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| Name | Class |
|---|---|
| University of Pittsburgh | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Grace Lim, MD, MS | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UPMC Montefiore Hospital CTRC | Pittsburgh | Pennsylvania | 15213 | United States | ||
| Minhnoi C Wroble Biglan |
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| ID | Title | Description |
|---|---|---|
| FG000 | Ketamine | 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 Ketamine: Subjects in the intervention arm will receive bolus and infusion dosing as noted in arm/group descriptions at the time of cord clamping. Duration of infusion will be 12 hours. Breastmilk, maternal serum and urine, side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and over 15 hours after infusion discontinuation. For the weaning population, they will receive a 12 hour infusion in the CTRC and stay an additional 12 hours in the CTRC (or until discharged). Breastmilk, maternal serum and urine, side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and for 12 hours after infusion discontinuation. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Ketamine | 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 Ketamine: Subjects in the intervention arm will receive bolus and infusion dosing as noted in arm/group descriptions at the time of cord clamping. Duration of infusion will be 12 hours. Breastmilk, maternal serum and urine, side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and over 15 hours after infusion discontinuation. For the weaning population, they will receive a 12 hour infusion in the CTRC and stay an additional 12 hours in the CTRC (or until discharged). Breastmilk, maternal serum and urine, side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and for 12 hours after infusion discontinuation. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | mcg*min/mL | 12 hour ketamine infusion |
|
6 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ketamine | 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 Ketamine: Subjects in the intervention arm will receive bolus and infusion dosing as noted in arm/group descriptions at the time of cord clamping. Duration of infusion will be 12 hours. Breastmilk, maternal serum and urine, side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and over 15 hours after infusion discontinuation. For the weaning population, they will receive a 12 hour infusion in the CTRC and stay an additional 12 hours in the CTRC (or until discharged). Breastmilk, maternal serum and urine, side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and for 12 hours after infusion discontinuation. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Light Headedness | Investigations | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Grace Lim, MD, MSc | UPMC | 412-641-1110 | limkg2@upmc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 28, 2021 | Nov 23, 2022 | Prot_003.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Nov 20, 2022 | Nov 20, 2022 | SAP_004.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 27, 2021 | Nov 23, 2022 | ICF_005.pdf |
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| ID | Term |
|---|---|
| D048949 | Labor Pain |
| D019052 | Depression, Postpartum |
| D001942 | Breast Feeding |
| D059787 | Acute Pain |
| D059350 | Chronic Pain |
| ID | Term |
|---|---|
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D007649 | Ketamine |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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Prospective observational open-label trial (Part 1)
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|
| 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 |
| Pittsburgh |
| Pennsylvania |
| 15232 |
| United States |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Number of pregnancies | Median | Full Range | pregnancies |
|
| Parity | Parity is the number of times a person has given birth to a live neonate. | Median | Full Range | live births |
|
| Maternal Weight | Mean | Full Range | Kilograms (kg) |
|
|
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| Primary | Steady State (Css) | Ketamine steady state (Css) is defined as the concentration of drug in plasma at steady state. | Posted | Number | ng/mL | 12 hours after ketamine infusion start |
|
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | Minutes | 27 hours postpartum or 24 hour CTRC appointment for weaning population |
|
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | Liters | 27 hours postpartum or 24 hour CTRC appointment for weaning population |
|
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | Ratio | 27 hours postpartum or 24 hour CTRC appointment for weaning population |
|
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | Ratio | 27 hours postpartum or 24 hour CTRC appointment for weaning population |
|
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | Ratio | 27 hours postpartum or 24 hour CTRC appointment for weaning population |
|
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | % Maternal ketamine in breastmilk | 27 hours postpartum or 24 hour CTRC appointment for weaning population |
|
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | % maternal dose in breast milk | 27 hours postpartum or 24 hour CTRC appointment for weaning population |
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| 0 |
| 8 |
| 0 |
| 8 |
| 7 |
| 8 |
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| D011644 | Puerperal Disorders |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D005247 | Feeding Behavior |
| D001519 | Behavior |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |