Ketamine to Improve Recovery After Cesarean Delivery - Part 1 - Clinical Trial for Obstetric Pain | NCT04037085

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Primary Purpose

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Ketamine

About this trial

This is an interventional prevention trial for Obstetric Pain

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

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)

Exclusion Criteria:

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
Significant psychiatric history (depression and anxiety NOT exclusion criteria), uncontrolled hyperthyroidism, cardiac disease, fever, hypertension
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

Sites / Locations

UPMC Montefiore Hospital CTRC
Minhnoi C Wroble Biglan

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ketamine

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Steady State (Css)

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

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.

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT04037085

First Posted

February 2, 2019

Last Updated

November 23, 2022

Sponsor

Grace Lim, MD, MS

Collaborators

University of Pittsburgh

1. Study Identification

Unique Protocol Identification Number

NCT04037085

Brief Title

Ketamine to Improve Recovery After Cesarean Delivery - Part 1

Acronym

KINETIC

Official Title

Evaluation of PK/PD, Breastmilk Transfer, and Effectiveness of Ketamine After Cesarean Delivery - Part 1

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Completed

Study Start Date

October 9, 2019 (Actual)

Primary Completion Date

August 1, 2021 (Actual)

Study Completion Date

August 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Grace Lim, MD, MS

Collaborators

University of Pittsburgh

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

No

Data Monitoring Committee

No

5. Study Description

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.

Detailed Description

Postpartum pain management strategies currently permit opioids for breakthrough pain, but strategies focused on minimizing or eliminating opioids are lacking. In the non-obstetric surgical population, modalities such as intravenous ketamine are well-recognized as effective adjuncts in opioid-reduction strategies for postoperative pain. Although there have been some studies of ketamine exposure in postpartum women without deleterious outcomes noted, these studies in pregnant and lactating women are limited by a lack of information on maternal pharmacokinetics, breastmilk secretion, and clinical effectiveness when used with standard multimodal analgesic approaches. There is also a lack of information on intermediate and long-term outcomes in this setting. This two-part trial will address these knowledge gap by advancing understanding of the safety and efficacy of ketamine and its metabolites in peripartum populations.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Model Description

Prospective observational open-label trial (Part 1)

Masking

None (Open Label)

Allocation

N/A

Enrollment

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ketamine

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Ketamine

Other Intervention Name(s)

Ketalar

Intervention Description

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.

Primary Outcome Measure Information:

Title

Ketamine (AUC)

Description

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.

Time Frame

12 hour ketamine infusion

Title

Steady State (Css)

Description

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

Time Frame

12 hours after ketamine infusion start

Title

Elimination Half Life (T1/2) for Ketamine

Description

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.

Time Frame