Clinical trial NCT05487196
Conditions: Pregnancy Related
Keywords: Pregnancy Vaginal Delivery Epidural Labor Analgesia
Sponsor: Grace Lim, MD, MS
Start date: 2022-09-28; Completion date: 2023-07-31
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this randomized controlled trial is to compare the effectiveness of epidural clonidine, dexmedetomidine, or fentanyl adjuncts for labor analgesia.

Detailed description:
Adjuncts for epidural labor analgesia have remained unchanged for decades, whereas changes in patient population and the opioid epidemic have created an increased demand for non-opioid alternative adjuncts to limit peripartum opioid exposure. This study aims to identify effective alternative and non-opioid adjunctive agents for epidural labor analgesia.

The opioid crisis in the United States has translated to an increasing number of pregnant women requiring care for labor and delivery. These trends have resulted in new questions about alternative epidural analgesia adjuncts besides lipophilic opioids (e.g., fentanyl and sufentanil) because: 1) many people with opioid or substance use disorder desire to avoid opioids in all formulations and routes of administration; and 2) epidural fentanyl or sufentanil administration for labor can potentially interfere with the accuracy of urine drug screening in the postpartum period, which has implications for postpartum social services considerations.

Some existing literature suggests that dexmedetomidine and clonidine are viable adjuncts to local anesthetics that offer a faster onset and a better quality of analgesia for patients requiring labor analgesia. However, the relative effectiveness of these adjunctive agents for labor analgesia have not been compared head-to-head. Better data on how these adjuncts compare with each other for labor analgesia efficacy, can result in more informed clinical care strategies.

This trial was initially initiated as a superiority design. After further scientific input, it was decided that a non-inferiority design would be more informative for the clinical question at hand. The hypothesis is that clonidine (Group C) and dexmedetomidine (Group D) are non-inferior to fentanyl (Group F) (usual care) as adjuncts for epidural labor analgesia. The null hypothesis is that clonidine and dexmedetomidine are inferior to fentanyl as adjuncts for epidural labor analgesia. Clinical Protocol specific methodology did not change throughout the trial and the full trial protocol document can be found in the relevant section below. An updated statistical analysis plan includes updated sample size calculations and has been reported to account for the noninferiority analysis plan. No data was analyzed prior to the completion of all data collection procedures.

Arms: arm 1: Bolus dose at epidural initiation, through the epidural catheter:

10 ml Ropivacaine 0.1 % combined with a single dose of Clonidine 60 mcg arm 2: Bolus dose at epidural initiation, through the epidural catheter:

10 ml Ropivacaine 0.1 % combined with a single dose of Dexmedetomidine 30 mcg arm 3: Bolus dose at epidural initiation, through the epidural catheter:

10 ml Ropivacaine 0.1 % combined with a single dose of Fentanyl 100mcg
Interventions: intervention 1: Clonidine intervention 2: Dexmedetomidine intervention 3: Fentanyl intervention 4: Ropivacaine
Intervention descriptions: intervention 1: Clonidine belongs to the drug classification of antihypertensives intervention 2: Dexmedetomidine belongs to the drug classification of sedatives intervention 3: Fentanyl belongs to the drug classification of analgesic opioid agonists and is used as the standard of care intervention 4: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care

Protocol documents:
ICF_002.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY TITLE: Effectiveness of Clonidine, Dexmedetomidine, and Fentanyl Adjuncts for Labor Epidural 
Analgesia: A randomized controlled trial (CLASSIER) 
IRB: STUDY22030095 
NCT05487196 
Informed Consent Document: 28 MAR 2023 


University of Pittsburgh STUDY22030095 
Effective: 3/28/2023 
Expires: 3/27/2024 
 
 
 
 
INFORMED CONSENT STATEMENT AND AUTHORIZATION FOR RESEARCH 
Dexmedetomidine Compared to Clonidine and Fentanyl as an Adjuvant to Epidural Solution for Labor 
Analgesia 
Principal Investigators: 
Grace Lim, MD MSc 
Dept of Anesthesiology & Perioperative Medicine 
412-641-2179 
Funding source: Dept of Anesthesiology & Perioperative Medicine 
 
 
ABOUT THIS RESEARCH 
You are being asked to participate in a research study. Scientists do research to answer important questions 
which might help change or improve the way we do things in the future. 
This consent and authorization form will give you information about this study to help you decide whether 
you want to participate. It is your choice whether or not you want to be in this research study. Please read 
this form, and ask any questions you have, before agreeing to be in this study. 
 
KEY INFORMATION 
Research studies include only people who choose to take part. The study team will explain the study to you 
and will answer any questions you might have. You should take your time to make your decision. 
 
The purpose of this study is to compare how well medications for pain during childbirth work. In this study, 
one of three medications will be added to the main drug that we will use for your epidural. (An “epidural” 
for childbirth is when we inject pain relieving medicine in an area around your spinal cord, known as the 
epidural space. It helps relieve labor pain.) In the United States (US), the usual medications for epidurals are 
to combine one medicine, called ropivacaine, with a small dose of an opioid, called “fentanyl” which is 
another type of pain reliever. This solution is then injected to a space between your vertebrae of your spine 
(called the epidural space) via a narrow tube called a catheter. This combination usually works very well. 


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However, some patients might benefit from an epidural protocol without opioids. For example, 
• 
patients who are treated with opioids for chronic pain might develop opioid tolerance (when a 
larger dose of medication is needed to obtain the same pain reducing effect) 
• 
patients with a known allergy to the opioid can’t use them in their epidural mixture. 
• 
patients who have an opioid use disorder may also develop opioid tolerance. In these patients, 
using opioids for epidural pain management is not the best approach. 
 
Our study will compare ropivacaine with one of three medications 
• 
A group that gets ropivacaine and fentanyl – what is called “usual care” 
• 
A group that gets ropivacaine with a drug called clonidine and 
• 
A group that gets ropivacaine with a drug called dexmedetomidine. 
The other two drugs can substitute for the fentanyl in the epidural solution and offer similar pain relief. 
 
Risks associated with this study include: 
• 
Risks associated with epidural labor analgesia (Fetal heart rate changes associated with rapid 
analgesia (10-20%)) 
• 
Risks of the study drugs may differ but include low blood pressure, high blood pressure, low heart 
rate, rapid heart rate, drowsiness, inability to walk until the effect of the epidural wears off 
• 
Likely: inconvenience/discomfort associated with answering study related questions 
• 
Less likely: potential breach of confidentiality, meaning someone could see your private 
information that is not authorized. 
 
Steps have been taken to minimize these risks as much as possible. 
 
We hope that the information obtained in this research study will help us to develop effective, safer, and 
tailored treatment options for women requiring epidural analgesia during labor. There will be no direct 
benefits to you for your participation in this study. If you decide not to participate in this research, you will 
receive your normal routine obstetric and pain management care. Whether you decide to participate in this 
research, there will be no change in the routine care for you and your baby during and after your delivery. 
 
Please review the rest of this document for more details about this study and the things you should know 
before deciding whether to participate in this study. 
 
WHO IS BEING ASKED TO PARTICIPATE? 
We are asking you if you want to be in this study because you: 
• 
Are in labor and intending to deliver vaginally 
• 
Are planning on asking for epidural analgesia 


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HOW MANY PEOPLE WILL TAKE PART? 
Up to 200 women and their newborn babies taking part in this study. 
 
WHAT WILL HAPPEN DURING THE STUDY? 
Upon admission to Magee, we will collect some information about your medical history. This information 
may be collected from you or your medical record. 
 
The research team will explain the protocol to you during a first visit and leave you this informed consent 
form. You will have time to read this form and choose if you desire to participate in this study. If you decide 
to participate in the study, the research team will be called prior to your epidural medications being 
decided. 
 
The technique for initiation of epidural analgesia is the same, whether you decide to participate in our 
study or not. The catheter will be installed by a qualified anesthesiologist upon your request. 
 
Your participation involves that you get a medication added to the local anesthetic solution depending on 
the group to which you are assigned. The nurses and doctors will not know which group you are assigned. 
This information is confidential, and the medication is prepared by the pharmacy so that they cannot be 
identified at bedside. 
 
Here are the three epidural solutions included in this protocol 
1. Ropivacaine 0.1 % (local anesthetic) and Fentanyl (opioid) – this is usual care. 
2. Ropivacaine 0.1% (local anesthetic) and Clonidine 
3. Ropivacaine 0.1% (local anesthetic) and Dexmedetomidine 
 
These medications are all approved by the US Food and Drug Administration and are being used off- label 
as is typical in clinical care for labor epidural analgesia. 
 
Once the epidural catheter is installed, a large initial dose of medication will be administered through the 
catheter as this is the standard protocol in our institution. The medications in the bolus dose will vary 
depending on your group. After the bolus dose is given, an epidural pump will allow pain medication to 
flow through the catheter in your epidural space. This medication will be a standardized local anesthetic 
medication (ropivacaine with fentanyl) until the time of delivery. 


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REDOSE PROTOCOL : 
Re-doses will be done for patients requesting them per current standard of care practice. Epidural re- doses 
will be protocolized through a “re-dose algorithm” to standardize breakthrough pain management. 
 
Protocolized re-dosing is a measure that will standardize the practice amongst our team of providers. 
Usually, when a patient is complaining of discomfort, the clinical team will be called at bedside to perform 
an evaluation, including a level assessment. Following this assessment, the provider at beside will “re-dose” 
the epidural (inject some additional medication) so that the patient achieves a better level of comfort. 
Given the large number of providers on our team, there may be some variance in the management and in 
the doses that are administered for these epidural “re-doses”. The standardization of epidural boluses 
during this clinical trial ensures uniform and safe practice for breakthrough pain management after epidural 
initiation. 
 
A person from the research team will come and collect information from you or your medical record at the 
time points below. This will include: 
• blood pressure 
• heart rate 
• Amount of oxygen in your blood 
• your rating of pain on a scale of 0-10 
• your rating of how sleepy you are 
• capacity to move your legs 
 
This information will be collected by the study team at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 60 
minutes, 90 minutes, and 120 minutes after epidural initiation and again shortly after you deliver. We will 
also collect information about the type of delivery, how long your labor lasts, if you need any additional 
medication if your heart rate slows down- this is standard of care for epidurals. 
 
We will also collect information from the medical record about your newborn, including the APGAR scores 
(this involves assessing the newborn’s Appearance, Pulse, Grimacing (facial expression), Activity and 
Respiration (breathing), their heart rate, or if there are any signs of an abnormal heart rate. 


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WHAT ARE THE RISKS OF TAKING PART IN THE STUDY? 
The medications evaluated in this study have documented side effects. The usual monitoring used in the 
labor and delivery room will detect these side effects. Normally, after the epidural is started, you are 
monitored for low blood pressure and low heart rate. There is also fetal monitoring since epidural 
medication can sometime induce some changes in your baby’s heart rate. The usual practice in our center is 
to monitor blood pressure, oxygen level in your blood and heart rate for 30 minutes after the epidural is 
started. Your baby’s heart rate is also monitored from epidural start until delivery. 
 
The medications that we are studying in this protocol are two alternates in comparison to the standard of 
care (opioid). These two medications are called Clonidine and Dexmedetomidine. Here are the documented 
side effects that you might experience. 
 
Research Activity 
Clonidine epidural administration 
Common Risks 
Low blood pressure 
Low heart rate 
Infrequent Risks 
Sleepiness 
Temporary inability to move legs 
Other Risks 
Low blood pressure when standing up 
Nausea 
Vomiting 
Mild skin itching 
Rash (itching) 
Dry mouth 
Mild changes in your liver function tests that are temporary 
 
Research Activity 
Dexmedetomidine epidural administration 
Common Risks 
Low blood pressure 
Low heart rate 
Infrequent Risks 
Sleepiness 
Temporary inability to move legs 
Other Risks 
Nausea 
Vomiting 
Mild skin itching 
Dry mouth 
Breathing rate slowed 
Constipation that may last a few hours or days 


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Research Activity 
Fentanyl epidural administration (this is usual care) 
Common Risks 
Drowsiness 
Changes in heart rate 
Stomach pain 
Anxiety 
Infrequent Risks 
Sleepiness 
Hallucinations 
Agitation 
Muscle stiffness 
Loss of coordination 
Loss of appetite 
Seizures 
Other Risks 
Nausea 
Vomiting 
Mild skin itching 
Dry mouth 
Breathing rate slowed 
Constipation that may last a few hours or days 
 
Risks of local anesthesia (lidocaine, bupivacaine, ropivacaine) 
Lidocaine, Bupivacaine and Ropivacaine are three medications that are widely used as local numbing agents 
to control pain for placement of the epidural catheter in your back. The catheter then allows medications 
to be administered to the epidural space in your spine (standard of care) to control pain during childbirth. 
 
The chance of you having a “Adverse” or negative reaction to these drugs being administered to you are 
very rare. If there was an overdose (too much drug ordered and/or given), or if the drug was inadvertently 
injected directly into a blood vessel, those results can be serious. The effects of systemic overdose and 
unintentional blood vessel injections would need to be distinguished from the physiological effects of the 
nerve block itself (for example, a decrease in blood pressure and heart rate during epidural anesthesia). 
 
Common risks of local anesthetics administered between the vertebrae are low blood pressure and urinary 
retention. If local anesthesia was injected into a blood vessel, you are at risk of developing signs and 
symptoms of problems with your central nervous system and heart rate and rhythm (see table below). 


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Research Activity 
Lidocaine, Bupivacaine and Ropivacaine epidural administration 
(this is usual care) 
Common Risks 
Low blood pressure, Urinary retention 
Infrequent Risks 
Nervous system disorders : Signs and symptoms of central nervous 
system toxicity (seizures, tingling sensation around the mouth, 
numbness of the tongue, visual disturbances, tremor, tinnitus 
[buzzing sound in your ears], slurred speech, loss of consciousness) 
Cardiovascular manifestations (decreased cardiac output, decreased 
heart rate, abnormal heart rate or rhythm) 
Other Risks 
Gastrointestinal disorders : nausea, vomiting 
Nervous system disorders: paresthesia (abnormal sensation of the 
skin [tingling, pricking, numbness] ), dizziness, nerve injury Immune 
system : allergic reaction 
 
A risk of answering surveys is that you may be uncomfortable while answering the questions. While 
completing the survey, you can skip any questions that make you uncomfortable or that you do not want to 
answer. 
 
You may be withdrawn from the study without your consent if there is an accidental dural puncture during 
the start of your standard of care epidural or if the epidural catheter has to be replaced within 60 minutes 
of starting the procedure. 
 
WHO WILL PAY FOR MY TREATMENT IF I AM INJURED? 
If you believe that the research procedures have resulted in an injury to you, immediately contact the 
Principal Investigator who is listed on the first page of this form. Emergency medical treatment for injuries 
solely and directly related to your participation in this research study will be provided to you by the 
hospitals of UPMC. Your insurance provider may be billed for the costs of this emergency treatment, but 
none of those costs will be charged directly to you. If your research-related injury requires medical care 
beyond this emergency treatment, you will be responsible for the costs of this follow-up care. At this time, 
there is no plan for any additional financial compensation. You do not waive any rights by signing this form. 


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WHAT ARE THE BENEFITS OF TAKING PART IN THE STUDY? 
There is no direct personal benefit to you from taking part in this study, but we hope to learn things that 
will help other people in the future. There may be an advantage to one of the pain medications that we are 
testing that you would benefit from if assigned to that group. 
 
WILL I BE PAID FOR PARTICIPATION? 
You will be paid a total of $20 for participating in this study. You will be paid on a reloadable debit card. 
Your name, address, and social security number are needed to create or load the card and this information 
will be released to the Accounting Office. All compensation is taxable income to the participant. If you 
receive $600 or more in a calendar year from one organization, that organization is required by law to file a 
Form 1099 – Miscellaneous with the IRS and provide a copy to the taxpayer. Individuals who do not provide 
a social security number may still participate in research, but the IRS requires that 24% of the payment be 
sent by the institution to the IRS for ‘backup withholding;’ thus you would only receive 76% of the expected 
payment. 
 
WILL IT COST ME ANYTHING TO PARTICIPATE? 
We expect neither you, nor your insurance provider will be charged for the cost of the procedures 
performed only for the purposes of this research study. You and/or your insurer will be billed in the usual 
manner for your standard medical care. 
 
HOW WILL MY INFORMATION AND SPECIMENS BE USED? 
The study team is asking your authorization to collect information from your and your baby’s medical 
records to do this study. This may include: 
1. Collecting information to make sure you meet the criteria to be in this study, including that you do 
not have any serious illness, 
2. Gathering information about medical history to include in the research data, 
3. To inspect and/or copy your research records for quality assurance and data analysis 
4. Collecting information about your epidural, your delivery and your infant that is routinely 
collected with an epidural 
 
The data collection will include information about your health and your delivery. Those records may 
contain information such as demographic data, height, weight, and gestational age. We will also collect 
information on the progression of delivery, vital signs, progression of labor, pain scores and data regarding 
the baby’s health at delivery (APGAR scores, blood pH in the cord blood). This information will be available 
for an indefinite period of time and your authorization does not expire. At these same time points, we will 
ask you what your level of pain is. We will also evaluate if you have nausea, vomiting, itching of the skin and 
shivering. 


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The following individuals and organizations may access or use your identifiable health information: 
• The researchers and research staff conducting the study 
• Representatives of the University of Pittsburgh Office of Research Protections for the purpose of 
monitoring the conduct of the research. 
• Regulatory agencies as required by law. 
• State or Federal agencies with research oversight responsibilities, including but not limited to: 
• 
Office for Human Research Protection (OHRP) 
• 
U.S Food and Drug Administration (FDA) 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law. This website 
will not include information that can identify you. At most, the website will include a summary of the 
results. You can search this website at any time. 
 
HOW WILL MY INFORMATION BE PROTECTED? 
Every effort will be made to keep your personal information confidential, but we cannot guarantee 
absolute confidentiality. No information which could identify you will be shared in publications about this 
study. 
 
We will store most of your study information with your name or other things that could identify you 
removed. Otherwise, you will be assigned a random ID number which will only be known known to study 
team members. This information will be stored on departmental computers that are protected by the 
UPMC firewall and required passwords to access. Access will be limited to study team members only. The 
document that links your random ID number to your name will protected by the PI, Dr. Lim. Paper records, 
like your consent form, will be in a locked file in a locked office. 
 
FUTURE DATA USE 
We may share de-identified data with other researchers in the future. 
 
WHO SHOULD I CALL WITH QUESTIONS OR PROBLEMS? 
For questions about the study, please contact the primary coordinator during normal business hours, 
Thomas Troyan at 412-641-2179. For emergencies, the PI, be contacted at 412-641-1000 Please ask for Dr. 
Lim to be paged. 


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WHAT IF I DO NOT PARTICIPATE OR CHANGE MY MIND? 
After reviewing this form and having your questions answered, you may decide to sign this form and 
participate in the study. Or you may choose not to participate in the study. This decision is up to you. If you 
choose not to participate in this study or change your mind after signing this document, it will not affect 
your usual medical care or treatment or relationship with UPMC or the University of Pittsburgh. 
 
If you choose to withdraw your authorization for use and disclosure of your protected health information 
from your medical record, you must do so in writing by notifying Dr. Lim at: 
Dr Grace Lim 
Department of Anesthesiology & Perioperative Medicine 300 Halket Street Suite 3510 
Pittsburgh, PA 15213 
 
If you withdraw your authorization, you will not be able to continue in this study. However, even if you 
cancel this authorization, the research team, research sponsor(s), and/or the research organizations may 
still use information about you that was collected as part of the research project between the date you 
signed this document and the date you cancelled this authorization. This is to protect the quality of the 
research results. Otherwise, this authorization remains valid until the research ends and required 
monitoring of the study has been completed. 
 
Per University of Pittsburgh policy, all research records must be maintained for at least 7 years following 
final reporting or publication of a project and for children until they reach age of 25. 
 
The researchers may stop your participation in the study even if you do not want to stop if the study doctor 
determines that it is in your interest. You will be told about new information that may affect your health, 
welfare, or willingness to stay in the study. 


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PARTICIPANT’S CONSENT AND AUTHORIZATION 
The above information has been explained to me and all my current questions have been answered. I 
understand that I am encouraged to ask questions, voice concerns or complaints about any part of this 
research study during this study. Any future questions, concerns or complaints will be answered by a 
qualified individual or by the investigator(s) listed on the first page of this consent document at the 
telephone number(s) given. I understand that I may always request that my questions, concerns or 
complaints be addressed by a listed investigator. I understand that I may contact the Human Subjects 
Protection Advocate of the Human Research Protection office, University of Pittsburgh (1-866-212- 2668) to 
discuss problems, concerns, and questions; obtain information; offer input; or discuss situations that 
occurred during my participation. By signing this form, I consent to participate in this research study and 
provide authorization to use and share my and my child’s medical records. A copy of this consent form will 
be given to me. 
 
 
 

SAP_003.pdf: 
Effectiveness of Clonidine and Dexmedetomidine Adjuncts for Labor Epidural Analgesia Initiation: 
A Randomized Double-Blind Fentanyl-Controlled Non-Inferiority Trial (The CLASSIER Trial) 
 
Draft Statistical Analysis Plan 
Edited: 01/11/2023 
 
 
 
Abstract 
The purpose of this trial is to compare the effectiveness of labor analgesia initiation with clonidine, dexmedetomidine, or 
fentanyl (usual care) adjuncts. 
 
Hypothesis 
The hypothesis is that clonidine (Group C) and dexmedetomidine (Group D) are non-inferior to fentanyl (Group F) (usual 
care) as adjuncts for epidural labor analgesia.  
 
The null hypothesis is that clonidine and dexmedetomidine are inferior to fentanyl as adjuncts for epidural labor analgesia. 
 
Background 
Labor pain is the worst pain that most women will experience in their lifetime, and poorly treated labor pain is associated 
with depression, birth trauma, and risk for cesarean delivery and its attendant lifetime morbidities. Currently, standard 
evidence-based epidural labor analgesia protocols combine lipophilic opioids with local anesthetics to increase analgesia 
quality, reducing side effects of plain local anesthesia solutions alone: hypotension, motor block, and instrumental vaginal 
delivery. However, some patients such as those with complex pain (e.g., chronic pain, opioid use disorder, OUD), often 
experience pain that is more difficult to treat. Further, they may desire complete opioid avoidance due to interference with 
treatment goals (both severe pain and opioid exposure risks return to use and resultant overdose death) or postpartum 
drug screening. There is a critical need for viable alternatives to opioid exposure for effective pain management in this 
population. Clonidine and dexmedetomidine are two alpha-2-adrenergic agonists that have been studied in the context of 
neuraxial analgesia and have demonstrated benefits, but head-to-head comparisons with the current standard, opioids, 
are lacking. This lack of comparative data leaves patients and clinicians ill equipped to identify appropriate opioid 
alternatives in labor analgesia. The CLASSIER trial will compare the effectiveness of these adjuvants against the current 
standard of epidural fentanyl. The results of this investigation will be definitive evidence regarding viable alternatives to 
opioids as adjuvants for epidural analgesia, maximizing analgesia while continuing to limit side effects. CLASSIER will 
engender future trials aimed at furthering individualized pain management strategies in special populations. 
 
Pain Outcome  
Pain intensity scores were measured by 0-10 numeric rating scale (NRS) where 0 is no pain and 10 is the worst 
imaginable. Scores were measured at baseline (immediately before the intervention), 5-, 10-, 15-, 30-, 60-, 90-, 120- 
minutes after the intervention. The first 30 minutes of analgesia was considered for the primary outcome, as we judged 
this period to be a clinically relevant time when anesthesia clinicians are most intensely involved in the initial labor 
analgesia encounter and clinical judgements are being made about labor analgesia effectiveness. The totality of the pain 
experience over the first 30 minutes was assessed using Area Under the Curve (AUC) (Cappelleri 2009). AUC was 
calculated by the trapezoidal rule (AUC = AUC + (X[i]-X[i−1])*((Y[i]+Y[i−1])/2), where X is the number of time intervals 
since intervention, and Y is the reported NRS pain score) using the 5-, 10-, 15-, 30-minute pain ratings. 
 
Exploratory Analyses 
We will perform two exploratory analyses. First, we will assess the noninferiority of the outcome of the totality of the pain 
experience over the first 120 minutes using AUC, PI-AUC120 between the 3 groups. Second, we will compare the primary 
outcome PI-AUC30 between dexmedetomidine and clonidine groups to explore noninferiority between clonidine and 
dexmedetomidine as adjuncts. 
 
Statistical Analysis Plan 
Descriptive statistics will be calculated for demographic variables. Normally distributed data will be expressed as mean 
(standard deviation [SD]) while non-parametrically distributed data will be reported as median (interquartile range [IQR]), 
and categorical variables will be summarized as counts and percentages. Box plots and histograms will be used to 
evaluate the normality of data distribution. Absolute standardized difference (ASD) will be determined to identify any 
imbalance for baseline characteristics between groups.  
 
The primary outcome (pain intensity burden AUC in first 30 minutes, PI-AUC30) will be analyzed using noninferiority 
testing. The noninferiority margin (δ) will be defined as 10% of the PI-AUC30 in the control (fentanyl) group. 
 


A conventional 1-sided 95% confidence interval (CI) will be constructed using normal distribution assumptions. Analysis 
will be by intent to treat. Assessments of any protocol violation will be reported. Treatment assignments will be evaluated 
against treatments received, and a sub-analysis of intention-to-treat analysis will be done if there are any study 
participants who did not receive their allocated intervention. 
 
Sample Size Calculation 
The primary outcome is pain intensity burden measured by area under the curve (AUC) for the first 30 minutes after 
initiation of epidural labor analgesia, PI-AUC30. A 1-sided P value of 0.05 was considered statistically significant for the 
primary outcome. If the confidence interval (CI) for mean differences of PI-AUC30 between groups (Group D and Group F 
and between Group C and Group F) lie above the lower limit of −δ with P < 0.05, then we define Group D and Group C as 
noninferior to Group F.  
 
We hypothesized that there would be no differences between the 3 groups in this noninferiority trial (Hida E 2018). We 
considered that up to 10% difference in pain burden (AUC) would not be clinically important. Therefore, the noninferiority 
margin was chosen based on a 10% difference in pain burden (AUC) between groups. We planned a priori to declare 
noninferiority of the dexmedetomidine or clonidine groups compared to the fentanyl groups if the upper bound of the 1-
sided 95% confidence interval (CI) of the difference in rates of analgesia between groups (specifically: fentanyl - 
dexmedetomidine, clonidine - dexmedetomidine) was less than 10%. Using a 1-sided α level of 0.05, 2-sample 
noninferiority test, 23 patients were required in each group (total n=69) to achieve at least power of 80%. 
 
Statistical analyses will be completed using PASS 23.0.2 (Kaysville, UT), Stata SE 17.0 (College Station, TX), and SAS 
9.4M8 (Cary, NC). 
 
  
References 
Hida E, Tango T. Design and analysis of a 3-arm noninferiority trial with a prespecified margin for the hazard ratio. Pharm 
Stat. 2018 Sep;17(5):489-503. doi: 10.1002/pst.1875. Epub 2018 Jul 9. PMID: 29984524. 
 
Cappelleri JC, Bushmakin AG, Zlateva G, Sadosky A. Pain responder analysis: use of area under the curve to enhance 
interpretation of clinical trial results. Pain Pract. 2009 Sep-Oct;9(5):348-53. doi: 10.1111/j.1533-2500.2009.00293.x. Epub 
2009 Jun 22. PMID: 19549060. 

Prot_000.pdf: 
 
 
 
 
 
 
 
 
STUDY TITLE: Effectiveness of Clonidine, Dexmedetomidine, and Fentanyl Adjuncts for Labor Epidural 
Analgesia: A randomized controlled trial (CLASSIER) 
IRB: STUDY22030095 
NCT05487196 
Study Protocol: 10 MAY 2022 
 
 


* Title of study: 
Effectiveness of Clonidine, Dexmedetomidine, and Fentanyl Adjuncts for Labor Epidural Analgesia: A 
Randomized Controlled Trial 
* Short title: 
CLASSIER Trial 
* Brief description: 
The purpose of this trial is to compare the effectiveness of labor analgesia with clonidine, 
dexmedetomidine, or fentanyl (usual care) adjuncts. 
Study Aims 
Research Key Question: 
Does the addition of dexmedetomidine to a ropivacaine solution used for epidural labor analgesia initiation, 
improve epidural labor analgesia when compared with a solution combining clonidine with ropivacaine, or a 
solution combining fentanyl with ropivacaine? 
Hypotheses: 
We hypothesize that the addition of dexmedetomidine to a ropivacaine solution used for epidural perfusion 
in labor analgesia improves epidural labor analgesia as evaluated by Visual Analogue Scores at various 
time points after epidural initiation compared with a solution combining clonidine with ropivacaine and 
fentanyl with ropivacaine. 
1. Background: 
In the current practice, the standardized epidural solution that is used in the labor analgesia 
protocol combines a local anesthetic with an opioid. The addition of opioids as adjuvants to local 
anesthetics has many advantages as they increase the quality of the epidural block. They also act by 
reducing the local anesthetic total dose which results in lower incidence of motor block and assisted vaginal 
delivery.  


 
The addition of opioids to the local anesthetic solution used for epidural perfusion has become a standard 
of practice in North America. Although the literature advocates for this practice, a small proportion of 
patients may benefit from a different approach.  
Patients with chronic pain and chronic opioid consumption are at risk of developing opioid 
tolerance defined as the use of the oral morphine equivalent of greater than or equal to 60 mg a day for 7 
days or longer. 5 Another population that could possibly benefit from this approach are parturient that are 
diagnosed with an opioid use disorder. These patients often develop opioid tolerance requiring higher 
dosage to address acute pain. Experts’ consensus advocates for a multimodal approach in this population.  
Moreover, some patients are consuming medication to treat opioid use disorders such as buprenorphine 
and methadone. These medications have an impact on the pharmacokinetics of opioids and alter their 
effect on the human body.  
Tailoring the approach to labor pain management in the population of parturient that are at risk for 
complex pain management is the cornerstone to an individualized approach, leading to optimal care. This 
approach may be achieved by substituting the opioid in the epidural solution with another adjuvant. For 
example, clonidine is an alpha-2-adrenergic agonist that has been extensively studied in the context of 
neuraxial anesthesia and analgesia 
Addition of clonidine to the epidural solution for postoperative analgesia has been studied widely in 
orthopedic and general surgery procedures. It offers a dose-sparing action of local anesthetics while 
increasing the duration of sensory blockade. It is also widely used for post-operative pain management 
after various pediatric surgical procedures and has shown a reassuring safety profile in this population.  
A systematic review and meta-analysis evaluated the effects of neuraxial clonidine added to local 
anesthetics in women admitted for caesarean section under neuraxial anesthesia. Their conclusions show 
that intrathecal clonidine reduced 24 h morphine consumption and prolonged time to first analgesic request. 


Neuraxial clonidine increased the incidence of intraoperative hypotension defined as a 20% reduction from 
the pre-anesthetic baseline systolic blood pressure. This augmentation of the intraoperative hypotension 
episodes did not translate into an augmentation of treatment with vasopressors such as ephedrine, which 
leads us to think that this hypotension was not clinically significant. Moreover, the usage of neuraxial 
clonidine did not negatively impact neonatal umbilical artery pH or Apgar scores. 
Clonidine added to ropivacaine for labor epidural analgesia has shown to provide a longer duration 
of analgesia and a reduction of the total ropivacaine dose over the first 4 hours.  It has been extensively 
studied for the initiation and maintenance of epidural analgesia in laboring women. The literature regarding 
the addition of clonidine to the local anesthetic solution perfused in epidural for labor shows an increased 
the quality of analgesia while reducing the need for rescue supplementation.  
It has also shown to prolong the duration of analgesia offered by a bupivacaine bolus after the initiation of 
epidural analgesia. Moreover, the addition of clonidine shortened the onset of analgesia and showed a 
decrease in the local anesthetic consumption in laboring patients.  
Dexmedetomidine is an alpha-2-agonist that has a greater affinity for the alpha-receptor. It is about 
8 times more selective towards this receptor. It is currently used in obstetric anesthesia for multimodal labor 
analgesia, post cesarean delivery analgesia and postoperative shivering. Some studies have also found a 
benefit in the quality of analgesia offered by dexmedetomidine when compared to opioids as adjuvants to 
epidural.  
A meta-analysis of randomized controlled trials reviewed the effects of epidural dexmedetomidine 
as an adjuvant to local anesthetics for labor analgesia. Nine studies were included in the qualitative 
synthesis presented in this meta-analysis. The group arrived to the conclusion that “epidural 
dexmedetomidine has the potential to oﬀer a better analgesic eﬀect than placebo, similar labor pain control 
to opioids, and has no deﬁnite adverse eﬀects on the parturient or fetus, but more high-quality studies are 
needed to conﬁrm these conclusions.” 


 
The usage of dexmedetomidine as an adjuvant to epidural during labor has been a subject of great 
interest in the last few years. Zhao and al. performed a RCT with 80 laboring patients that received an 
epidural with low concentration of epidural ropivacaine (0.125%) alone or combined with dexmedetomidine 
(0.5 mg/kg) as bolus. This anesthetic regimen that included dexmedetomidine reduced the pain scores at 
most time intervals evaluated after epidural initiation. It is also reassuring to see that other outcome such as 
the duration of the ﬁrst and second stage of labor, the rate of instrumental delivery and cesarean section, 
Apgar scores, umbilical artery pH, maternal motor blockade scores, intensity of maternal sedation, and the 
incidence of maternal complications did not show signiﬁcant diﬀerence between the two studied groups.  
Selim and al. carried out a study where they evaluated the impact of dexmedetomidine as an adjunct to 
bupivacaine compared to a standard fentanyl – bupivacaine solution. They aimed to explore uterine artery 
pulsatility index and umbilical artery pulsatility index during uterine contractions and relaxations. They were 
able to show that the bupivacaine – dexmedetomidine group had a shorter onset of analgesia and an 
increased duration of analgesia. Their analysis of the uterine artery pulsatility index and umbilical artery 
pulsatility index showed that dexmedetomidine did not induce any deleterious effects of uteroplacental 
circulation or neonatal outcomes.  
Zhang and al. did show that the combination of dexmedetomidine with ropivacaine for labor 
analgesia offered similar sensory block when compared to a control group that received a ropivacaine only 
solution. Moreover, the duration of the first and second stage of labor, the mode of delivery and the Apgar 
scores and umbilical arterial pH after birth were similar between both groups. Finally, side effects such as 
hypotension, bradycardia and pruritus were also similar between both cohorts.  
Dexmedetomidine has been used as an adjuvant to epidural in various surgical interventions. It has 
also been compared to clonidine to evaluate the benefits of this novel molecule compared to clonidine 
which has been on the market for a few decades. Dexmedetomidine is a better neuraxial adjuvant 


compared to clonidine since it provides early onset of sensory analgesia superior intraoperative analgesia, 
a prolonged postoperative analgesia while offering stability of the cardiorespiratory parameters. 
The intrathecal administration of dexmedetomidine in a cohort of patients admitted for lower limb 
surgery is associated with prolonged sensory and motor block, hemodynamic stability, and a reduction in 
the consumption of rescue analgesics in 24h period as compared to clonidine, fentanyl, or bupivacaine 
alone. When comparing dexmedetomidine to clonidine as adjuvants to local anesthetics in labor analgesia, 
it seems that both molecules offer an excellent quality of analgesia and a great safety profile. However, 
dexmedetomidine has shown a faster onset of analgesia a prolonged analgesia and a decrease in the time 
to achieve maximal analgesia.  
2. Significance/Rationale: (Why is the question worth pursuing? Will it reduce complications or costs, 
improve outcome, change practice?) 
This study is significant because it can potentially alternative non-opioid adjunctive agents for 
epidural labor analgesia. The opioid crisis in the United States has translated to an increasing number of 
pregnant women requiring care for labor and delivery. These trends have resulted in new questions about 
alternative epidural analgesia adjuncts besides lipophilic opioids (e.g., fentanyl and sufentanil) because: 1) 
many people with OUD desire to avoid opioids in all formulations and routes of administration; and 2) 
epidural fentanyl or sufentanil administration for labor can potentially interfere with the accuracy of urine 
drug screening in the postpartum period. 
Regarding the scope of the problem: A retrospective study evaluated the incidence of maternal 
opiate usage using a database that compiled information from 7.4 million discharges in 44 states. It shows 
that the maternal consumption of opioids has increased nearly fivefold in a 9-year observation period 
(2000-2009)57 while others report prevalence of opioid use disorder during pregnancy Increasing by 127% 
from 1998 to 2011. 58 It is estimated that 4.5% of pregnant women aged 15–44 years are using illicit or 
prescription opioid medications, which emphasizes the importance of this issue.  


 
Tailoring the approach to labor pain management in the population of parturient that are at risk for 
complex pain management is the cornerstone to an individualized approach, leading to optimal care. This 
approach may potentially be achieved by substituting the opioid in the epidural solution with another 
adjuvant such as clonidine or dexmedetomidine, two alpha2-adrenergic agonists. 
Some existing literature suggests that dexmedetomidine and clonidine are adjuncts to local 
anesthetics that offer a faster onset and a better quality of analgesia for patients requiring labor analgesia. 
Further studies are required to precise the dosage and regimens in a population of laboring patients. 
Study Design 
Total number of subjects to be enrolled at this site: 
400 (200 Mothers and their infants (200)) 
Describe and explain the study design: 
• This study is designed as a randomized, parallel arm, controlled trial in 3 groups allocated in a 
1:1:1 ratio 
Describe the primary and secondary study endpoints: 
Primary outcomes 
Pain as defined by Numeric Rating Score (NRS) (0-10 where 0 is no pain and 10 Is the worst Imaginable) 
at 30 minutes after initiation of epidural analgesia 
Secondary outcomes 
0-10 pain scores, obstetric outcomes related to delivery details; hemodynamic outcomes; patient reported 
scales of symptoms and ratings including nausea, vomiting, shivering, pruritus, satisfaction; fetal and 
newborn outcomes. 
Duration of an individual subject's active participation: 


Approximately 24 hours (duration of labor). Study participation ends 10 minutes after delivery ( for the 
newborn Apgar) 
Inclusion criteria 
1. >/ = 18 years 
2. ASA Physical Status 2 or 3 
3. Term pregnancy [> 37 gestational weeks] 
4. Planning epidural labor analgesia 
5. Singleton pregnancy 
6. Vertex presentation 
7. Planned vaginal delivery 
Exclusion criteria 
1. Pre-eclampsia with or without severe features 
2. New initiation of antihypertensive agent within 24 hours prior to enrollment 
3. Uncontrolled systemic comorbidities [i.e., diabetes, hepatic, renal or cardiac] 
4. Known or suspected fetal abnomalies 
5. Allergy to study agents 
6. Contra-indication to neuraxial anesthesia 
7. Inability to communicate or to participate in study procedures 
8. Current beta blocker therapy