Effectiveness of IV Acetaminophen and IV Ibuprofen in Reducing Post Procedural Pain in the UFE Procedure

Study Overview
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Brief Summary
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The uterine fibroid embolization (UFE) procedure is a treatment option for abnormal heavy menstrual bleeding and/or bulk symptoms associated with uterine fibroids and adenomyosis. Post UFE procedural pain and nausea are expected events. These symptoms are treated with current standard of care medications, including opiates. Intra procedure pain medications include midazolam, fentanyl and hydromorphone. Some centers include nonsteroidal anti-inflammatory medications (NSAIDS), including oral ibuprofen and IV ketorolac. Post procedural pain control is centered on a hydromorphone patient-controlled analgesia (PCA) infusion pump, as well as a NSAID regimen. Intra procedure and post procedure nausea control medications include a transcutaneous scopolamine patch and IV anti-nausea medications such as ondansetron and prochlorperazine. This study is being conducted to compare two new medications for pain, IV ibuprofen and IV acetaminophen, administered for 24 hours following UFE. The primary safety objective of non-inferiority will be met and the primary efficacy objective of superiority, decreased pain and nausea, will be accessed when compared to current standard of care regimens. This is a 4 arm, double blind, randomized, controlled study. All patients will receive standard of care baseline pain medications, including IV midazolam, fentanyl and hydromorphone intra procedure, followed by a hydromorphone PCA infusion pump post procedure. The 4 arms will include: [ Arm 1] IV ibuprofen/IV placebo, [Arm 2] IV acetaminophen/IV placebo, [Arm 3] IV ibuprofen/IV acetaminophen, and [arm 4] IV placebo/IV placebo. These medications will be given during the procedure and extended over a 24 hour stay. Arm 4 (IV placebo/IV placebo) would replicate current standard of care, and therefore will include IV push (IVP) ketorolac, which would be given at the end of the procedure and be continued every 6 hours for the 24 hour stay. An IVP of saline will be given as a control every 6 hours for the 24 hour stay to arms 1, 2 and 3. Pain and nausea will be measured at intervals prior to the procedure, throughout the stay and at 2 weeks post procedure.

Detailed Description
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A prospective, double blind, randomized controlled trial evaluating the effects of two new IV medications, IV ibuprofen and IV acetaminophen, on standard of care pain and anti-emetic management in Uterine Fibroid Embolization patients. Four arm, double blind, randomized controlled study: all patients will receive standard of care baseline pain medications, including IV midazolam, fentanyl and hydromorphone during the procedure, followed by a hydromorphone PCA infusion pump during their recovery. The four arms will include an IV ibuprofen/IV placebo, an IV acetaminophen/IV placebo, an IV ibuprofen/IV acetaminophen, and a control arm (IV placebo/IV placebo). The same amount of normal saline will be substituted for the experimental treatments if the patient receives the placebo. These medications will be given during the procedure and extended over a 24 hour recovery period. The medications given will be blinded to the patient, the administrator, and the surveyor. The placebo/placebo arm would replicate current standard of care, and therefore include IV push (IVP) ketorolac, which would be given at the end of the procedure and be continued for 24 hours at q6hour dosing. An IVP of saline would be given as a control for 24 hours at q6hour dosing to the other three arms. Dosage of medications will be standardized based on formulary indications: IV Ketorolac 30 mg/dose IVP, acetaminophen 1 gram/dose IV piggy back over 15 minutes every 6 hours, ibuprofen 800 mg/dose IV piggy back over 30 minutes every 6 hours. Variables measured: mean and maximum pain (VAS score at 0 hours, 6 hours, discharge and 2 weeks post procedure), opioid requirements, mean and maximum nausea (VAS score at 0 hours, 6 hours, discharge and 2 weeks post procedure), anti-emetic medication requirements. Weighted sum of pain intensity differences, with pain intensity measured on VAS over 24 hours (SPID24) will be used as a primary outcome. Satisfaction scores will be measured at 24 hours using the validated APS-POQ-R questionnaire (6). Other variables recorded: Age, height, weight, history of postoperative nausea and vomiting or motion sickness, diagnosis, uterine volume, dominant fibroid size, arteries embolized, presence of prominent ovarian arteries, volume of particle used, fluoroscopy time for the procedure. Technical parameters, which would remain constant, include: pre procedure and 6 month follow up MRI contrast with gadolinium which is standard of care, embolization using 500-700 micron Embospheres (with limited use of 700-900 micron Embospheres), IV hydration with 0.9% normal saline, antibiotics (IV ciprofloxacin 400 mg every 12 hours, IV metronidazole 500 mg every six hours), urinary catheter placement, lower extremity compression devices, and early ambulation. In the interim analysis, the investigators will have 40 subjects in total with unequal randomization ratio of 1:1:4:4. Additional subjects will be enrolled for a total of 35 subjects per arm for the final analysis (sum total N=140)

Official Title
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A Prospective, Double Blind, Randomized, Placebo Controlled Study to Compare the Effectiveness of Intravenous Acetaminophen and Intravenous Ibuprofen in Reducing Post Procedural Pain in the Uterine Fibroid Embolization Procedure

Conditions
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Symptomatic Uterine Fibroids and Adenomyosis

Intervention / Treatment
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* Drug: IV Ibuprofen
* Drug: IV Acetaminophen
* Drug: Intravenous placebo/Intravenous placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients being considered for UFE including bleeding and/or bulk symptoms. Women of all ethnicities Ages 21-60 Exclusion Criteria: Patients with current malignancy receiving treatment Women who are pregnant Cognitive impairment Clinically significant kidney disease Clinically significant liver disease Any recent history of gastrointestinal bleed or ulcer Weight less than 50 kg (medication dosing requirements change below 50 kg) Women with a body mass index (BMI) equal to or over 50 (with other co-morbidities) Known allergy or hypersensitivity to NSAID or acetaminophen Administration of acetaminophen, NSAID, narcotic or any other analgesic less than 6 hours prior to UFE procedure Any chronic use of pain medications including acetaminophen, NSAID, narcotic or analgesic Patients who cannot or choose not to consent to participate in the study

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous Ibuprofen<br>Ibuprofen 800mg IV piggyback and Saline IVP q 6 hours x 4 during uterine fibroid embolization | Drug: IV Ibuprofen<br>* Uterine fibroid embolization<br>* Other names: Uterine artery embolization;|
| Experimental: Intravenous acetaminophen<br>Acetaminophen 1 gram IV piggyback and Saline IVP q6 hours x 4 during uterine fibroid embolization | Drug: IV Acetaminophen<br>* Uterine fibroid embolization<br>* Other names: Uterine artery embolization;|
| Experimental: IV ibuprofen/IV acetaminophen<br>Ibuprofen 800 mg/ Acetaminophen 1 gram IV piggyback and Saline IVP 6 hours x 4 during uterine fibroid embolization | Drug: IV Ibuprofen<br>* Uterine fibroid embolization<br>* Other names: Uterine artery embolization;Drug: IV Acetaminophen<br>* Uterine fibroid embolization<br>* Other names: Uterine artery embolization;|
| Active Comparator: Intravenous placebo/Intravenous placebo<br>Saline/Saline IV piggyback and IVP Ketorolac 30 mg q6 hours x 4 during uterine fibroid embolization | Drug: Intravenous placebo/Intravenous placebo<br>* Uterine fibroid embolization<br>* Other names: Uterine artery embolization;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Maximum Pain Intensity Change Over 24 Hours With the Addition of IV Acetaminophen and IV Ibuprofen | Primary efficacy objective is to compare the change in maximum level of pain experienced by patient over 24 hours between IV acetaminophen and IV ibuprofen (alone and in combination), and the current standard of care medication regimen. This comparison will be measured using a visual analog scale (VAS) from 0 to 10, 0 signifying no pain and 10 signifying the worst possible pain. The scores reported are the mean of all patients' VAS scores in each respective category. | 24 hours | 
| Evaluation of Mean Pain Intensity Over 24 Hours With the Addition of IV Acetaminophen and IV Ibuprofen | Primary efficacy objective is to compare the change in mean pain intensity score over 24 hours between IV acetaminophen and IV ibuprofen (alone and in combination), and the current standard of care medication regimen. This comparison will be measured using a visual analog scale (VAS) from 0 to 10, 0 signifying no pain and 10 signifying the worst possible pain. The scores reported are the mean of all patients' VAS scores in each respective category. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Nausea Intensity | Assessment of mean nausea by mean of VAS scores over a 24-hour period. VAS score is measured using a scale of 0 to 10, 0 signifying no nausea and 10 signifying the worst possible nausea. The scores reported are the mean of all patients' VAS scores in each respective category. | 24 hours | 
| Opioid Consumption | Mean opioid consumption in morphine equivalents over 24 hours | 24 hours | 
| Anti-Emetic Consumption | Mean dose of anti-emetic medication in milligrams given over 24 hours | 24 hours | 
| Maximum Nausea Intensity | Assessment of maximum level of nausea experienced by patient, by mean of VAS scores over a 24-hour period. VAS score is measured using a scale of 0 to 10, 0 signifying no nausea and 10 signifying the worst possible nausea. The scores reported are the mean of all patients' VAS scores in each respective category. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uterine Fibroid Embolization, Pain, UFE, Fibroids, Adenomyosis, Bleeding, IV Acetaminophen, IV Ibuprofen, Menorrhagia, Leiomyoma, Patient Satisfaction