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出境医 / 临床实验 / Preeclampsia And Nonsteroidal Drugs for Analgesia: a Randomized Non Inferiority Trial (PANDA)

Preeclampsia And Nonsteroidal Drugs for Analgesia: a Randomized Non Inferiority Trial (PANDA)

Study Description
Brief Summary:
A randomized non-inferiority trial of women with preeclampsia with severe features to determine if the addition of nonsteroidal anti-inflammatory drugs is inferior or non-inferior to standard analgesic bundles in their impact on postpartum hypertension.

Condition or disease Intervention/treatment Phase
Preeclampsia Severe Preeclampsia Postpartum Drug: Ibuprofen 600 mg Drug: Ketorolac Drug: Acetaminophen Drug: Oxycodone Phase 2

Detailed Description:

Recently published clinical guidelines for the care of women with hypertensive disorders recommended that nonsteroidal anti-inflammatory drugs (NSAIDs) should be withheld from patients with hypertension that persists for more than one day postpartum (1). This recommendation is based in data from the general medicine literature, which suggests a role of NSAIDs in precipitating hypertension in non-pregnant adults (2,3). It may also draw from previously published case reports of post-partum hypertension that were thought to be NSAID induced (4). There has been a paucity of data from the obstetric literature to support or rebuff this recommendation. As the opioid crisis worsens in the United States, additional attention and resources have focused on limiting the use of narcotic medications. The effective employment of non-opioid analgesics has been shown to reduce narcotic use (5). Ibuprofen and other NSAIDs are the most effective and most commonly prescribed analgesics for postpartum pain, but clinicians now find themselves stuck between these recommendations and their efforts to limit unnecessary opioid prescriptions.

The investigators propose a randomized controlled non-inferiority trial of women with preeclampsia comparing a postpartum analgesic protocol that includes NSAIDs, to one that excludes them. The central hypothesis is that NSAID use does not worsen hypertensive diseases of pregnancy.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 286 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized non-inferiority clinical trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Preeclampsia And Nonsteroidal Drugs for Analgesia (PANDA): a Randomized Non Inferiority Trial
Actual Study Start Date : June 10, 2019
Estimated Primary Completion Date : May 27, 2021
Estimated Study Completion Date : July 27, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: NSAID Analgesic bundle
Ibuprofen 600mg PO q 6 hrs as needed for pain, Acetaminophen 1000mg q 8 hrs as needed for pain, and Oxycodone 5 to 10 mg q 4 hrs as needed for pain. In patients undergoing cesarean section, ketorolac 30mg IV q 6 hrs may be substituted as an IV alternative to ibuprofen for the first 24 hours after surgery
 Drug: Ibuprofen 600 mg
NSAID pain medication to be used in the experimental bundle for postpartum analgesia

Drug: Ketorolac
NSAID analgesic to be used in the experimental bundle for postpartum analgesia in patients who underwent cesarean section

Drug: Acetaminophen
Analgesic medication to be used in both treatment arms

Drug: Oxycodone
Analgesic medication to be used in both treatment arms
Active Comparator: NSAID free analgesic bundle
Acetaminophen 1000mg q 8 hrs as needed for pain, and Oxycodone 5 to 10 mg q 4 hrs as needed for pain.
 Drug: Acetaminophen
Analgesic medication to be used in both treatment arms

Drug: Oxycodone
Analgesic medication to be used in both treatment arms
Outcome Measures
Primary Outcome Measures :
  1. postpartum antihypertensive requirements [ Time Frame: at the end of hospitalization, up to 7 days after randomization ]
    measurement of anti-hypertensive requirements at time of discharge


Secondary Outcome Measures :
  1. Postpartum pain scores [ Time Frame: From randomization to 6 weeks after randomization ]
    Evaluate the effect of NSAIDs on patient perception of pain

  2. Postpartum opioid use [ Time Frame: From randomization to 6 weeks after randomization ]
    Compare the opioid requirements in each arm

  3. Mean arterial blood pressure [ Time Frame: From randomization to 6 weeks after randomization ]
    Compare peak, average and median MAPs postpartum

  4. End organ damage [ Time Frame: during hospitalization, an average of 4 days ]
    Evaluate for evidence of renal, hepatic or neurological injury in the poatpartum period

  5. Hospital readmission [ Time Frame: From randomization to 6 weeks after randomization ]
    Evaluate the incidence of hospital readmission rate postpartum

  6. Continued anti-hypertensive requirement [ Time Frame: up to 6 weeks ]
    evaluate the need for antihypertensive medications at 6 weeks postpartum


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Women at > 23 weeks gestational age undergoing vaginal or cesarean delivery at Barnes-Jewish Hospital with:
  • An antepartum diagnosis of preeclampsia with severe features
  • Pre-eclampsia with severe features will be defined as:
  • Elevated blood pressure ≥ 160/110, or
  • Pre-eclampsia in the setting of thrombocytopenia (platelet count < 100,000), or
  • Impaired liver function (AST elevated to twice upper limit of normal), or
  • Persistent epigastric pain, or
  • Renal insufficiency (serum creatinine of 1.1 mg/dl or doubling of prior value), or
  • Pulmonary edema, or
  • New onset visual disturbance or headache unresponsive to therapy.

Exclusion Criteria:

  • NSAID allergy
  • Allergy to acetaminophen
  • Antihypertensive use in this pregnancy prior to 20 weeks gestation
  • Chronic kidney disease or Acute kidney injury with Creatine clearance less than 60 mL/min
  • Inability to obtain consent
  • Opioid abuse disorder
  • Peptic ulcer disease.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Jonathan S Hirshberg, MD 314-362-5000 jhirshberg@wustl.edu
Contact: Tracy Burger 3147471390 tburger@wustl.edu

Locations
Layout table for location information
United States, Missouri
Barnes Jewish Hospital Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Jonathan Hirshberg, MD    314-362-5000    jhirshberg@wustl.edu   
Sponsors and Collaborators
Washington University School of Medicine
Tracking Information
First Submitted Date  ICMJE May 18, 2019
First Posted Date  ICMJE June 7, 2019
Last Update Posted Date August 10, 2020
Actual Study Start Date  ICMJE June 10, 2019
Estimated Primary Completion Date May 27, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2019) 		postpartum antihypertensive requirements [ Time Frame: at the end of hospitalization, up to 7 days after randomization ]
measurement of anti-hypertensive requirements at time of discharge
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2019)
  • Postpartum pain scores [ Time Frame: From randomization to 6 weeks after randomization ]
    Evaluate the effect of NSAIDs on patient perception of pain
  • Postpartum opioid use [ Time Frame: From randomization to 6 weeks after randomization ]
    Compare the opioid requirements in each arm
  • Mean arterial blood pressure [ Time Frame: From randomization to 6 weeks after randomization ]
    Compare peak, average and median MAPs postpartum
  • End organ damage [ Time Frame: during hospitalization, an average of 4 days ]
    Evaluate for evidence of renal, hepatic or neurological injury in the poatpartum period
  • Hospital readmission [ Time Frame: From randomization to 6 weeks after randomization ]
    Evaluate the incidence of hospital readmission rate postpartum
  • Continued anti-hypertensive requirement [ Time Frame: up to 6 weeks ]
    evaluate the need for antihypertensive medications at 6 weeks postpartum
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Preeclampsia And Nonsteroidal Drugs for Analgesia: a Randomized Non Inferiority Trial
Official Title  ICMJE Preeclampsia And Nonsteroidal Drugs for Analgesia (PANDA): a Randomized Non Inferiority Trial
Brief Summary A randomized non-inferiority trial of women with preeclampsia with severe features to determine if the addition of nonsteroidal anti-inflammatory drugs is inferior or non-inferior to standard analgesic bundles in their impact on postpartum hypertension.
Detailed Description

Recently published clinical guidelines for the care of women with hypertensive disorders recommended that nonsteroidal anti-inflammatory drugs (NSAIDs) should be withheld from patients with hypertension that persists for more than one day postpartum (1). This recommendation is based in data from the general medicine literature, which suggests a role of NSAIDs in precipitating hypertension in non-pregnant adults (2,3). It may also draw from previously published case reports of post-partum hypertension that were thought to be NSAID induced (4). There has been a paucity of data from the obstetric literature to support or rebuff this recommendation. As the opioid crisis worsens in the United States, additional attention and resources have focused on limiting the use of narcotic medications. The effective employment of non-opioid analgesics has been shown to reduce narcotic use (5). Ibuprofen and other NSAIDs are the most effective and most commonly prescribed analgesics for postpartum pain, but clinicians now find themselves stuck between these recommendations and their efforts to limit unnecessary opioid prescriptions.

The investigators propose a randomized controlled non-inferiority trial of women with preeclampsia comparing a postpartum analgesic protocol that includes NSAIDs, to one that excludes them. The central hypothesis is that NSAID use does not worsen hypertensive diseases of pregnancy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomized non-inferiority clinical trial
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Preeclampsia Severe
  • Preeclampsia Postpartum
Intervention  ICMJE
  • Drug: Ibuprofen 600 mg
    NSAID pain medication to be used in the experimental bundle for postpartum analgesia
  • Drug: Ketorolac
    NSAID analgesic to be used in the experimental bundle for postpartum analgesia in patients who underwent cesarean section
  • Drug: Acetaminophen
    Analgesic medication to be used in both treatment arms
  • Drug: Oxycodone
    Analgesic medication to be used in both treatment arms
Study Arms  ICMJE
  • Experimental: NSAID Analgesic bundle
    Ibuprofen 600mg PO q 6 hrs as needed for pain, Acetaminophen 1000mg q 8 hrs as needed for pain, and Oxycodone 5 to 10 mg q 4 hrs as needed for pain. In patients undergoing cesarean section, ketorolac 30mg IV q 6 hrs may be substituted as an IV alternative to ibuprofen for the first 24 hours after surgery
    Interventions:
    • Drug: Ibuprofen 600 mg
    • Drug: Ketorolac
    • Drug: Acetaminophen
    • Drug: Oxycodone
  • Active Comparator: NSAID free analgesic bundle
    Acetaminophen 1000mg q 8 hrs as needed for pain, and Oxycodone 5 to 10 mg q 4 hrs as needed for pain.
    Interventions:
    • Drug: Acetaminophen
    • Drug: Oxycodone
Publications *
  • Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov;122(5):1122-1131. doi: 10.1097/01.AOG.0000437382.03963.88.
  • Lo JO, Mission JF, Caughey AB. Hypertensive disease of pregnancy and maternal mortality. Curr Opin Obstet Gynecol. 2013 Apr;25(2):124-32. doi: 10.1097/GCO.0b013e32835e0ef5. Review.
  • Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005 Feb 26-Mar 4;365(9461):785-99. Review.
  • Mogos MF, Salemi JL, Spooner KK, McFarlin BL, Salihu HH. Hypertensive disorders of pregnancy and postpartum readmission in the United States: national surveillance of the revolving door. J Hypertens. 2018 Mar;36(3):608-618. doi: 10.1097/HJH.0000000000001594.
  • Viteri OA, England JA, Alrais MA, Lash KA, Villegas MI, Ashimi Balogun OA, Chauhan SP, Sibai BM. Association of Nonsteroidal Antiinflammatory Drugs and Postpartum Hypertension in Women With Preeclampsia With Severe Features. Obstet Gynecol. 2017 Oct;130(4):830-835. doi: 10.1097/AOG.0000000000002247.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 5, 2019) 		286
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 27, 2021
Estimated Primary Completion Date May 27, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Women at > 23 weeks gestational age undergoing vaginal or cesarean delivery at Barnes-Jewish Hospital with:
  • An antepartum diagnosis of preeclampsia with severe features
  • Pre-eclampsia with severe features will be defined as:
  • Elevated blood pressure ≥ 160/110, or
  • Pre-eclampsia in the setting of thrombocytopenia (platelet count < 100,000), or
  • Impaired liver function (AST elevated to twice upper limit of normal), or
  • Persistent epigastric pain, or
  • Renal insufficiency (serum creatinine of 1.1 mg/dl or doubling of prior value), or
  • Pulmonary edema, or
  • New onset visual disturbance or headache unresponsive to therapy.

Exclusion Criteria:

  • NSAID allergy
  • Allergy to acetaminophen
  • Antihypertensive use in this pregnancy prior to 20 weeks gestation
  • Chronic kidney disease or Acute kidney injury with Creatine clearance less than 60 mL/min
  • Inability to obtain consent
  • Opioid abuse disorder
  • Peptic ulcer disease.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jonathan S Hirshberg, MD 314-362-5000 jhirshberg@wustl.edu
Contact: Tracy Burger 3147471390 tburger@wustl.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03978767
Other Study ID Numbers  ICMJE 201901202
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jonathan (Jake) Hirshberg, Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Washington University School of Medicine
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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