Non-invasive bioELEctroniC Treatment foR pOst-cesarean paiN (ELECTRON)
Phase: NA
Conditions: Post-cesarean Pain
Sponsor: Ohio State University

Non-invasive bioELEctroniC Treatment 
foR pOst-cesarean paiN (ELECTRON) 
IRB Protocol Number: 2022H0046 
National Clinical Trial (NCT) Identified Number: NCT05250830 
Funded by:  
TrueRelief LLC 
Version Number: v2.0 
April 20, 2022 

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1.1 
Synopsis 
1 
Protocol Summary 
 
Title: 
Non-invasive bioELEctroniC treatment  foR pOst-cesareaN 
(ELECTRON) 
Study 
Description: 
This is a randomized trial of 134 individualized post-cesarean delivery 
who will be randomized to three times  use of non-invasive 
bioelectronic treatment with TrueRelief device or identical appearing 
sham device for post-cesarean pain management. 
 
Objectives: 
Primary: To evaluate whether post-cesarean use of non-invasive 
bioelectronic treatment reduces inpatient postoperative opioid 
consumption in morphine milligram equivalents (MME).  Secondary: 
To evaluate whether post-cesarean use of non-invasive bioelectronic 
treatment 1) improves pain management defined as the 
presence/absence of moderate to severe pain on post-operative day 2. 
Moderate to severe pain is defined as a value of 4 or higher on the Brief 
Pain Inventory worst pain scale (0-10) at discharge, 2) decreases the 
total amount of opioid tablets prescribed, 3) decreases an opioid refill 
prescription 4) reduces adverse maternal and infant outcomes. 
Endpoints: 
Total inpatient opioid consumption in morphine milligram equivalents. 
Brief Pain Inventory pain severity (worst, least, average, current) in last 
24 hours on post-operative day 2, Brief Pain Inventory pain interference 
during the past week, number of opioid tablets prescribed at discharge, 
number of opioid prescriptions filled beyond that prescribed at 
discharge, maternal and infant outcomes. 
Study 
Population: 
Individuals with a cesarean delivery who deliver at The Ohio State 
Wexner Medical Center 
Description of 
Study 
Intervention: 
Non-invasive bioelectronic treatment with TrueRelief device for 
post-cesarean pain management.  
Study Duration: 
Recruitment between April 2022 -November 2022. Follow-up, 
closeout and data analysis by December 2022. 
Participant 
Duration: 
6 weeks postpartum 

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1.2 
Schema 
 

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1.3 
Schedule of Activities 
 
Measure 
Visit 0: 
Screening & 
randomization 
Visit 1: 
Discharge  
Visit 2: 
6-wk postpartum 
in-person or virtual 
visit 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Randomization 
X 
Number of inpatient 
opioids used (MME)  
X 
 
BPI pain severity  
 
X 
 
Edinburgh Postnatal 
Depression Scale 
 
X 
Number of opioids 
prescribed  (MME)  
X 
 
Opioid prescription 
refilled (or initially 
filled if not prescribed at 
discharge) 
 
X 
Opioid-related side 
effects 
X 
 

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Measure 
Visit 0: 
Screening & 
randomization 
Visit 1: 
Discharge  
Visit 2: 
6-wk postpartum 
in-person or virtual 
visit 
Breastfeeding 
 
X 
X 
Maternal & infant 
outcomes 
X 
X 
 

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2.1 
Study Rationale 
2 
Introduction 
 
Cesarean delivery is the most commonly performed major surgical procedure in the United States. 
Systemic opioids have been universally used for post-cesarean analgesia management, with the number 
of tablets prescribed varying significantly among providers and institutions. Pain thresholds and 
analgesic requirements vary among patients, but studies suggest that most women are given 
prescriptions at discharge for at least 10 more tablets than needed.1,2 The consequence of over-
prescribing opioids for 1.2 million cesareans annually is at least 12.5 million unused tablets. These 
unused tablets often go unguarded, and undisposed, providing an important reservoir of opioids that may 
be misused, diverted or accidentally ingested, contributing to the opioid crisis. Growing recognition of 
the role that post-cesarean opioid prescribing plays in the opioid crisis has led to a search for alternative 
methods to control postoperative pain.  
 
2.2 
Background 
 
In 2017, approximately 1 in 3 women (32%) in the US gave birth by cesarean delivery.3 More than 80% 
of women take at least one opioid medication for pain after cesarean.1 Recent studies show that up to 
75% of women who have a cesarean delivery and fill their opioid prescription after their discharge from 
hospital have unused tablets. The majority of women do not dispose of the excess tablets 
appropriately.2,4-6 These unused opioids are then available for diversion, non-medical use, overdose and 
development of chronic dependence.   
Between 2007 and 2016, the rate of pregnancy-associated mortality involving opioids more than doubled (1.3 to 
4.2 per 100,000), as did the percentage of all pregnancy-associated deaths (4% to 10%).8 It is becoming clear that 
opioid overprescribing plays a significant role in maternal mortality. Surgery contributes to the ongoing opioid 
crisis in two ways. First, opioids provided to treat acute post-surgical pain may lead to chronic opioid use 
(defined by continued use at 90 days, which occurs in approximately 3-6% of post-surgical patients).9,10 1 in 300 
to 1 in 50 opioid-naïve women in the US will develop a persistent opioid use at one year after a cesarean 
delivery.1,11 Secondly, surgeons tend to provide more opioids than patients use postoperatively, leading to excess 
opioids in a patient’s possession. As approximately 60% of adults report that they obtained opioids for 
nonmedical use from a friend or relative,10 decreasing the number of excess opioids available to the general 
population is critical to combating the opioid crisis in the US.  
Physicians today struggle to balance the need for adequate control of acute pain after surgery with the 
desire to limit opioid use and avoid overprescribing, development of dependence and diversion. This had 
led to a search for effective pain control methods with less short and long-term risks than opioids.  
The use of multimodal analgesia to control postoperative pain can decrease opioid requirements 
postoperatively. Multimodal analgesia protocols typically emphasize timed and consistently 
administered non-opioid analgesics (such as non-steroidal anti-inflammatory drug (NSAIDs) and 
acetaminophen), with opioid analgesics as needed for breakthrough pain. Use of local treatments and 
novel devices remains an under-explored adjunct for postoperative pain control as part of a multimodal 
protocol.  
Electrical nerve stimulation represents a promising adjunctive therapy. Originally utilized for chronic 
pain, transcutaneous electrical nerve stimulation has recently been shown to reduce acute pain and opioid 
requirements postoperatively, including after total knee arthroplasty and hernia repair.12,13 TrueRelief is a 
novel FDA-cleared bioelectronic device that delivers high-frequency (20,000 Hz) pulsed direct electrical 
current transcutaneously via stainless steel probes. Efficacy of this technology for pain control after 
cesarean delivery has not been studied, but it may represent an important adjunct to improve pain control 
while reducing opioid use. 

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2.3 
Risk /Benefit Assessment 
 
2.3.1 Known Potential Risks 
Risks of electroceutical treatment in the postoperative period are minimal. The treatment itself is painless and takes 
only a few minutes. Treatment with the TrueRelief device or sham device will be administered three times  
beginning on postoperative day zero until discharge. Aside from the treatment itself, patients will receive usual 
inpatient care postoperatively, including standard non-opioid and opioid pain medications available as needed.  
 
2.3.2 Known Potential Benefits 
Use of the TrueRelief device may improve pain control after cesarean delivery. If treatment successfully 
decreases opioid requirements, patients may benefit from decreased risk of tolerance, dependence and 
diversion.
     2.3.3 Assessment of Potential Risks and Benefits 
  As described above, potential risks are not more than encountered in usual care after cesarean delivery.       
   
Treatment with the TrueRelief device may improve pain control and reduce opioid requirements. 
 
3. Study Design 
This is a blinded randomized trial of 134 individuals undergoing a cesarean delivery who are 
randomized after cesarean to three times  use of non-invasive bioelectronic treatment with TrueRelief 
device or identical appearing sham device for post-cesarean pain management.  
The primary endpoint is the total inpatient morphine milligram equivalents used during hospital 
admission. The primary hypothesis is that three times  use of non-invasive bioelectronic treatment with 
TrueRelief device decreases the total inpatient morphine milligram equivalents used during hospital 
admission compared to use with identical appearing sham device. Consenting women will be assigned 
in a 1:1 ratio to one of the two arms using a secure internet based randomization system. Individuals will 
be followed through 6 weeks postpartum. 
 
 
 
 
 
, 

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4. Objectives and Endpoints 
 
OBJECTIVES 
ENDPOINTS 
Primary 
To evaluate whether non-invasive 
bioelectronic treatment reduces inpatient 
post-cesarean opioid consumption. 
Total inpatient postoperative opioid consumption in morphine 
milligram equivalents (MME). 
 
Secondary 
To evaluate whether non-invasive 
bioelectronic treatment post-cesarean 
decreases opioid refill prescriptions. 
Opioid prescription filled (beyond that prescribed at discharge) 
between discharge and six weeks postpartum. 
Total number of opioid prescriptions filled by six weeks 
postpartum (beyond that prescribed at discharge). 
To evaluate whether non-invasive 
bioelectronic treatment post-cesarean 
decreases the total amount of opioid 
tablets prescribed at discharge. 
Number of opioid tablets prescribed at discharge. 
To evaluate whether non-invasive 
bioelectronic treatment post-cesarean 
reduces pain intensity pain scores 
Pain severity scores (worst, least, average, current) in last 24 
hours assessed on the Brief Pain Inventory numeric scale from 0 
to 10 at discharge  
To evaluate whether non-invasive 
bioelectronic treatment post-cesarean 
reduces  opioid related side effects, 
wound disruption and increases rates 
of breastfeeding  
• 
Opioid related side effects including  nausea and constipation 
• 
Surgical site would disruption/infection 
• 
Breastfeeding rates at discharge and 6 weeks postpartum 
• 
Maternal depression score ≥ 13 at 6 weeks postpartum 
 
 
5. STUDY POPULATION 
   5.1.1 Inclusion Criteria  
In order to be eligible to participate in this study, an individual must meet all of the following criteria:  
Post cesarean delivery (combined vaginal/cesarean deliveries are not eligible) 
Singleton, or twin gestation 
 
5.1.2 Exclusion Criteria 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
• 
Fetal or neonatal death prior to randomization 
• 
Inability to randomize on postoperative day 0  
• 
Inability to complete all three non-invasive bioelectronic treatment during inpatient stay  as assessed by 
research staff 
• 
Language barrier (non-English or Spanish speaking) 

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• 
Participation in another intervention study that influences the primary outcome in this trial 
 
5.2 
Lifestyle Considerations 
 
There are no lifestyle considerations specific for this study. General post-cesarean instructions will be 
given to participants during admission and prior to discharge. 
 
5.3 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomized 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. Minimal information 
includes screen failure details, eligibility criteria, and any serious adverse event. 
 
5.4 
Strategies for Recruitment and Retention 
 
5.4.1Recruitment Plan 
Good recruitment will depend on access, promotion, education and clinical staff buy-in. Research staff 
will view the daily schedule to review who has had a cesarean. If eligible by medical record review, 
research staff will approach participants preoperatively or post-operative day 0 to inform them about the 
study. Randomization should occur on postoperative day 0, but not earlier. 
Care providers will be educated about the study via targeted information sessions. It has been found to be 
helpful to provide in-person informative sessions with specific groups of providers, for example faculty, 
residents and fellows.  
The Ohio State Wexner Medical Center is a large academic medical center with over 5000 deliveries per 
year. Assuming a 30% rate of cesarean deliveries this is approximately 1500 cesarean deliveries per year. 
Not every day has 24/7 coverage; therefore it is conservatively assumed that approximately 4 individuals 
daily are potentially available to enroll on a weekday. It is expected that the number of women who meet 
the exclusion criteria will be less than 1 percent. Even if 20% of physicians are reluctant to allow their 
patients to participate (relevant in the setting of private physician deliveries within a hospital) and 60% of 
women refuse consent for the trial, over 360 women could be enrolled annually. 
We are currently conducting a randomized trial in women undergoing cesarean delivery. The aim of the 
trial is to determine whether an individualized opioid prescription protocol (IOPP) at discharge after 
cesarean delivery is non-inferior to a prescription for a fixed amount of opioid tablets which 
approximates current standard of care has similar pain control. 
Women are randomized after cesarean delivery and research staff has to be present on day of discharge 
for randomization. Even with these major barriers to recruitment, sites have been able to recruit 
approximately 24 participants/ month. While these barriers do not apply to this trial, this study does 
require a medically trained individual to administer the intervention. Thus the study should 
conservatively be able to enroll at least 24 participants per month. 

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6. Study Intervention 
6.1 
Study Intervention Administration 
 
6.1.1 Study Intervention Description 
Women will be randomized on post-operative day 0 to receive treatments with non-invasive 
bioelectrical device or identical appearing sham device. Three treatments will be given to each patient. 
The first treatment should be given as soon as is practical after the cesarean section and not longer than 
two hours after the procedure. The second treatment will be administered 12 hours after the first 
treatment, but can be given within a range of 10-14 hours after the first treatment to avoid having to 
wake the patient when sleeping or otherwise disrupt other care being given to the patient. The third and 
final treatment will be administered 12 hours after the second treatment, but can be given within a 
range of 10-14 hours after the second treatment to avoid having to wake the patient when sleeping or 
otherwise disrupt other care being given to the patient. 
6.1.1.1 
Inpatient  opioid consumption (morphine milligram equivalents [MMEs]) 
Opioid use will be converted to equianalgesic doses of morphine sulfate (morphine milligram equivalents 
[MMEs]) using standard ratios. Table 1 demonstrates opioid conversions. 
Table 1. Opioid Conversion Table  
 
Opioid (mg/day) 
Conversion factor 
hydrocodone 5mg 
1 
hydrocodone 20mg 
1 
oxycodone 5mg 
1.5 
oxycodone 20mg 
1.5 
 
Prior to discharge, participants will complete a brief pain inventory questionnaire. The number of opioid 
pills prescribed at discharge will be at the discretion of the discharging provider.  

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6.1.2 Administration 
Trained clinic research nurses will apply device three times after cesarean section before discharge  (at 
least 10-14 hrs apart) for duration of 12 minutes each.  
6.2 
Measures to Minimize Bias: Randomization and Blinding 
 
Selection bias is minimized by the randomized design. However, adequate concealment of the 
assignment and a clear definition of the point of randomization are also important. Eligible and 
consenting women will be randomized by certified research staff using a secure internet based 
randomization system. Once the randomization program has been run by the staff member and the 
assignment revealed, the participant will be considered randomized even if the woman reneges. 
Assignment to device or sham device will be in a 1:1 ratio according to a randomization sequence. The 
simple urn method will be used to generate the randomization sequences because it provides a high 
probability of balance in treatment assignments, it is unpredictable, and it allows an explicit 
randomization analysis to be conducted with relative ease.37 
 
Research staff will be responsible for randomization and for administering the intervention or sham 
device. Clinicians will be blinded to the patient’s group assignment.   
 
6.3 
Concomitant Therapy 
 
Medications for postoperative pain management will be at the discretion of the clinical team. Our 
institution uses standardized postoperative medication order sets that include oxycodone, acetaminophen 
and/or ibuprofen. 
 
6.4 
Discontinuation of Study Intervention 
 
Since the intervention is a treatment with device during inpatient stay, participants may choose to not 
continue with intervention. Women will be followed through 6 weeks postpartum regardless of their 
treatment assignment.

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7. Study Assessments and Procedures 
7.1 
Study Assessments 
 
7.1.1 Screening & Randomization 
All women with a cesarean delivery will be screened for eligibility. If appropriate, study personnel will 
invite the patient to serve as a study participant. The initial approach will occur pre-operatively or on 
post-operative day 0 to ensure individual care is not modified as a result of the study design prior to 
randomization. Study personnel will describe the study in detail and review the study protocol with the 
participant. Women agreeing to participate will sign the consent form.  
7.1.2 Baseline Procedures 
If the patient is eligible and signs the consent form, participants be randomized to 
TrueRelief device or identical appearing sham device: 
In addition to information collected for eligibility, the following information will be obtained from an 
interview with the participant and/or through the electronic medical record: 
• 
Demographic factors (e.g., maternal date of birth, age, BMI, race/ethnicity, education, 
employment status, marital status, household income, insurance) 
• 
Factors related to persistent opioid use including tobacco use, history of mental health conditions 
(e.g., depression, anxiety), use of anti-depressants or benzodiazepines, chronic pain conditions 
(e.g., back pain, migraines, fibromyalgia). 

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Medical history including obstetrical outcomes from the current delivery (e.g., indication for 
cesarean, repeat cesarean, labor prior to cesarean, operative time, type of anesthesia, peri- 
operative complications, gestational age, birth weight, neonatal outcomes). 
• 
Opioid and non-opioid analgesics (e.g., acetaminophen, ibuprofen) use post cesarean through 
discharge 
7.1.3 Follow-up 
Participants will be followed through  6 weeks postpartum. 
 
 
7.2 
Adverse Events and Serious Adverse Events 
 
7.2.1 Definition of Adverse Events (AE) 
An adverse event is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not the event is considered drug related. 
Events should be reported also if they are unexpected in nature, severity, frequency, or fit the single IRB 
definition of adverse event. The unexpected nature of the event is determined based on the research 
procedures and the characteristics of the subject population being studied. If the event is not one that is 
usually seen in this context or reported in the principal investigator / participant brochure, it should be 
considered unexpected. 
7.2.2 Definition of Serious Adverse Events (SAE) 
A serious adverse event is one of the following that occurs in the mother, neonate, or infant through 90 
days postpartum: 
• 
Death 
• 
Life-threatening event 
• 
Inpatient re-hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Other important medical event may meet the definition of serious if it jeopardizes the participant 
7.2.3 Classification of an Adverse Event 
7.3.3.1 
Relationship to Study Intervention 
All adverse events 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 occurs in a plausible time relationship to 
study intervention administration and cannot be explained by concurrent disease or other drugs or 

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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 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. 
• 
Possibly 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 – A clinical event 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). 
• 
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. 
7.3.3.2 
Expectedness 
The Center PI, or designee will be responsible for determining whether an adverse event is expected or 
unexpected. An adverse event 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. 
7.2.4 Time Period and Frequency for Event Assessment and Follow-up 
Adverse events will be recorded from randomization through 6 weeks postpartum. If a serious adverse 
event occurs after the consent is signed and before randomization, it will also be reported. 
Participants will be instructed to contact research staff to report an adverse event that occurs during study 
participation. In addition, research staff will ask participants at each study visit if they have experienced 
any side effects or adverse events since the last study visit. 
Adverse and Serious Adverse Events will be reported on the Adverse Event Form. 
7.2.5 Adverse Event Reporting 
7.2.6 Non-serious adverse events must be entered into the study database within 7 days of being 
notified. Adverse events are reviewed in real-time by PI. Serious Adverse Event Reporting 
Any maternal death, neonatal death, or life threatening maternal event must be entered into the adverse 
events database within 24 hours of being notified, but no later than 72 hours from the onset of the event if 
it occurs prior to delivery discharge. If a death is reported, a copy of the 

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participant’s de-identified medical record will be uploaded to the adverse events database. Other serious 
adverse events must be entered into the study database within 7 days of being notified. 
Serious adverse events are reviewed in real-time by PI.  
7.2.7 Reporting Events to Participants 
Participants will not be informed about adverse events, serious adverse events, or study-related results 
unless the PI decides such information should be reported to participants. As noted in Section 7.2, an 
Edinburgh depression score of 13 or higher, or a value other than ‘never’ on the Edinburgh question 10 
(harming oneself), will be reported to the participant and the clinical provider. 
 
7.3 
Unanticipated Problems 
 
7.3.1 Definition of Unanticipated Problems (UAP) 
An investigator may not initiate a change in research activity without single IRB approval unless the 
change is necessary to eliminate apparent immediate hazards to human subjects, in which case it should 
be reported to the single IRB as an unanticipated problem (UAP). 
The Office of Human Research Protections (OHRP) and the single IRB defines an unanticipated problem 
as an event that: 
• 
Is unexpected (in terms of nature, severity, or frequency) given the research procedures and the 
characteristics of the subject population being studied; and 
• 
Is related or possibly related to a subject’s participation in the research; and 
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
7.3.2 Unanticipated Problem Reporting 
For an event that a PI considers to be an unanticipated problem that is also an adverse event, the AE 
should be entered into the database within the timeframes established above. 
In addition, regardless of whether the UAP is an adverse event or not, a report should be emailed by the 
PI. The email should contain the following information: 
• 
Protocol identifying information 
• 
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 a UAP 
• 
A description of any corrective actions that are proposed in response to the UAP 
Potential unanticipated problems will be reviewed by PI to determine whether changes to the protocol or 
consent form should be considered. UAP reports should be submitted through the online IRB system no 
later than 2 weeks (10 business days) from the notification. 

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7.3.3 Reporting Unanticipated Problems to Participants 
An unanticipated problem will be reported to the specific participant involved. Changes to the protocol or 
consent form, or the event itself, may also warrant reporting to participants who are currently on study as 
well as those who have completed the study. In this case, the PI will recommend the course of action (for 
example, a letter to participants) which will be submitted to the single IRB. 
 
7.4 
Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time upon request. 

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8 
Statistical Considerations 
8.1 
Statistical Hypotheses 
 
The primary endpoint is the amount of inpatient opioid consumed post-cesarean measured by total 
morphine milligram equivalents used. The null hypothesis is that there is no difference in amount of 
inpatient MME in the non-invasive bioelectrical device intervention group compared to sham device 
group. The alternative hypothesis is that the amount of inpatient MME in the non-invasive bioelectrical 
device intervention group is less then MME in the sham device group.  
Key secondary endpoints include: 
• 
Worst pain score assessed at discharge measured by presence or absence of moderate to severe pain at 1 
week post-discharge, defined as a value of 4 or more on the BPI worst pain in the last 24 hours numeric 
scale (0 to 10). 
• 
Opioid prescription beyond that prescribed at discharge within 6 weeks postpartum 
• 
Opioids prescribed at discharge 
• 
Opioid side effects, wound complications and breastfeeding rates 
For the secondary endpoints, the null hypothesis is there is no true difference between the two groups. 
The alternative hypothesis is there is a difference between the groups. For the key secondary outcomes, 
the level of significance will be adjusted for multiple comparisons using the false discovery rate 
method.41 
 
8.2 
Sample Size Determination 
 
Review of inpatient post-operative data, showed that from post-operative day 0 to 2 our patients consume on 
average MME 42 with SD 15. For 20% reduction in MME to 33.6 and 90% power would need total sample size of 
134. Resulting in 67 intervention group and 67 participants in control group.  
 
8.3 
Population for Analyses 
 
All statistical analyses will be based upon the total cohort of participants randomized into the trial. 
Although data on some patients may be missing, all relevant data available from each participant will be 
employed in the analyses. Patients will be included in the treatment group to which they were randomly 
assigned regardless of compliance. 
 
8.4 
Statistical Analyses 
 
8.4.1 General Approach 
In general, summaries of categorical data will be presented as number of observations and a percentage. 
Summaries of continuous data will be presented as means with standard deviation if the variable follows a 
normal distribution, or else as the median and 95% confidence interval. 
Binary or categorical will be reported as a proportion with relative risk and 95% confidence intervals 
as appropriate. For normally distributed continuous outcomes, least squares means general linear 
regression will be used to estimate means and 95% confidence intervals. For continuous outcomes 
that are not normally distributed and cannot be transformed to approximate normality, the Wilcoxon 
test and the Hodges-Lehmann estimators of the median will be reported. 
8.4.2 Analysis of the Primary Endpoint 
The primary outcome is continuous and defined as MME consumed inpatient post-cesarean not normally 

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distributed and cannot be transformed to approximate normality, the Wilcoxon test and the Hodges-
Lehmann estimators of the median will be reported. If normally distributed then paired t-test and mean 
with standard deviations will be reported.   
Analysis of Secondary Endpoint 
Secondary outcomes that are binary or categorical will be reported as a proportion with relative risk and 
95% confidence intervals as appropriate. For normally distributed continuous outcomes, least squares 
means general linear regression will be used to estimate means and 95% confidence intervals. For 
continuous outcomes that are not normally distributed and cannot be transformed to approximate 
normality, the Wilcoxon test and the Hodges-Lehmann estimators of the median will be reported. 
8.4.3 Baseline Descriptive Statistics 
Baseline factors will be compared by treatment group. If the treatment groups are found to differ on a key 
pre-treatment factor known to be a risk factor for the outcome, the statistical analyses will adjust for these 
differences. 
8.4.4 Planned Interim Analyses 
No interim analyses are planned given the short duration of enrollment and follow-up. 
Subgroup Analyses 
Interactions will be evaluated and subgroup analyses conducted to determine whether the effect or lack 
thereof prevails throughout particular subgroups of participants. The following factors will be considered 
for subgroup analysis, if there is a significant interaction between the factor of interest and the treatment 
effect: 
• 
Race/ethnicity 
• 
BMI category (obese vs non-obese) 
• 
Type of labor (labor vs no labor) 
• 
Type of anesthesia 
o General, spinal, combined spinal-epidural, epidural 
o Neuraxial morphine administration 
• 
Skin incisional type (low transverse vs vertical midline) 
• 
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• 
Time from delivery to discharge (<48 hours, ≥ 48 hours). 
8.4.7 Tabulation of Individual Participant Data 
Participant data will only be reported in aggregate in study abstracts, presentations or manuscripts. 

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9 
Supporting Documentation and Operational Considerations 
9.1 
Data Regulatory, Ethical, and Study Oversight Considerations 
 
9.1.1 Informed Consent 
A single IRB will be used for this study. A HIPAA Waiver of Consent for recruitment purposes will be 
obtained to allow clinical sites to review electronic medical records to identify potentially eligible 
participants. 
Prior to cesarean delivery or within first 24 hours after cesarean delivery, women will be approached for 
participation into the study. Full disclosure of the nature and potential risks of participating in the trial is 
to be made. Women that elect to participate in the study will sign the study consent. The consent form 
describes in detail the study intervention, study procedures, and risks is given to the participant and 
written documentation of informed consent is required prior to randomization. 
The following consent materials are submitted with this protocol: study consent and assent, participant 
completed questionnaire..All participant materials will be IRB approved.. Both verbal and written 
informed consent and authorization will be obtained in the participant’s fluent language. Participants not 
fluent in English will be excluded. 
9.1.2 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and persons or organizations working with the sponsor. All research activities will be 
conducted in as private a setting as possible. The following individuals and/or agencies will be able to 
review medical and research records: 
• 
The study doctor, study staff and other medical professionals who may be evaluating the study. 
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. 
Additional details are provided in the full study consent form and authorization. 
9.1.3 Clinical Monitoring 
Clinical monitoring is performed by PI. 
9.1.4 Data Handling and Record Keeping 
Data will be collected on standardized forms on which nearly all responses have been pre-coded. Data 
collection is the responsibility of the clinical trial staff at the site under the supervision of the principle 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
9.1.5 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. A list of 
protocol deviations that must be submitted to the IRB are included in the manual of procedures. 
9.1.6 Conflict of Interest Policy 
All investigators will have conflict of interests reviewed by the single IRB. The single IRB requires that a 
series of questions be answered at the time of initial submission related to financial and non-financial COI 
relevant to the research protocol. These questions apply to the investigator, the study staff, and their 

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immediate families inclusive of spouse and each dependent child. Any new financial interests or 
increased value of a previously reported financial interest that occurs during the course of the study, must 
be reported to the single IRB within 30 business days of the change. 

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