Ketamine to Improve Recovery After Cesarean Delivery - Part 1

NCT04037085 | Completed Phase 2 Results FDA Drug

• 1 other identifier: STUDY18120046
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 2

Brief Summary

The objective of this study is evaluate the breastmilk transfer and pharmacokinetics (Part 1) and effectiveness (Part 2) of a post-cesarean delivery intravenous ketamine bolus-and-infusion strategy, as a preventive analgesic modality to reduce pain and opioid requirements. In Part 1, physiochemical analysis of pharmacokinetic/pharmacodynamic (PK/PD) and breastmilk transfer of ketamine and its metabolites will be assessed. Additionally calculated estimations for neonatal and infant exposure will be assessed. In Part 2, PK/PD assessments will continue in a larger cohort; endpoints will also include postpartum pain, depression scores, central sensitization measures, patient-reported postpartum recovery scores, breastfeeding, and parent-infant bonding, assessed in the acute post-cesarean period and up to 12 weeks postpartum in a randomized controlled trial.

Conditions

Obstetric Pain; Postpartum Depression; Breastfeeding; Pain, Acute; Pain, Chronic; Obstetric Anesthesia Problems; Drug Effect; Opioid Use

Outcome Measures

Primary Outcomes (9)

• Ketamine (AUC)

  Plasma will be used to calculate area under the plasma concentration-time curve (AUC 0-∞) of ketamine levels during infusion. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug.

  12 hour ketamine infusion

• Steady State (Css)

  Ketamine steady state (Css) is defined as the concentration of drug in plasma at steady state.

  12 hours after ketamine infusion start

• Elimination Half Life (T1/2) for Ketamine

  Postpartum maternal plasma serum will be used to calculate postpartum maternal ketamine half-life (T1/2). b. Elimination half-life (t½) is the time required for drug concentration to decrease by one-half at the end drug dosing. Elimination half-life was obtained from the slope of terminal elimination phase.

  27 hours postpartum or 24 hour CTRC appointment for weaning population

• Volume of Distribution Steady State (Vdss)

  Volume Distribution Steady State (Vdss) is the period of dynamic equilibrium of the drug calculated as the amount of drug in the body at time, t divided by the plasma concentration of the drug at time, t.

  27 hours postpartum or 24 hour CTRC appointment for weaning population

• Ketamine Milk to Plasma Ratio (M:P)

  Milk to plasma ratio for KET were calculated by dividing the concentration of the respective components Ketamine in human milk by plasma concentration at the corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of ketamine and the metabolites would be higher in breastmilk than in maternal plasma concentrations.

  27 hours postpartum or 24 hour CTRC appointment for weaning population

• Nor-ketamine Milk to Plasma Ratio

  Milk to plasma ratio of the Ketamine metabolite, Norketamine, calculated as the percentage of the maternal ketamine dose found from breastmilk. Milk to plasma ratio for NKET was calculated by dividing the concentration of the respective components Ketamine and Ketamine metabolites in human milk by plasma concentration at the corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of metabolites would be higher in breastmilk than in maternal plasma concentrations.

  27 hours postpartum or 24 hour CTRC appointment for weaning population

• Hydroxynorketamine M:P Ratio

  Milk to plasma ratio of the Ketamine metabolite, Hydroxynorketamine, calculated as the percentage of the maternal ketamine dose found from breastmilk. Milk to plasma ratio for hydroxynorketamine was calculated by dividing the concentration of the respective ketamine metabolites in human milk by plasma concentration at the corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of the metabolites would be higher in breastmilk than in maternal plasma concentrations.

  27 hours postpartum or 24 hour CTRC appointment for weaning population

• Relative Infant Dose of Ketamine (RID KET)

  Relative infant dose will be calculated as the percentage of the maternal ketamine dose found from breastmilk. The relative infant dose was calculated from the concentrations of ketamine in breast milk at different times following ketamine administration to the women. The concentration of ketamine was converted to amount by multiplying with the volume of breast milk collected at various time intervals. The cumulative dose of ketamine was calculated. An RID ≤10% was considered low.

  27 hours postpartum or 24 hour CTRC appointment for weaning population

• Relative Infant Dose of Ketamine Equivalent (Ketamine, Norketamine, Dehydro-norketamine)

  Relative infant dose (RID) will be calculated as the percentage of the maternal ketamine dose found from breastmilk. The relative infant dose was calculated from the concentrations of ketamine and its metabolites (ketamine, norketamine \& dehydro-norketamine) in breast milk at different times following ketamine administration to the women.

  27 hours postpartum or 24 hour CTRC appointment for weaning population

Study Arms (1)

Ketamine

EXPERIMENTAL

Ketamine - IV after cord clamping; IV infusion for 12 hours OR in the weaning population IV Ketamine infusion for 12 hours in the Montefiore CTRC

Drug: Ketamine

Interventions

Ketamine DRUG

Subjects in the intervention arm will receive infusion dosing as noted in arm/group descriptions at the time of cord clamping. Duration of infusion will be 12 hours. Concentrations of ketamine and ketamine metabolites (nor-ketamine, NKET; and dehydro-nor-ketamine, DHNK) are measured in maternal plasma and urine as well as breastmilk. Maternal side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and over 15 hours after infusion discontinuation.

Also known as: Ketalar

Ketamine

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult female patients (i.e., ≥18 years of age) and able to provide informed consent
• Cesarean Delivery, Scheduled or Non-Emergent (delivery within 15 minutes not necessary), or female weaning off of breastfeeding
• Cesarean cohort: ASA PS 2 or 3, with or without E designation (delivery within 15 minutes not necessary), Scheduled or Non-Emergent
• Spinal anesthesia with intrathecal morphine if Cesarean Delivery, Scheduled or Non-Emergent
• Multimodal postop analgesia with IV ketorolac, PO NSAID, and PO APAP if Cesarean Delivery, Scheduled or Non-Emergent
• Women who do not plan to breastfeed or who want to temporarily withhold breastfeeding or who are weaning off of breastfeeding (Part 1)

You may not qualify if:

• Cesarean Delivery under General Anesthesia
• Allergies to study medications
• ASA PS 4 or 4E
• ASA PS with E designation because delivery within 15 minutes required
• ASA PS greater than 4 (moribund patients)
• Contraindications to spinal anesthesia
• Contraindications to NSAIDs (gastric bypass, etc.)
• Contraindication to any other multimodal analgesia medicine
• Adverse occurrence during caesarean section such as hemorrhage, need for transfusion, hemodynamic instability
• Placenta accreta spectrum or previa with large anticipated blood loss
• History of hallucinations, alcohol or illicit substance use/abuse, chronic opioid therapy, or chronic pain (chronic pain - defined by any condition requiring consistent follow up with pain specialist or daily administration of pain medications that could augment sedative effects)
• Pre-eclampsia with severe features

Sponsors & Collaborators

• Grace Lim, MD, MS: lead
• University of Pittsburgh: collaborator

Study Sites (2)

UPMC Montefiore Hospital CTRC

Pittsburgh, Pennsylvania, 15213, United States

Location

Minhnoi C Wroble Biglan

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Labor Pain; Depression, Postpartum; Breast Feeding; Acute Pain; Chronic Pain

Interventions

Ketamine

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Puerperal Disorders; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Depressive Disorder; Mood Disorders; Mental Disorders; Feeding Behavior; Behavior

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Results Point of Contact

• Title: Grace Lim, MD, MSc
• Organization: UPMC

limkg2@upmc.edu

412-641-1110

Study Officials

• Grace Lim, MD, MS

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Prospective observational open-label trial (Part 1)

Study Record Dates

• First Submitted: February 2, 2019
• First Posted: July 30, 2019
• Study Start: October 9, 2019
• Primary Completion: August 1, 2021
• Study Completion: August 1, 2021
• Last Updated: December 20, 2022
• Results First Posted: December 20, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)