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Ketamine to Prevent PPD After Cesarean (PoCKet)

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ClinicalTrials.gov Identifier: NCT04227704
Recruitment Status : Recruiting
First Posted : January 14, 2020
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Tracking Information
First Submitted Date  ICMJE November 20, 2019
First Posted Date  ICMJE January 14, 2020
Last Update Posted Date November 17, 2020
Actual Study Start Date  ICMJE November 12, 2020
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 13, 2020)
  • The incidence of PPD, as defined as EPDS greater than 10 out of 30 [ Time Frame: 42 days postpartum ]
    Establish a sufficient burden of disease (>10%) in our population to warrant a full RCT
  • Percentage of eligible patients consenting to participation [ Time Frame: Through study completion, an average of 1 year ]
    Establish a recruitment rate of greater than 50% to confirm the feasibility of conducting an RCT in our population
  • Percentage of patients with a complete dataset [ Time Frame: Through study completion, an average of 1 year ]
    Ensure that the design of assessments and data collection make it possible to achieve a complete dataset in >90% of participants
  • Number of patients in study arms experiencing one or more severe side effects [ Time Frame: Through study completion, an average of 1 year ]
    Ascertain that neither of the chosen routes of administration of ketamine are intolerable to patients, as defined as the incidence of one or more severe side effects experienced by >10% of participants in that study arm.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 10, 2020)
  • Dose of opiate analgesics administered [ Time Frame: Intraoperative phase ]
    Intraoperative supplementary analgesia in morphine milligram equivalents
  • Dose of ketorolac administered [ Time Frame: Intraoperative phase ]
    Intraoperative supplementary analgesia
  • Incidence of intraoperative hypotension of a systolic BP of less than 90 [ Time Frame: Intraoperative phase ]
    Incidence of systolic BP less than 90 mmHg
  • Maximum intraoperative pain (NRS) [ Time Frame: Intraoperative phase ]
    Reported maximal level of intraoperative pain on the numerical rating scale 0 - 10
  • Adverse effects [ Time Frame: Intraoperative and 2 and 6 hours postoperatively ]
    Incidence and severity (mild, moderate or severe) of nausea, vomiting, pruritus, dizziness, sedation, shivering, anxiety, euphoria, hallucinations, amnesia, blurred vision, diplopia, nystagmus
  • Plasma concentrations of ketamine [ Time Frame: At baseline and approximately 20, 40 and 100 minutes postpartum ]
    Assays of venous blood samples
  • Total opiate consumption in morphine equivalents [ Time Frame: In the first 2 days postpartum ]
    Morphine equivalents
  • Surgical site pain: numerical rating scale (NRS 0-10) [ Time Frame: At 2, 6, 24 and 48 hours after delivery and on postpartum days 21 and 42 ]
    On a numerical rating scale (NRS 0-10)
  • Edinburgh Postpartum Depression Scale (0 - 30, a higher score represents greater depressive symptomatology) [ Time Frame: On postpartum days 1, 2, 21 and 42 ]
    Validated measure of depressive symptoms in the postpartum period
  • Apgar scores [ Time Frame: At 1 and 5 minutes after delivery ]
    Score out of 10, of neonatal status
  • Admission to NICU [ Time Frame: Postpartum day 1 ]
    Incidence of admission
  • Breastfeeding success [ Time Frame: Postpartum days 1 and 2 ]
    Yes or no
  • Incidence of intraoperative hypertension of a systolic BP greater than 140 mmHg [ Time Frame: Intraoperative phase ]
    Systolic hypertension of greater than 140 mmHg
  • Incidence of intraoperative bradycardia of less than 40 bpm [ Time Frame: Intraoperative phase ]
    Bradycardia less than 40 bpm
  • Incidence of intraoperative tachycardia of greater than 110 bpm [ Time Frame: Intraoperative phase ]
    Tachycardia greater than 110 bpm
  • Incidence of Anxiety on the Generalized Anxiety Disorder- 7 item scaleGAD-7 [ Time Frame: On day of surgery, and postpartum days 1, 2, 21 and 42 ]
    Validated scale for anxiety. Score out of 21.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2020)
  • Dose of opiate analgesics administered [ Time Frame: Intraoperative phase ]
    Intraoperative supplementary analgesia in morphine milligram equivalents
  • Dose of ketorolac administered [ Time Frame: Intraoperative phase ]
    Intraoperative supplementary analgesia
  • Incidence of intraoperative hypotension of a systolic BP of less than 90 [ Time Frame: Intraoperative phase ]
    Incidence of systolic BP less than 90 mmHg
  • Maximum intraoperative pain (NRS) [ Time Frame: Intraoperative phase ]
    Reported maximal level of intraoperative pain on the numerical rating scale 0 - 10
  • Adverse effects [ Time Frame: Intraoperative and 2 and 6 hours postoperatively ]
    Incidence and severity (mild, moderate or severe) of nausea, vomiting, pruritus, dizziness, sedation, shivering, anxiety, euphoria, hallucinations, amnesia, blurred vision, diplopia, nystagmus
  • Plasma concentrations of ketamine [ Time Frame: At baseline and approximately 20, 40 and 100 minutes postpartum ]
    Assays of venous blood samples
  • Total opiate consumption in morphine equivalents [ Time Frame: In the first 2 days postpartum ]
    Morphine equivalents
  • Surgical site pain: numerical rating scale (NRS 0-10) [ Time Frame: At 2, 6, 24 and 48 hours after delivery and on postpartum days 21 and 42 ]
    On a numerical rating scale (NRS 0-10)
  • Edinburgh Postpartum Depression Scale (0 - 30, a higher score represents greater depressive symptomatology) [ Time Frame: On postpartum days 1, 2, 21 and 42 ]
    Validated measure of depressive symptoms in the postpartum period
  • Apgar scores [ Time Frame: At 1 and 5 minutes after delivery ]
    Score out of 10, of neonatal status
  • Admission to NICU [ Time Frame: Postpartum day 1 ]
    Incidence of admission
  • Breastfeeding success [ Time Frame: Postpartum days 1 and 2 ]
    Yes or no
  • Incidence of intraoperative hypertension of a systolic BP greater than 140 mmHg [ Time Frame: Intraoperative phase ]
    Systolic hypertension of greater than 140 mmHg
  • Incidence of intraoperative bradycardia of less than 40 bpm [ Time Frame: Intraoperative phase ]
    Bradycardia less than 40 bpm
  • Incidence of intraoperative tachycardia of greater than 110 bpm [ Time Frame: Intraoperative phase ]
    Tachycardia greater than 110 bpm
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine to Prevent PPD After Cesarean
Official Title  ICMJE Postpartum Depression After Cesarean Delivery: Ketamine as a Preventative Intervention: A Feasibility Pilot-study
Brief Summary The investigators plan to randomise participants to receive ketamine or placebo control subcutaneously or by 40-minute intravenous infusions and will follow them up for 42 days to assess the incidence of postpartum depression. This feasibility pilot study is designed to explore the adequacy of the study procedures and tolerability of the interventions.
Detailed Description

Postpartum depression (PPD)

PPD is one of the most common perinatal medical complications and can have a detrimental effect on both mother and baby. Suicide exceeds hemorrhage and hypertensive disorders as a cause of maternal mortality and maternal psychopathology interferes with the parent-infant relationship. It has been estimated to have a period prevalence of 19.2% in the first 3 postpartum months. The rapid decline in reproductive hormones is thought to contribute to the development of PPD in susceptible women, although the specific pathogenesis is unknown. The American College of Obstetricians and Gynecologists recommend that all women should be routinely screened for depressive symptoms in the perinatal period.

Risk factors for PPD include:

  • Depression during pregnancy • Breastfeeding problems
  • Preterm birth/infant admission to neonatal intensive care (NICU)
  • Traumatic birth experience
  • History of depression
  • Anxiety during pregnancy

Ketamine's anti-depressant effect

Ketamine, a phencyclidine derivative, is a non-competitive antagonist at the N-methyl-D-aspartic acid (NMDA) receptor that is commonly used as an anesthetic or sedative agent and has proven analgesic effect after a variety of surgeries including CD, where it has also been shown to reduce shivering. It has been demonstrated to have a rapid anti-depressant effect in treatment-resistant depression outside of pregnancy. The most commonly employed intravenous (IV) dose for this purpose is 0.5 mg/kg over 40 minutes, as single or repeated infusions. It has been postulated that prolonged blockade of NMDA receptors causes long-term changes in signal transduction leading to sustained clinical improvement, some investigators have explored longer term infusions such as those used to treat chronic pain. A recent pilot study assessing the feasibility of a 96-hour (~0.5mg/kg/hr) infusion compared with a single 40-minute (0.5 mg/kg) infusion suggested a trend toward greater efficacy in the prolonged infusion but confirmation of a statistically significant result is awaited.

Ketamine and PPD

This promising anti-depressant effect has prompted investigation of ketamine as a preventative measure in patients undergoing CD. There have been 2 studies to date, one which failed to demonstrate any benefit from a bolus dose of 0.25 mg/kg and one which documented a large reduction (1 and 22% in the treatment and control, respectively) in the (6 week) period prevalence of postpartum depression after a 4 mg/kg dose of ketamine over 50 hours (~0.08 mg/kg/hr).

The prolonged IV infusion, was achieved by adding the ketamine to a sufentanil patient-controlled analgesic (PCA) pump with a background infusion. This PCA pump is a standard part of their post-cesarean analgesic regimen. In our institution, it is standard practice to discontinue IV infusions and to remove IV cannulae as early as it is safe to do so. This practice is essential to the attempts to enhance postoperative recovery and aid mother's bonding with their babies and facilitate their early-life care. This reflects patients' expectations and preferences and is in line with other maternity units across North America and Europe.

The natural course of PPD varies and, although it may resolve spontaneously within weeks, approximately 20% of women with PPD still have depression at 12 months and beyond. As many as 13% will still have depressive symptoms at 2 years and 40% will have a relapse. Considering the maternal suffering, disruption to the family, potential impairment of the social, emotional, and cognitive development of the child, and the rare cases of infanticide and suicide caused by PPD, the impact on families and society as a whole is difficult to overemphasize. An intervention that promises such a large reduction in this devastating disease warrants extensive research. In an attempt to achieve the benefit whilst employing methods more acceptable to our patients we have designed a pilot study to assess the feasibility of our study design and collect preliminary tolerability and efficacy data on ketamine administered by two alternative routes: 40-minute IV infusion (i.v.) and subcutaneous (s.c.) injection.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Participants will be randomised to one of three groups (two interventional and one control).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
The ketamine and placebo study injectates (subcutaneous and intravenous) will be prepared, in way that does not allow differentiation, by pharmacy staff who are otherwise uninvolved in the study. Participants will be allocated to groups using a random sequence generator. The patients, investigators and outcome assessors will remain unaware of their group until data collection is complete for all participants.
Primary Purpose: Prevention
Condition  ICMJE Postpartum Depression
Intervention  ICMJE
  • Drug: Ketamine 50 MG/ML
    Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion).
  • Drug: Control
    Administration of 0.9% Sodium Chloride (N/S)
Study Arms  ICMJE
  • Placebo Comparator: Control
    Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection and 40-minute intravenous infusion of 0.9% sodium chloride.
    Intervention: Drug: Control
  • Experimental: Ketamine SC
    Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.5 mg/kg of ketamine and a 40-minute intravenous infusion of 0.9% sodium chloride.
    Interventions:
    • Drug: Ketamine 50 MG/ML
    • Drug: Control
  • Experimental: Ketamine IVI
    Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.9% sodium chloride and a 40-minute intravenous infusion of 0.5 mg/kg ketamine.
    Interventions:
    • Drug: Ketamine 50 MG/ML
    • Drug: Control
Publications * Not Provided

*   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: January 13, 2020)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2021
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • Term pregnancy
  • Age 18-45 years of age
  • Scheduled cesarean delivery under neuraxial anesthesia

Exclusion criteria:

  • ASA classification IV or V
  • History of psychotic episodes
  • History of allergy to ketamine
  • Inability to communicate in English or any other barrier to providing informed consent
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ben Swan 314-273-8257 bswan@wustl.edu
Contact: Kristi Kraus, RN 314-273-7921 kristinkraus@wustl.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04227704
Other Study ID Numbers  ICMJE 201910191
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.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party 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 November 2020

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