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The purpose of this randomized controlled trial is to compare the effectiveness of epidural clonidine, dexmedetomidine, or fentanyl adjuncts for labor analgesia.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Clonidine | Experimental | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Clonidine 60 mcg |
|
| Dexmedetomidine | Experimental | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Dexmedetomidine 30 mcg |
|
| Ropivacaine + Fentanyl | Active Comparator | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Fentanyl 100mcg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clonidine | Drug | Clonidine belongs to the drug classification of antihypertensives |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Pain Burden, AUC (30 Minutes) | Pain score AREA UNDER THE CURVE (AUC), which is a calculated area under curve using the trapezoidal rule, where pain scores measured from 0 (no pain) to 10 (worst imaginable pain) are on the y axis, and time is on the x axis (pain scores were measured at 5 minutes, 10 minutes,15 minutes, 30 minutes after epidural initiation for the primary outcome assessment). The scale for AUC is not 0-10 but rather is completely dependent upon the area generated under the curve created by pain scores for the first 30 minutes of epidural analgesia (primary outcome time frame): in this case, the scale is 0-250 pain units*minute, given maximum pain score possibility of 10 and time period of 30 minutes. The units of AUC are the units of Y axis times units of X axis, in this case, pain score units * minutes. Pain AUC was compared between Fentanyl, Clonidine and Dexmedetomidine groups. | First 30 minutes of analgesia |
| Measure | Description | Time Frame |
|---|---|---|
| Pain Burden, AUC (120 Minutes) | Pain score AREA UNDER THE CURVE (AUC), which is a calculated area under curve using the trapezoidal rule, where pain scores measured from 0 (no pain) to 10 (worst imaginable pain) are on the y axis, and time is on the x axis (pain scores were measured at 5 minutes, 10 minutes,15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after epidural initiation). The scale for AUC is not 0-10 but rather is completely dependent upon the area generated under the curve created by pain scores for the first 120 minutes of epidural analgesia: in this case, the scale is 0-850 pain units*minute, given maximum pain score possibility of 10 and time period of 120 minutes. The units of AUC are the units of Y axis times units of X axis, in this case, pain score units * minutes. Pain AUC was compared between Fentanyl, Clonidine and Dexmedetomidine groups. |
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Pregnant minors were not enrolled in this trial.
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Grace Lim, MD, MS | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UPMC Magee-Womens Hospital | Pittsburgh | Pennsylvania | 15213 | United States |
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Pregnant subjects were enrolled at the time of admission to labor and delivery. Both mothers and infants were considered enrolled for the purpose of capturing specific infant information from the infant medical record after delivery (i.e., Apgar scores, cord gases). However, only mothers received the study medication for labor pain control. All other outcomes were assessed on maternal subjects only. Enrollment number & number of subjects started/completed represents the number of dyads enrolled.
Participant flow numbers reflect mother-fetus dyads (1 mother + 1 infant per dyad). Intervention groups were assigned at the maternal level.
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| ID | Title | Description |
|---|---|---|
| FG000 | Clonidine | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Clonidine 60 mcg Clonidine: Clonidine belongs to the drug classification of antihypertensives Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care Pregnant subjects were enrolled at the time of admission to labor and delivery. Both mothers and infants were considered enrolled for the purpose of capturing specific infant information from the infant medical record after delivery (i.e., Apgar scores, cord gases). However, only mothers received the study medication for labor pain control. All other outcomes were assessed on maternal subjects only. Enrollment number & number of subjects started/completed represents the number of dyads enrolled. |
| FG001 | Dexmedetomidine | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Dexmedetomidine 30 mcg Dexmedetomidine: Dexmedetomidine belongs to the drug classification of sedatives Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care Pregnant subjects were enrolled at the time of admission to labor and delivery. Both mothers and infants were considered enrolled for the purpose of capturing specific infant information from the infant medical record after delivery (i.e., Apgar scores, cord gases). However, only mothers received the study medication for labor pain control. All other outcomes were assessed on maternal subjects only. Enrollment number & number of subjects started/completed represents the number of dyads enrolled. |
| FG002 | Ropivacaine + Fentanyl | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Fentanyl 100mcg Fentanyl: Fentanyl belongs to the drug classification of analgesic opioid agonists and is used as the standard of care Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care Pregnant subjects were enrolled at the time of admission to labor and delivery. Both mothers and infants were considered enrolled for the purpose of capturing specific infant information from the infant medical record after delivery (i.e., Apgar scores, cord gases). However, only mothers received the study medication for labor pain control. All other outcomes were assessed on maternal subjects only. Enrollment number & number of subjects started/completed represents the number of dyads enrolled. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Baseline data were derived from maternal subjects at the time of enrollment. Baseline data were not collected from fetuses (because enrollment and the study medication administration occurred during pregnancy).
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| ID | Title | Description |
|---|---|---|
| BG000 | Clonidine (Maternal) | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Clonidine 60 mcg Clonidine: Clonidine belongs to the drug classification of antihypertensives Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Pain Burden, AUC (30 Minutes) | Pain score AREA UNDER THE CURVE (AUC), which is a calculated area under curve using the trapezoidal rule, where pain scores measured from 0 (no pain) to 10 (worst imaginable pain) are on the y axis, and time is on the x axis (pain scores were measured at 5 minutes, 10 minutes,15 minutes, 30 minutes after epidural initiation for the primary outcome assessment). The scale for AUC is not 0-10 but rather is completely dependent upon the area generated under the curve created by pain scores for the first 30 minutes of epidural analgesia (primary outcome time frame): in this case, the scale is 0-250 pain units*minute, given maximum pain score possibility of 10 and time period of 30 minutes. The units of AUC are the units of Y axis times units of X axis, in this case, pain score units * minutes. Pain AUC was compared between Fentanyl, Clonidine and Dexmedetomidine groups. | Maternal only | Posted | Median | Inter-Quartile Range | pain units*minutes | First 30 minutes of analgesia |
|
From enrollment until 3 days after delivery.
Definition of adverse event and/or serious adverse event used to collect adverse event information was per definitions available on clinicaltrials.gov.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Clonidine (Maternal) | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Clonidine 60 mcg Clonidine: Clonidine belongs to the drug classification of antihypertensives Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Prolonged Deceleration | Pregnancy, puerperium and perinatal conditions | Systematic Assessment | One dyad had a prolonged deceleration documented around 17h10 (01/26/2023). Fetal heart tones were down to 70-90 from baseline of 120 for 7 min. Condition o called and maternal terbutaline was given to decrease uterine tone. Event resolved completely |
The primary limitation of this study is related to the clonidine and dexmedetomidine doses used for analgesia initiation. The doses were chosen based on what was available in existing literature and clinical experience. Another limitation is that many patients who were eligible and approached declined participation, citing lack of interest in research or primarily a desire to receive only current institutional standards for epidural labor analgesia.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Grace Lim, MD, MSc | UPMC Magee Women's Hospital | 412-641-1778 | limkg2@upmc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 10, 2022 | Jul 11, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 11, 2023 | Nov 12, 2024 | SAP_003.pdf |
| ICF | No | No | Yes | Informed Consent Form | Mar 28, 2023 | Jul 11, 2024 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D003000 | Clonidine |
| D020927 | Dexmedetomidine |
| D005283 | Fentanyl |
| D000077212 | Ropivacaine |
| ID | Term |
|---|---|
| D048288 | Imidazolines |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
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This study is designed as a randomized, quadruple blinded, parallel arm, controlled, non-inferiority trial in 3 groups allocated in a 1:1:1 ratio
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| Dexmedetomidine |
| Drug |
Dexmedetomidine belongs to the drug classification of sedatives |
|
| Fentanyl | Drug | Fentanyl belongs to the drug classification of analgesic opioid agonists and is used as the standard of care |
|
| Ropivacaine | Drug | Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care |
|
| First 120 minutes of analgesia |
| Pain Scores | Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable. | 15 minutes after initiation of epidural analgesia |
| Pain Scores | Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable. | 30 minutes after initiation of epidural analgesia |
| Pain Scores | Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable. | Immediately after delivery |
| Cesarean Delivery | This will be measured by yes/no response to cesarean delivery mode of delivery outcome. We report the raw numbers of patients who did receive a cesarean delivery according to group. | At the time of delivery |
| Hypotension | This is measured as any hypotensive event occurring any time between 0-120 min after study drug administration. | Between 0-120 min after study drug administration |
| Nausea | Patient self-report of nausea at any time between 0-120 min after study drug administration | 0-120 min after study drug administration |
| Vomiting | Patient self-report of vomiting at any time between 0-120 min after study drug administration | 0-120 min after study drug administration |
| Shivering | Patient self-report of shivering at any time between 0-120 min after study drug administration | 0-120 min after study drug administration |
| Pruritus | Patient self-report of pruritus at any time between 0-120 min after study drug administration | 0-120 min after study drug administration |
| Patient Treatment Satisfaction | Patient self-report regarding satisfaction with analgesia on a scale of 1-10; 1 = not satisfied, 10 = the most satisfied. | Immediately after delivery |
| Newborn Apgar Score | The Apgar score is a method of assessing newborn health at the time of delivery. Score range 0 to 10 where 0 is poor health and 10 is the best health. | 1 minute after delivery |
| BG001 | Dexmedetomidine (Maternal) | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Dexmedetomidine 30 mcg Dexmedetomidine: Dexmedetomidine belongs to the drug classification of sedatives Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care |
| BG002 | Ropivacaine + Fentanyl (Maternal) | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Fentanyl 100mcg Fentanyl: Fentanyl belongs to the drug classification of analgesic opioid agonists and is used as the standard of care Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Only female participants. | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Clonidine |
Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Clonidine 60 mcg Clonidine: Clonidine belongs to the drug classification of antihypertensives Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care |
| OG001 | Dexmedetomidine | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Dexmedetomidine 30 mcg Dexmedetomidine: Dexmedetomidine belongs to the drug classification of sedatives Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care |
| OG002 | Ropivacaine + Fentanyl | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Fentanyl 100mcg Fentanyl: Fentanyl belongs to the drug classification of analgesic opioid agonists and is used as the standard of care Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care |
|
|
|
| Secondary | Pain Burden, AUC (120 Minutes) | Pain score AREA UNDER THE CURVE (AUC), which is a calculated area under curve using the trapezoidal rule, where pain scores measured from 0 (no pain) to 10 (worst imaginable pain) are on the y axis, and time is on the x axis (pain scores were measured at 5 minutes, 10 minutes,15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after epidural initiation). The scale for AUC is not 0-10 but rather is completely dependent upon the area generated under the curve created by pain scores for the first 120 minutes of epidural analgesia: in this case, the scale is 0-850 pain units*minute, given maximum pain score possibility of 10 and time period of 120 minutes. The units of AUC are the units of Y axis times units of X axis, in this case, pain score units * minutes. Pain AUC was compared between Fentanyl, Clonidine and Dexmedetomidine groups. | Maternal only | Posted | Mean | Inter-Quartile Range | pain units*minutes | First 120 minutes of analgesia |
|
|
|
|
| Secondary | Pain Scores | Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable. | Maternal only | Posted | Mean | Standard Deviation | score on a scale | 15 minutes after initiation of epidural analgesia |
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|
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| Secondary | Pain Scores | Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable. | Maternal only | Posted | Mean | Standard Deviation | score on a scale | 30 minutes after initiation of epidural analgesia |
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| Secondary | Pain Scores | Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable. | Maternal only | Posted | Mean | Standard Deviation | score on a scale | Immediately after delivery |
|
|
|
|
| Secondary | Cesarean Delivery | This will be measured by yes/no response to cesarean delivery mode of delivery outcome. We report the raw numbers of patients who did receive a cesarean delivery according to group. | Maternal only | Posted | Count of Participants | Participants | At the time of delivery |
|
|
|
|
| Secondary | Hypotension | This is measured as any hypotensive event occurring any time between 0-120 min after study drug administration. | Maternal only | Posted | Count of Participants | Participants | Between 0-120 min after study drug administration |
|
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|
| Secondary | Nausea | Patient self-report of nausea at any time between 0-120 min after study drug administration | Maternal only | Posted | Count of Participants | Participants | 0-120 min after study drug administration |
|
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| Secondary | Vomiting | Patient self-report of vomiting at any time between 0-120 min after study drug administration | Maternal only | Posted | Count of Participants | Participants | 0-120 min after study drug administration |
|
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| Secondary | Shivering | Patient self-report of shivering at any time between 0-120 min after study drug administration | Maternal only | Posted | Count of Participants | Participants | 0-120 min after study drug administration |
|
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|
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| Secondary | Pruritus | Patient self-report of pruritus at any time between 0-120 min after study drug administration | Maternal only | Posted | Count of Participants | Participants | 0-120 min after study drug administration |
|
|
|
|
| Secondary | Patient Treatment Satisfaction | Patient self-report regarding satisfaction with analgesia on a scale of 1-10; 1 = not satisfied, 10 = the most satisfied. | Maternal only | Posted | Mean | Inter-Quartile Range | score on a scale | Immediately after delivery |
|
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| Secondary | Newborn Apgar Score | The Apgar score is a method of assessing newborn health at the time of delivery. Score range 0 to 10 where 0 is poor health and 10 is the best health. | Neonatal only | Posted | Median | Inter-Quartile Range | score on a scale | 1 minute after delivery |
|
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| 18 |
| 30 |
| EG001 | Dexmedetomidine (Maternal) | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Dexmedetomidine 30 mcg Dexmedetomidine: Dexmedetomidine belongs to the drug classification of sedatives Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care | 0 | 29 | 0 | 29 | 10 | 29 |
| EG002 | Ropivacaine + Fentanyl (Maternal) | Bolus dose at epidural initiation, through the epidural catheter: 10 ml Ropivacaine 0.1 % combined with a single dose of Fentanyl 100mcg Fentanyl: Fentanyl belongs to the drug classification of analgesic opioid agonists and is used as the standard of care Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care | 0 | 29 | 0 | 29 | 19 | 29 |
| EG003 | Clonidine (Fetal-neonatal) | Per maternal. Study drug was given during pregnancy while uteroplacental perfusion remained intact. Monitoring for AE/SAE for fetus and infant occurred during labor and delivery (fetal safety monitoring) as well as from day 0 through 3 of life (neonatal safety monitoring). | 0 | 30 | 0 | 30 | 1 | 30 |
| EG004 | Dexmedetomidine (Fetal-neonatal) | Per maternal. Study drug was given during pregnancy while uteroplacental perfusion remained intact. Monitoring for AE/SAE for fetus and infant occurred during labor and delivery (fetal safety monitoring) as well as from day 0 through 3 of life (neonatal safety monitoring). | 0 | 29 | 0 | 29 | 0 | 29 |
| EG005 | Ropivacaine + Fentanyl (Fetal-neonatal) | Per maternal. Study drug was given during pregnancy while uteroplacental perfusion remained intact. Monitoring for AE/SAE for fetus and infant occurred during labor and delivery (fetal safety monitoring) as well as from day 0 through 3 of life (neonatal safety monitoring). | 0 | 29 | 0 | 29 | 0 | 29 |
|
| Maternal Nausea | Nervous system disorders | Systematic Assessment | Patient self-report of nausea at any time between 0-120 min after study drug administration |
|
| Maternal Vomiting | Nervous system disorders | Systematic Assessment | Patient self-report of vomiting at any time between 0-120 min after study drug administration |
|
| Maternal Shivering | Nervous system disorders | Systematic Assessment | Patient self-report of shivering at any time between 0-120 min after study drug administration |
|
| Maternal Pruritus | Nervous system disorders | Systematic Assessment | Patient self-report of pruritus at any time between 0-120 min after study drug administration |
|
| Maternal Hypotension | Nervous system disorders | Systematic Assessment | This is measured as any hypotensive event occurring any time between 0-120 min after study drug administration. |
|
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| D006571 |
| Heterocyclic Compounds |
| D010880 | Piperidines |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
| D000588 | Amines |
| Between 18 and 65 years |
|
| >=65 years |
|
| Male |
|