacaine into skin before or
after incision for trocar placement during robotic/laparoscopic- assisted
sacrocolpopexy
Study Duration:
18 months
Participant Duration:
2 weeks
1.2
SCHEMA
Visit 0
●
New patient/Surgical discussion Visit
○
Screen potential for inclusion and exclusion criteria
○
If meets criteria
■
Pamphlet provided to patient in regard to study information
Visit 1
●
Preoperative visit
○
Discuss study in further detail, answer questions after patient read pamphlet,
risks/benefits discussed and offer patient participation
○
If patient consents:
■
First Brief Pain Inventory Questionnaire to fill out prior to surgery. The Narcotic
Diary will be given to patient with the instructions to fill out after surgery and to
document all narcotic pills used including provided and any additional.
○
If a patient is undecided, then will follow up by phone call prior to surgical day. If she
decides after follow up phone call then will have patient sign consent on day of surgery
Visit 2
●
Day of surgery
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
○
If patient does not consent at preoperative visit, but decides to participate after follow
up phone call:
■
Obtain consent if patient has agreed by phone call (phone call which is after
preoperative visit) on the day of surgery
■
Provide narcotic diary and first Brief Pain Inventory Questionnaire to fill out (if
patient has not already filled it out previously). Patient only needs to fill out one
brief pain inventory questionnaire prior to surgery, the patient should fill this out
on the day that they sign the consent for participation (whether it is at the
preoperative visit or in the preoperative suite on the day of surgery). The
Narcotic Diary will be given to patient with the instructions to fill out after
surgery and to document all narcotic pills used including provided and any
additional.
○
Randomization
■
Arm 1: 64 patients; Arm 2: 64 patients
Visit 3
●
Postoperative Day 1
○
Obtain Likert-pain scale score between 18-24 hours post-surgery
Visit 4
●
Postoperative Visit (14 days +/- 3 days)
○
Narcotic Diary collected
○
Second Brief Pain Inventory Questionnaire given to patient to complete
1.3
SCHEDULE OF ACTIVITIES (SOA)
Procedures
Screening
Visit (Visit
0)
Preoperativ
e Visit
(Visit 1)
Day of
Surgery
(Visit 2)
Postoperative
Day#1
(Visit 3)
Final Study Visit
Day 14
+/-3 day
(Visit 4)
Informed consent
X
Demographics
X
X
Medical history
X
X
Randomization
X
Administer study
intervention
X
Concomitant
medication review
X
X
X
X
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
Physical exam
(including height and
weight)*
X
X
X
Vital signs*
X
X
X
x
X
Height*
X
x
Weight*
X
x
X
Hematology*
X
X
Serum chemistry*
X
Pregnancy Test*
X
EKG (as indicated)*
X
Adverse event review
and evaluation
X
X-------------------------X
X
Radiologic/Imaging
assessment*
X
X
Other assessments (e.g.,
immunology assays,
pharmacokinetic)*
X
X
X
X
Complete Case Report
Forms (CRFs)
X
X
X
X
Brief Pain Inventory
Questionnaire **
x
x
x
*Results of these standard of care procedures (if available) will be collected for research purposes via medical record review
**Patient will fill out this only one time prior to surgery on the day she consents to participate in the clinical trial.
2
INTRODUCTION
2.1
STUDY RATIONALE
Pelvic organ prolapse is becoming more common as women’s life expectancy is increasing and
the prevalence of obesity is rising. Many women undergo pelvic reconstructive surgery to treat their
prolapse and improve their quality of life. The incidence of pelvic organ prolapse is 1.5-1.8 surgeries per
1,000 women years (1). Approximately 300,000 pelvic reconstructive surgeries are performed each year
in the United States (1). There is a wide variety in surgical approaches and procedures for prolapse. One
such procedure is a sacrocolpopexy in which the cervix or vaginal cuff is lifted to the anterior longitudinal
ligament overlying the sacrum via a mesh graft. This can be done in a minimally invasive fashion with a
laparoscopic or robotic approach or in an open abdominal approach. Numerous studies have shown this
procedure to have a high success rate and long-term durability (2). As robotic/laparoscopic approach to
surgery has shown shorter hospital-stays and improved patient outcomes, the robotic-assisted
sacrocolpopexy has been rapidly incorporated into clinical practice (2).
In general, surgery causes a release of painful chemical mediators which has led to increased
narcotic use, increased narcotic addiction, and number of pills prescribed. Most individuals who undergo
surgery will require narcotics postoperatively to control their pain and some individuals have to extend
their hospital stay until adequate pain control is achieved. Our study is aimed to reduce narcotic use,
decrease hospital stay due to pain issues and determine if timing of adjunct pain medication improves
pain scales for patients.
As postoperative pain after minimally invasive surgery is complex, specialists suggest that the
effective analgesic treatment should be a multimodal approach (4). Use of local anesthetic with
bupivacaine at robotic/laparoscopic trocar sites is the standard of care, however, there is no standard as
to optimal timing that is most beneficial for patients to decrease pain. Currently, bupivacaine is used by
providers at the trocar sites at either the beginning of the case or at the end of the case. From clinical
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
observation, it appears that postoperative pain levels reported from patients receiving either at the
beginning of surgery (pre-) or end (post-incision) of the surgery are similar. This study aims to examine
the difference in POD1 pain levels reported by patients between the two infiltration methods.
2.2
BACKGROUND
Subcutaneous infiltration with bupivacaine at robotic/laparoscopic port sites is standard of care. It is
currently injected into incision sites during laparoscopic or robotic trocar sites before or after the incision
is made. However, there is no standard as to which time during the procedure is the most beneficial for
patients in order to decrease pain. Currently, there is lack of studies in the current literature that
describe pre-incisional vs post-incisional local infiltration of numbing medication during
robotic/laparoscopic-assisted sacrocolpopexy. There have been similar studies for patients undergoing
laparoscopic cholecystectomy in which timing of the Marcaine was given to one group prior to incision
and in another group at the end of the procedure, however in this study there was no difference in the
pain scores at various times evaluates postoperatively. Our study is aimed to determine if the timing of
local infiltration improves pain scales during robotic/laparoscopic sacrocolpopexy, which is a
considerably longer procedure (approximately 3-5 hours). There is currently no literature on comparing
Likert-pain scale scores in patients during robotic/laparoscopic sacrocolpopexy.
2.3
RISK/BENEFIT ASSESSMENT
2.3.1
KNOWN POTENTIAL RISKS
Bupivacaine (brand name: Marcaine)
•
Immediate common risks: edema at insertion site, seroma
•
Long-range common risks: hypersensitivity reaction, hypotension, localized numbness, cardiac
arrest, methemoglobinemia and dose related toxicity
•
Injection of Marcaine at skin incision sites will be lower than the dose that causes potential risks
This research will collect subject’s personal health information, and there is a risk of breach of
confidentiality.
Some of the questions on the questionnaires are personal and subjects may feel embarrassed or
stressed.
Since subjects will be randomized to one of the two groups, some may receive less effective treatment
and/or have more side effects than those in the other group.
2.3.2
KNOWN POTENTIAL BENEFITS
Subjects will be randomized, and some may experience less pain and/or fewer side effects than those in
the other group.
2.3.3
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
•
Local infiltration of incision sites with bupivacaine is standard of care for surgery.
•
Adverse short term and long term risks: we will be using a standard dose that is currently used in
the operating suite, which is lower than what would cause adverse side effects
3
OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR
ENDPOINTS
Primary
Difference in Likert-pain scale score
difference between pre-incision
versus post-incision subcutaneous
infiltration with 4-5mL 0.25%
Bupivacaine at 18-24 hours
postoperatively
Likert-pain scale score difference
between pre-incision and
post-incision subcutaneous
infiltration at 18-24 hours
postoperatively.
To determine if timing
of local anesthetic
affects postoperative
pain scores.
Secondary
To compare total narcotic usage
over two weeks
Total number of narcotic tablets used
in the first two weeks postoperatively
between pre-incision and
post-incision subcutaneous
infiltration with 4-5mL 0.25%
Bupivacaine
To decrease
postoperative narcotic
usage
Secondary
Compare brief pain inventory
questionnaire survey score
To compare score levels of
the
brief
pain
inventory
questionnaire
at
POD14
between
the
two
study
groups
To decrease pain score
for patient post surgery
4
STUDY DESIGN
4.1
OVERALL DESIGN
●
Central Objective To examine patients reported pain levels or narcotic usage between
pre-incision versus post-incision subcutaneous infiltration of 4-5mL 0.25% Bupivacaine
after a robotic/laparoscopic-assisted sacrocolpopexy.
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
Research Plan:
●
Randomized, controlled, single-blinded study
Setting of the study:
●
Operating room of patients undergoing robotic/laparoscopic sacrocolpopexy
Participants:
●
Patients aged 18 years old and above who are scheduled to undergo
robotic/laparoscopic-assisted sacrocolpopexy (with or without hysterectomy and with or
without midurethral sling)
Randomization Scheme
●
Randomization will be accomplished using the Biostatistics Randomization Management
System
●
1:1 Randomization, permuted blocks
●
Subjects will be randomized using a computer generated table into one of two groups:
○
Arm one: subcutaneous infiltration pre-incision
○
Arm two: subcutaneous infiltration post-incision
●
Surgeons will be notified by e-mail of their patient allocation on day of surgery
Pre-surgery
●
Consent will be obtained and the patient will be given a Brief Pain Inventory Questionnaire to
complete. The Brief Pain Inventory Questionnaire is a validated medical questionnaire to
measure pain. The questionnaire measures the patient’s pain intensity and the amount of
interference the pain has on their being able to function in their daily living.
●
Intervention or experimental aspect of the study
○
General anesthesia will be given as per standard protocol
○
Preoperative pain medication will be ordered for each patient as per standard
enhanced recovery protocol
○
Operative Time: Generally total of 180 – 300 minutes
○
Total dose of 0.25% Bupivacaine injection:
■
8-10 mm incisions x 5 incisions = 20-25 mL (4-5 mL each)
■
20-25mL of 0.25% Bupivacaine distributed over 5 trocar sites (4-5mL per
incision)
■
Skin closure: subcutaneous closure with monofilament absorbable
suture with 4-0 absorbable suture and fascia closure of the umbilical
port site with #0 delayed absorbable suture and skin closure with 4-0
absorbable suture
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
■
Pre-incision arm: Marcaine (bupivacaine) injected in the umbilical port
site subcutaneously, while in the other 4 sites injection under direct
visualization
■
Post-incision arm: local anesthetic infiltrated subcutaneously at the end
of the procedure after trocar removal and after skin closure with suture
○
Postoperative pain medication will be ordered for each patient as per standard
enhanced recovery protocol
○
On Postoperative Day 1, the patient will be asked her pain scale on the
Likert-pain scale. The Likert-pain scale is a 0-10 discrete integer scale. The
investigators will check for patient’s pain medication use before questionnaire
administration. If a patient has received postoperative pain medication, the
questionnaire will be administered at least 1.5 hours after the patient has
received the pain medication.
○
Discharge medications will be ordered for each patient as per standard
enhanced recovery protocol
○
The Brief Pain Inventory Questionnaire will be given to the patient at the 2
–week postoperative visit to be filled out and collected at the postoperative
visit.
○
The Narcotic diary (in which the patient writes down how many narcotic tablets
they have used per day since the surgery (provided and additional included) will
be collected at the postoperative visit.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The rationale for this study is to determine if timing of local anesthetic infiltration impacts overall pain
score or narcotic usage. Although use of local anesthetic has been shown to reduce pain, there is no
literature in gynecologic surgery regarding the timing of infiltration and its impact, if any, on pain.
4.3
JUSTIFICATION FOR DOSE
Standard dose used.
4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if the patient has completed all phases of the
study including the narcotic pain diary and brief pain inventory questionnaire at the first postoperative
visit at approximately two weeks.
5
STUDY POPULATION
5.1
INCLUSION CRITERIA
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
●
Females 18+ years old who are undergoing robotic/laparoscopic assisted sacrocolpopexy
○
With/without hysterectomy
○
With/without unilateral/bilateral salpingectomy
○
With/without unilateral/bilateral oophorectomy
○
With/without midurethral sling
○
With/without anterior/posterior vaginal repair
●
English or Spanish speaking
●
Weight ≥120 lbs
5.2
EXCLUSION CRITERIA
●
Females < 18 years old
●
Chronic pelvic pain/chronic pain syndromes
●
Fibromyalgia
●
Pregnant or breastfeeding patients
●
Concomitant procedure for hernia repair or rectal prolapse repair
●
Undergoing primary vaginal prolapse surgery
●
Contraindications to taking the following medications: Bupivacaine
●
Patients who weight is < 120lb
●
Hypersensitivity to bupivacaine hydrochloride, amide-type local anesthetics, or any component
of the formulation
●
Pudendal or spinal nerve block given during surgery
5.3
LIFESTYLE CONSIDERATIONS
Our standard post-operative instructions will remain.
5.4
SCREEN FAILURES
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).
5.5
STRATEGIES FOR RECRUITMENT AND RETENTION
●
Patients will be screened and recruited from the Urogynecology outpatient clinic who are
scheduled to undergo surgical management to correct their prolapse.
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
●
At the visit in which the patient is considering surgical management for prolapse, all questions
will be answered and she may be given a printed pamphlet that describes and details the study
●
At the preoperative visit, if the patient has decided to under the robotic/laparoscopic-assisted
sacrocolpopexy, patient will again have an opportunity to ask questions of the study, counseled
on the risks/benefits of its participation and informed consent with be obtained
○
If she is undecided about joining the study, but is planning to undergo
robotic/laparoscopic-assisted sacrocolpopexy, then she will be given additional time and
called prior to surgery to answer any additional questions about the study and evaluate
participation
○
If the patient did not sign on the preoperative visit, then she will be given another
opportunity to sign the consent form on the day of surgery in the preoperative area and
answer any further additional questions
●
Email and phone call reminders to patients for postoperative appointment date and to fill out
narcotic diary
●
No vulnerable populations will be targeted for recruitment
●
No incentives will be provided
6
STUDY INTERVENTION
6.1
STUDY INTERVENTION(S) ADMINISTRATION
6.1.1
STUDY INTERVENTION DESCRIPTION
Study Drug
●
0.25% Bupivacaine
○
Mechanism of action: blocks both the initiation and conduction of nerve impulses by
decreasing the neuronal membranes permeability to sodium ions, which results in
inhibition of depolarization with resultant blockade of conduction
6.1.2
DOSING AND ADMINISTRATION
Study Drug
●
Anesthesia team will be notified the total dose of medication being injected prior to case start
●
Anesthesia team will be notified when the study drug is being injected
●
4-5 mL of 0.25% Bupivacaine given subcutaneously at each of the injection sites (total of 5
incisions)
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
6.2.1
ACQUISITION AND ACCOUNTABILITY
●
Study drug will be obtained from the hospital pharmacy
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017
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Clinical effectiveness of pre-incision versus post-incision local anesthetic during laparoscopic/robotic sacrocolpopexy
Version 1.0.
Protocol 21-0422
29 July 2021
●
Any expired local anesthetic will not be used at the time of surgery, as per standard protocol
●
Any remaining medication will be disposed at the end of procedure, as per standard protocol
●
Study intervention will be emailed to investigator before surgery
6.2.2
FORMULATION, APPEARANCE, PACKAGING, AND LABELING
0.25% Bupivacaine is already pre-packaged and comes with the label of Marcaine (Bupivacaine) 0.25%
directly to the hospital pharmacy. This drug is then pre-ordered and brought to the operating room
where the designated amount will be drawn up into sterile syringes.
6.2.3
PRODUCT STORAGE AND STABILITY
●
Product will be obtained from the hospital pharmacy where the medication is stored at room
temperature
●
In the operating room, the medication seal will be broken after confirming expiration date has
not passed
●
The medication will be stored at room temperature in the operating room until time for
administration
6.2.4
PREPARATION
●
The medication will be provided by hospital pharmacy
●
No special dilution or mixing required
●
Medication will be drawn up in sterile syringes by operating room staff
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
●
Patient-blinded study
●
Multi-site study
●
The surgeon at the time of intervention will not be blinded as to which arm the patient belongs
●
Randomization will be performed using 1:1 randomization, permuted blocks
Randomization will be accomplished using the Biostatistics Randomization Management System
according to hospital site.
6.4
STUDY INTERVENTION COMPLIANCE
Adherence to the protocol will be confirmed and assessed by speaking directly with the primary surgeon
prior to the procedure and at the end of procedure. The surgeon will be informed of each participant
study allocation. The surgeons have been informed and continued to review how to inject the
medication depending on the patient groups during monthly research meetings per discussion and
teachings. The patient’s Likert-pain scale will be assessed 18-24 hours after surgery. Documents that are
mandatory to complete by the patient will be a participant drug log, in which the number of narcotic
tablets used and pain score will be recorded daily by the patient.
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6.5
CONCOMITANT THERAPY
Patients who participate in the study will receive the following standardized pain regimen:
●
General anesthesia will be given as per standard protocol
●
Preoperative pain medication will be ordered for each patient as per standard enhanced
recovery protocol.
●
Postoperative pain medication will be ordered for each patient as per standard enhanced
recovery protocol.
●
Discharge medications will be ordered for each patient as per standard enhanced recovery
protocol.
6.5.1
RESCUE MEDICINE
Not applicable
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
DISCONTINUATION OF STUDY INTERVENTION
If the first ten patients do not tolerate the study medication, then we will evaluate which adverse
reaction the patients experience and as to which arm they were randomized. We will also evaluate at
which time point they experienced an adverse reaction and if it was to a preoperative/postoperative
medication or if it was to the study drug. Pending the determination of these, we will halt recruitment. It
is possible for a patient to discontinue participating in the study after surgery, but not during surgery.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
An investigator may discontinue or withdraw a participant from the study for the following reasons:
●
Pregnancy
●
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
●
If the participant meets an exclusion criterion (either newly developed or not previously
recognized) that precludes further study participation
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive
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the study intervention may be replaced. Subjects 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 for her scheduled visit and is
unable to be contacted by the study site staff.
The following actions must be taken if a participant fails to return to the clinic for a required study visit:
●
The site will attempt to contact the participant and reschedule the missed visit within one week
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, three telephone calls 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, she will be considered to have withdrawn
from the study with a primary reason of loss to follow-up.
8
STUDY ASSESSMENTS AND PROCEDURES
8.1
EFFICACY ASSESSMENTS
Efficacy will be assessed by regular discussions with the primary surgeon by email and by phone call. We
will discuss which patients have consented to the study on a weekly basis and then discussions will be
had on the morning of each procedure to determine which arm the patient has been randomized into.
We will be having regular weekly meetings to ensure that the protocol is being followed and that the
co-investigators are aware of which patients have already consented and which patients have agreed to
the study over the phone but need to have consent done on the day of surgery. We have reviewed how
injections will be given in the two groups during our monthly research meetings and will continue to
review these at the monthly meetings. After the surgery is complete, efficacy will be again assessed to
ensure that the patient received the local infiltration pending which arm the patient was randomized
into by phone call or email with the co-investigator.
8.2
SAFETY AND OTHER ASSESSMENTS
Patients will be screening for allergy to or contraindications to study medication. If they meet criteria and
consent for the study, then each patient will be monitored for safety in multiple forms. For each patient,
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vital signs are monitored in the operating room and during recovery until discharge as part of routine
clinical care. Electrocardiogram monitoring will also be continuously ongoing in the operating room as
part of routine clinical care. Assessment of adverse events throughout hospital stay will be done by
review of charts and discussion with other members involved in patient care.
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.
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 the
investigator, 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”.
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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 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.
•
Related – The AE is known to occur with the study intervention, there is a reasonable possibility
that the study intervention caused the AE, or there is a temporal relationship between the study
intervention and event. Reasonable possibility means that there is evidence to suggest a causal
relationship between the study intervention and the AE.
•
Not Related – There is not a reasonable possibility that the administration of the study
intervention caused the event, there is no temporal relationship between the study intervention
and event onset, or an alternate etiology has been established.
8.3.3.3 EXPECTEDNESS
The Principal Investigator and all other investigators a part of the study 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.
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Dr. Vini Chopra, co-investigator, will record all adverse 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
Adverse events will be reported to the independent medical monitor. The independent medical monitor
will record all serious and non-serious adverse events and this will be reported to the principal
investigator that occurs within the 2 weeks of the study time length.
8.3.6
SERIOUS ADVERSE EVENT REPORTING
The study clinician will immediately report any serious adverse event, whether or not considered study
intervention related, including those listed in the protocol or investigator brochure 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 relationship between the
study intervention and the event (e.g., death from anaphylaxis). In that case, the investigator must
immediately report the event.
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.
The co-investigator will be responsible for notifying the Food and Drug Administration (FDA) of any
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later
than 7 calendar days after the initial receipt of the information. In addition, the investigator must notify
FDA and all participating investigators in a safety report of potential serious risks, from clinical trials or
any other source, as soon as possible, but in no case later than 15 calendar days.
8.3.7
REPORTING EVENTS TO PARTICIPANTS
If any adverse event meets definition of an unanticipated problem that results in a consent form
modification, subjects will be notified via the re-consenting process.
8.3.8
EVENTS OF SPECIAL INTEREST
Not applicable
8.3.9
REPORTING OF PREGNANCY
Not applicable
8.4
UNANTICIPATED PROBLEMS
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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 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 within 5 business days of
the investigator becoming aware of the event.
•
Any other UP will be reported to the IRB within 5 business days of the investigator becoming
aware of the problem.
•
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 decision.
8.4.3
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS
For unanticipated problems that result in a consent form modification, subjects will be notified via the
re-consenting process. For other unanticipated problems that require reporting to participants as
determined by the IRB, subjects will be as per the IRB’s determination.
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8.4.4
DATA AND SAFETY MONITORING PLAN
DATA AND SAFETY MONITORING PLAN (DSMP)
In accordance with federal guidelines, this study requires a DSMP. The PI has identified an independent Medical
Monitor (Dr. Gary Goldberg) with expertise in pelvic organ prolapse and robotic/laparoscopic-assisted
sacrocolpopexy who does not have any scientific, financial, or other conflict of interest related to the study and
who is not responsible for patient care at any of the participating sites. Safety will be formerly monitored by the
study team and the independent Medical Monitor throughout the duration of the study, and the independent
Medical Monitor will review safety data in aggregate every 6 months. The independent medical monitor and
research team members will prepare a safety report for these regular reviews comprised of anticipated safety
events and actions taken. The PI will contact the independent Medical Monitor for ad hoc reviews of any
unanticipated safety events. The study protocol will be carried out in accordance with FDA guidelines and
requirements. In the event of a serious adverse event during the study protocol, it will be reported immediately to
the PI, the co-investigators, and the independent Medical Monitor. It will also be reported to the Northwell IRB for
the study and to all members of the research team. With the approval of the participants and families, the
information will be provided to other care providers as directed.
RISK ASSESSMENT
This study involves greater than minimal risk to the subjects. The primary concern is the development of numbness
and bruising of injection site, severe allergic reaction and abnormal heart rhythm leading to death.
Subjects will be monitored throughout the study for these potential adverse events by phone call on the first
postoperative day and then an office visit at two weeks post-surgery. The PI (or another designated Investigator in
her absence) will be notified of any abnormal results so that the safety measures outlined below are implemented.
The primary physician will also be notified of any abnormal results and any changes to the subject’s care, and will
also be provided with the test results. The potential risks and protections are as follows:
1. Abnormal Heart Rhythm
Monitoring: Electrocardiogram monitoring in the operating room where the Marcaine will be
given and monitoring of vital signs in the operating room and after surgery is complete
Actions:
o
If severe abnormal heart rhythms at screening, subject will not be enrolled.
o
If severe abnormal heart rhythms at any study visit, subject will be taken off
therapy, but will continue to be followed until end of study.
o
If the subject complains of symptoms concerning for abnormal heart rhythm
(shortness of breath, chest pain, dizziness, abnormal heart beat), Abnormal heart
rhythm will be checked in addition to any other clinical testing requested by
primary physician.
2. Severe allergic reaction:
Monitoring: vital sign monitoring and patient monitoring before, during and after surgery
Actions:
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o
If patient has an allergy to local numbing medication at screening, subject will not
be enrolled.
o
If severe allergic reaction at any study visit, Marcaine (generic name:
Bupivacaine) will not be furthermore given and the patient will be followed for
two weeks post procedure.
o
If the subject complains of symptoms concerning for severe allergic reaction
(chest pain, shortness of breath, rashes), Severe allergic reaction will be checked
in addition to any other clinical testing requested by primary physician.
3. Methemoglobinemia
●
Monitoring: oxygen status and any skin discoloration will be monitored in the
operating room after injection has been given and after surgery
●
Actions:
●Immediate discontinuation of bupivacaine injection
●Depending on the severity of the signs and symptoms, patients may
respond to supportive care (oxygen, continued ventilation, and hydration)
●A more severe clinical presentation may require treatment with methylene
blue, exchange transfusion or hyperbaric oxygen.
9. STATISTICAL CONSIDERATIONS
9.1 STATISTICAL HYPOTHESES
●
Primary Efficacy Endpoint(s):
●
Assessment of infiltration at pre-incision (pre) and infiltration at post-incision (post)
associated pain score using a Likert-pain scale. The Likert-like pain scale is a validated,
subjective measure for acute and chronic pain. The primary endpoint of pain score
measurement will take place on postoperative day 1 (18-24 hr post-surgery,
postoperative day 1). Scores are recorded by choosing an integer only number on a 0-10
scale that represents between “no pain” and “worst pain”.
●
Secondary Efficacy Endpoint(s):
●
The need for additional narcotic usage over 2 weeks between the 2 arms
●
Compare questionnaires between the initial brief pain inventory questionnaire
(pre-surgery) and postoperative brief pain inventory questionnaire
9.2
SAMPLE SIZE DETERMINATION
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We used pain score measured at POD1 as our primary outcome of interest. Sample size calculation was
calculated using two independent sample t test, under the assumption that the pain scores are normally
distributed. At the following test settings:
Hnull: Mean difference of pain levels reported on a Likert-pain scale by patients between pre- and post-
incision arms at POD1 = 0;
Ha: Mean difference of pain levels reported on a Likert-pain scale by patients pre- and post- incision arms
at postoperative day one ≠0, and the expected mean difference of pain levels between the two groups is
1 likert point*.
Further we assume,
Standard deviation (std) = 2;
With the following default set-up values:
Alpha = 0.05
Power = 0.8
Weight between study arms = 1 (equal sample size in each arm)
Drop-out rate = 0
The required sample size for the current study is 64 per arm or 128 in total.
*No well-established mean difference between the two study groups can be found in the literature. Based on
clinical observations and experience from physicians that the two different infiltration methods are currently used
interchangeably with no obvious difference in patients reported POD1 pain, we hypothesize the likely difference of
pain levels between the two study groups to be 1. With standard deviation of 2 (see below), our targeted effect size
is 0.5, or a median size effect based on Cohen’s rule (Cohen, 1989).
**This SD value was estimated from the study by Yeung et al. (Liposomal Bupivacaine During Robotic Colpopexy
VOL. 131, NO. 1, JANUARY 2018) using data from Table 3, average pain with rest at POD1 for the Bupivacaine group.
Yeung et al. showed that the mean pain level with rest at POD1 in patients treated with liposomal Bupivacaine was
18.0, with the range of data being 81, on a 100mm-VAS scale. Therefore, a ‘rule-of-thumb’ of estimating standard
deviation: range of data/4 was taken, yielding sd of ~20mm on a VAS scale. This was further translated to a sd of 2
on a 10-point Likert scale as one of the parameters for the sample size calculation for the current study.
9.3
POPULATIONS FOR ANALYSES
Intention to Treat (ITT) and Per Protocol (PP) analysis data sets:
The ITT dataset will consist of all randomized patients. If applicable, a modified ITT (mITT) dataset will
consist of all ITT patients who receive the actual assigned timing of infiltration. We expect no protocol
violation based on the design of the study. The safety population will consist of all mITT patients.
9.4
STATISTICAL ANALYSES
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9.4.1
GENERAL APPROACH
Summary statistics: Demographic and clinical data will be summarized according to treatment arm using
means, S.D.s, medians, quartiles, and proportions, as appropriate. As per ICH E-9 guidelines, no
inferential comparisons of the two arms will be carried out.
9.4.2
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S)
Analysis of the primary outcome: For the primary outcome, which we assume will be normally
distributed, the two independent sample t test comparing two independent groups will be used to
compare the pain scores from study arms at POD1. In the event that normal assumption does not hold, a
suitable data transformation (e.g., arcsine square-root, logit) will be applied.
A 95%, two-tailed confidence interval for the difference of mean pain scores between the two arms will
be constructed. If both upper and lower confidence intervals lay within the ± 1-unit margin, we will
conclude that the pain scores associated with the two routes of wound infiltration are equivalent.
Otherwise, we cannot conclude that the effects between the two modes of wound infiltration on
postoperative pain are equivalent.
As per ICH E-9 guidelines, a supporting analysis will be conducted whereby analysis of covariance
(ANCOVA) will be used to compare the two groups, adjusting for nuisance covariates.
All continuous secondary outcomes will be analyzed using two sample t-test or Mann-Whitney test
depending on whether normal assumption holds or not. ANCOVA will be used adjusting for baseline
values and other associated covariates and will be considered as supportive analysis.
All categorical secondary outcomes will be analyzed using chi-square test for proportions or Fisher’s
exact test, as appropriate.
9.4.3
ANALYSIS OF THE SECONDARY ENDPOINT(S)
Analysis of the secondary outcome:
●
The need for additional Narcotic usage over 2 weeks between the 2 arms
All patients will be discharged with 12 standard narcotic pills for managing post-operative
pain by needs. However, patients can request additional narcotic pain killers if needed. The
needs for extra amount of pain reliever is an indicator of pain level and a secondary aim of
the current study.
The need for additional narcotic usage is a binary-coded variable with values of ‘yes’ or ‘no’.
The rate/percentage of patients requesting additional narcotic medication will be calculated
for each study arm, and compared in a 2 by 2 contingency table format using chi-square test
or Fisher’s exact test, as appropriate.
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●
Compare pain scores between each arm at 2 weeks post-operative visit
At the two-week post-operative visit, patients will be asked to fill out the brief pain inventory
to indicate their current pain levels, as well as the mildest and worst pain scores within the
past 24 hours. The pain scores will also be evaluated by Likert-pain scale (the same pain
assessment tool used at POD1. The mean pain scores between the two arms will be
compared by a two-sample t-test or a Wilcoxon rank-sum test, where appropriate. Statistical
significance between the two arms is considered if the p-value for the tests are <0.05.
9.4.4
9.4.4 SAFETY ANALYSES
Patients will be screening for allergy to or contraindications to study medication. If they meet criteria and
consent for the study, then each patient will be monitored for safety in multiple forms. For each patient,
vital signs are monitored in the operating room and during recovery until discharge. Electrocardiogram
monitoring will also be continuously ongoing in the operating room. Assessment of adverse events
throughout hospital stay will be done by review of charts and discussion with other members involved in
patient care.
9.4.5
BASELINE DESCRIPTIVE STATISTICS
Demographic and clinical data (including operative time and procedure performed) will be summarized
according to treatment arm using means, S.D.s, medians, quartiles, and proportions, as appropriate. As
per ICH E-9 guidelines, no inferential comparisons of the two arms will be carried out.
All continuous secondary outcomes will be analyzed using two sample t-test or Mann-Whitney test
depending on whether normal assumption holds or not. ANCOVA will be used adjusting for baseline
values and other associated covariates and will be considered as supportive analysis.
All categorical secondary outcomes will be analyzed using chi-square test for proportions or Fisher’s
exact test, as appropriate.
9.4.6
PLANNED INTERIM ANALYSES
No interim analysis will be conducted.
9.4.7 SUB-GROUP ANALYSES
No planned subgroup analysis.
9.4.7
TABULATION OF INDIVIDUAL PARTICIPANT DATA
Not applicable
9.4.9 EXPLORATORY ANALYSES
Not applicable.
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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/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS
Consent forms describing 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 following consent materials are submitted with this protocol.
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION
Informed consent is a process that is initiated prior to the individual 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. The
investigator will explain the research study to the participant and answer any questions that may arise. A
verbal explanation will be provided in terms suited to the participant’s comprehension of the purposes,
procedures, and potential risks of the study and of their rights as research participants. Participants will
have the opportunity to carefully review the written consent form and ask questions prior to signing. The
participants should have the opportunity to discuss the study with their family or think about it prior to
agreeing to participate. The participant will sign the informed consent document prior to any procedures
being done specifically for the study. Participants must be informed that participation is voluntary and
that they may withdraw from the study at any time, without prejudice. A copy of the informed consent
document will be given to the participants for their records. The informed consent process will be
conducted and documented in the source document (including the date), and the form signed, before
the participant undergoes any study-specific procedures. The rights and welfare of the participants will
be protected by emphasizing to them that the quality of their medical care will not be adversely affected
if they decline to participate in this study.
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, and IRB. If the study
is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study
participants and the Institutional Review Board (IRB), 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.
Circumstances that may warrant termination or suspension include, but are not limited to:
●
Determination of unexpected, significant, or unacceptable risk to participants
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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 IRB and any other regulatory bodies.
10.1.3 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators and their
staff. This confidentiality is to the clinical information relating to participants. 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.
All research activities will be conducted in as private a setting as possible.
Representatives of the Institutional Review Board (IRB), 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 or Institutional policies.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will
be transmitted to and stored in REDCAP. This will include the participant’s contact or identifying
information. Individual participants and their research data will be identified by their name into REDCAP.
The study data entry and study management systems used by clinical sites and by REDCAP research staff
will be secured and password protected. At the end of the study, all study databases will be de-identified
and archived in REDCAP.
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA
Data collected for this study will be analyzed and stored in REDCAP. After the study is completed, the
de-identified, archived data will be transmitted to and stored in REDCAP. Permission to transmit data to
the REDCAP will be included in the informed consent.
10.1.5 KEY ROLES AND STUDY GOVERNANCE
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Principal Investigator
Independent Medical Monitor
HARVEY WINKLER, MD
GARY GOLDBERG, MD
NORTHWELL HEALTH
NORTHWELL HEALTH
865 NORTHERN BLVD
270-05 76th AVENUE
516-622-5100
516-390-9242
HWINKLER@NORTHWELL.ED
U
GGOLDBERG2@NORTHWELL
.EDU
10.1.6 SAFETY OVERSIGHT
Safety oversight will be under the direction of an independent medical monitor, Dr. Gary Goldberg, who
has the appropriate expertise, including prior research experiences in clinical trials. The medical monitor
is independent from the study conduct and free of conflict of interest, or measures will be in place to
minimize perceived conflict of interest. The independent medical monitor (Dr. Goldberg) will review
safety data in aggregate every 6 months to assess safety and efficacy data on each arm of the study.
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 Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).
•
Monitoring for this study will be performed by the independent medical monitor Dr. Gary
Goldberg and associates
•
Central monitoring to occur by investigators to ensure that safe practices are being performed
•
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP
describes in detail who will conduct the monitoring, at what frequency monitoring will be done,
at what level of detail monitoring will be performed, and the distribution of monitoring reports.
•
Independent audits will be conducted by investigators to ensure monitoring practices are
performed consistently across all participating sites and that monitors are following the CMP.
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data, 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.
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Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is
conducted and data are generated and biological specimens are collected, documented (recorded), and
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good
Manufacturing Practices (GMP)).
The investigational site will provide direct access to all trial related sites, source data/documents, and
reports for the purpose of 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 medical monitor 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.
Hardcopies 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 recorded in the electronic case report
form (eCRF) derived from source documents should be consistent with the data recorded on the source
documents.
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions
data) and clinical laboratory data will be entered into REDCAP, a 21 CFR Part 11-compliant data capture
system provided by the REDCAP. The data system includes password protection and internal quality
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or
inaccurate. Clinical data will be entered directly from the source documents.
10.1.9.2 STUDY RECORDS RETENTION
Study documents should be retained for a minimum of 2 years after the last approval of a marketing
application in an International Conference on Harmonisation (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 DEVIATIONS
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) 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:
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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.
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations
within 7 working days of identification of the protocol deviation, or within 3 working days of the
scheduled protocol-required activity. All deviations must be addressed in study source documents,
reported to REDCAP. 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. Further details about the handling of protocol deviations will be included in the MOP.
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:
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 2 years after the
completion of the primary endpoint by contacting Vini Chopra.
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 Northwell 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.
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10.3 ABBREVIATIONS
AE
Adverse Event
ANCO
VA
Analysis of Covariance
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement
Amendments
CMP
Clinical Monitoring Plan
COC
Certificate of Confidentiality
CONS
ORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
DSMP
Data Safety Monitoring Plan
eCRF
Electronic Case Report Forms
FDA
Food and Drug Administration
FDAA
A
Food and Drug Administration Amendments
Act of 2007
FFR
Federal Financial Report
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
GWAS
Genome-Wide Association Studies
HIPAA
Health Insurance Portability and
Accountability Act
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal
Editors
IDE
Investigational Device Exemption
IND
Investigational New Drug Application
IRB
Institutional Review Board
ISO
International Organization for Standardization
ITT
Intention-To-Treat
LSME
ANS
Least-squares Means
MedDR
A
Medical Dictionary for Regulatory Activities
MOP
Manual of Procedures
MSDS
Material Safety Data Sheet
NCT
National Clinical Trial
NIH
National Institutes of Health
NIH IC
NIH Institute or Center
OHRP
Office for Human Research Protections
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PI
Principal Investigator
QA
Quality Assurance
QC
Quality Control
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SMC
Safety Monitoring Committee
SOA
Schedule of Activities
SOP
Standard Operating Procedure
UP
Unanticipated Problem
US
United States
10.4 PROTOCOL AMENDMENT HISTORY
Version
Date
Description of Change
Brief Rationale
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11 REFERENCES
1. (n.d.). Retrieved from
https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Bulletins/Committee-on-Practice-Bulleti
ns-Gynecology/Pelvic-Organ-Prolapse
2. Hudson CO, Northington GM, Lyles RH, Karp DR. Outcomes of robotic sacrocolpopexy: a systematic
review and meta-analysis. Female Pelvic Med Reconstr Surg. 2014;20(5):252-260.
doi:10.1097/SPV.0000000000000070
3. Rouholamin, S., Jabalameli, M., & Mostafa, A. (2015). Retrieved from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550955/
4. Castillo-Garza G, Díaz-Elizondo JA, Cuello-García CA, Villegas-Cabello O. Irrigation with bupivacaine
at the surgical bed for postoperative pain relief after laparoscopic cholecystectomy. JSLS.
2012;16(1):105-111. doi:10.4293/108680812X13291597716221
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