Obstetric PainPhase 2KINETICNCT04037085
Ketamine to Improve Recovery After Cesarean Delivery - Part 1
A Phase 2 study testing Ketamine in people with Obstetric Pain and Postpartum Depression, run by Grace Lim, MD, MS at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 99 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Obstetric Pain, Postpartum Depression, Breastfeeding
- What is being tested?
- Ketamine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 2 sitesUnited States
- Study dates
- 9 Oct 2019to 1 Aug 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- Women only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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
Show all 13Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
UPMC Montefiore Hospital CTRC
Pittsburgh, Pennsylvania, 15213
Minhnoi C Wroble Biglan
Pittsburgh, Pennsylvania, 15232
About this study
Official title: Evaluation of PK/PD, Breastmilk Transfer, and Effectiveness of Ketamine After Cesarean Delivery - Part 1
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.
Read the 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.
- Conditions
- Obstetric Pain, Postpartum Depression, Breastfeeding, Pain, Acute, Pain, Chronic, Obstetric Anesthesia Problems
- Being tested
- Ketamine
- Medical subject headings
- Labor Pain, Depression, Postpartum, Breast Feeding, Acute Pain, Chronic Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KetamineDrug
Also called Ketalar
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.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: Ketamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 hour ketamine infusion
Steady State (Css)
Ketamine steady state (Css) is defined as the concentration of drug in plasma at steady state.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 27 hours postpartum or 24 hour CTRC appointment for weaning population
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jul 2019
- Study start9 Oct 2019
- Primary completion1 Aug 2021
- Study completion1 Aug 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Obstetric PainStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Prospective observational open-label trial (Part 1)
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Grace Lim, MD, MS
- Sponsor type
- University, hospital or other
- Collaborators
- University of Pittsburgh
- Responsible party
- Sponsor-investigator, Grace Lim, MD, MS, University of Pittsburgh
- Investigators
- Grace Lim, MD, MS, Principal investigator, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04037085
- Sponsor's protocol ID
- STUDY18120046
- Acronym
- KINETIC
- Status last verified
- Nov 2022
- First submitted
- 2 Feb 2019
- Last updated
- 20 Dec 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of PK/PD, Breastmilk Transfer, and Effectiveness of Ketamine After Cesarean Delivery - Part 1
- ClinicalTrials.gov ID
- NCT04037085
- Acronym / sponsor ID
- KINETIC / STUDY18120046
- Conditions
- Obstetric Pain, Postpartum Depression, Breastfeeding, Pain, Acute, Pain, Chronic, Obstetric Anesthesia Problems
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Grace Lim, MD, MSUniversity, hospital or other
- Collaborators
- University of Pittsburgh
- Study start
- 9 Oct 2019 (actual)
- Primary completion
- 1 Aug 2021 (actual)
- Study completion
- 1 Aug 2021 (actual)
- First posted
- 30 Jul 2019 (actual)
- Results
- Posted 20 Dec 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Prospective observational open-label trial (Part 1)
| Arm | Type | Receives |
|---|---|---|
| Ketamine | Experimental | Drug: KetamineKetamine - IV after cord clamping; IV infusion for 12 hours OR in the weaning population IV Ketamine infusion for 12 hours in the Montefiore CTRC |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (13 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| KetamineAlso: KetalarSubjects 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. | Drug | Ketamine |
Primary outcome
Ketamine (AUC)
Time frame: 12 hour ketamine infusion
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)
Time frame: 12 hours after ketamine infusion start
Ketamine steady state (Css) is defined as the concentration of drug in plasma at steady state.
Elimination Half Life (T1/2) for Ketamine
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
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)
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
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)
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
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
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
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
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
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)
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
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)
Time frame: 27 hours postpartum or 24 hour CTRC appointment for weaning population
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Dec 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Grace Lim, MD, MS principal investigator
University of Pittsburgh
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ketamine in people with Obstetric Pain and Postpartum Depression, run by Grace Lim, MD, MS at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Dec 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ketamine (AUC) (time frame: 12 hour ketamine infusion). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Dec 2022.