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Minocycline Pharmacokinetics (ACUMIN)

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ClinicalTrials.gov Identifier: NCT03369951
Recruitment Status : Completed
First Posted : December 12, 2017
Results First Posted : August 27, 2020
Last Update Posted : August 27, 2020
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE December 7, 2017
First Posted Date  ICMJE December 12, 2017
Results First Submitted Date  ICMJE July 16, 2020
Results First Posted Date  ICMJE August 27, 2020
Last Update Posted Date August 27, 2020
Actual Study Start Date  ICMJE March 28, 2018
Actual Primary Completion Date July 20, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 13, 2020)
  • Calculated Exposure Measures for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose ]
    Total AUC0-24 is defined as area under the plasma minocycline concentration-time curve from 0 to 24 hours after a dose (milligrams x hours per liter (mg•hr/L)). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The AUC0-24 was calculated using numerical integration using the data from 0 to 24 hours post-dose.
  • Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Free-drug Concentrations [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Free-drug (unbound) AUC0-inf is defined as area under the plasma minocycline concentration-time curve from 0 to infinity after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate unbound concentration-time profiles. The AUC0-inf was calculated as Dose/CL.
  • Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Total-drug Concentrations [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Total AUC0-inf is defined as area under the plasma minocycline concentration-time curve from 0 to infinity after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The AUC0-inf was calculated as Dose/CL.
  • Calculated Exposure Measures for Area Under the Curve to the Last Quantifiable Sample (AUC0-last) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    AUC0-last is defined as the area under the plasma minocycline concentration-time curve from 0 to the time of the last quantifiable sample after a dose (mg•hr/L). This was not calculated for the primary outcome measure using the individual post-hoc PK parameters, however was calculated as part of the Non-compartmental analysis using the linear trapezoidal rule (linear up, log down calculation method).
  • Calculated Exposure Measures for Maximum Plasma Concentration (Cmax) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Total-drug Cmax is defined as the maximum plasma total minocycline concentration (mg/L) Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. Total Cmax was calculated for each simulated patient as the maximum simulated concentration.
  • Calculated Exposure Measures for Plasma Concentration at 24 Hours After Dose (C24) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose ]
    Total-drug C24 is defined as total plasma minocycline concentration at 24 hours after a dose (mg/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The total C24 were calculated for each simulated patient as the simulated concentration at 24 hours after dose.
  • Individual Post-hoc PK Parameter Estimates for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose ]
    Total AUC0-24 is defined as area under the plasma minocycline concentration-time curve from 0 to 24 hours after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The AUC0-24 was calculated for each individual using numerical integration using the data from 0 to 24 hours post-dose. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
  • Individual Post-hoc PK Parameter Estimates for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Free-drug Concentrations [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Free-drug (unbound) AUC0-inf is defined as area under the plasma minocycline concentration-time curve from 0 to infinity after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate unbound concentration-time profiles. The AUC0-inf was calculated for each individual as Dose/CL. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
  • Individual Post-hoc PK Parameter Estimates for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Total-drug Concentrations [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Total AUC0-inf is defined as area under the plasma minocycline concentration-time curve from 0 to infinity after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The AUC0-inf was calculated for each individual as Dose/CL. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
  • Individual Post-hoc PK Parameter Estimates for Area Under the Curve to the Last Quantifiable Sample (AUC0-last) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    AUC0-last is defined as the area under the plasma minocycline concentration-time curve from 0 to the time of the last quantifiable sample after a dose (mg•hr/L). This was not calculated of the primary outcome measure for the population PK model, however was calculated as part of the Non-compartmental analysis using the linear trapezoidal rule (linear up, log down calculation method).
  • Individual Post-hoc PK Parameter Estimates for Maximum Plasma Concentration (Cmax) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Total-drug Cmax is defined as the maximum plasma total minocycline concentration (mg/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The Individual post-hoc PK parameter estimate for total Cmax was calculated for each simulated patient as the maximum simulated concentration. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
  • Individual Post-hoc PK Parameter Estimates for Plasma Concentration at 24 Hours After Dose (C24) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose ]
    Total-drug C24 is defined as total Plasma minocycline concentration at 24 hours after a dose (mg/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The Individual post-hoc PK parameter estimates for the total C24 were calculated for each simulated patient as the simulated concentration at 24 hours after dose. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
  • Magnitude of the Inter-individual Variability for Central Volume of Distribution (Vc) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Vc was estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1. Magnitude of the inter-individual variability is expressed as percent coefficient of variation (%CV).
  • Magnitude of the Inter-individual Variability for Distribution Clearance (CLd) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    CLd was estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1. The standard error of the mean as fixed. Magnitude of the inter-individual variability is expressed as percent coefficient of variation (CV%).
  • Magnitude of the Inter-individual Variability for Free-drug Clearance (CL) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Unbound minocycline concentration is determined as the product of total minocycline concentrations and fub. Total minocycline concentrations and fub were estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. Magnitude of the inter-individual variability is expressed as percent coefficient of variation (%CV).
  • Magnitude of the Inter-individual Variability for Peripheral Volume of Distribution (Vp) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Vp was estimated from the structural two-compartment population PK model with constant fraction unbound (fub), which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
  • Magnitude of the Inter-individual Variability for Total-drug Clearance (CL) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    CL was estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1. Magnitude of the inter-individual variability is expressed as percent coefficient of variation (%CV).
  • Population Mean PK Parameter Estimates for Central Volume of Distribution (Vc) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Vc was estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
  • Population Mean PK Parameter Estimates for Distribution Clearance (CLd) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    CLd was estimated from the structural two-compartment population PK model with constant fraction unbound (fub), which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
  • Population Mean PK Parameter Estimates for Free-drug Clearance (CL) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Unbound minocycline concentration is determined as the product of total minocycline concentrations and fub. Total minocycline concentrations and fub were estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients.
  • Population Mean PK Parameter Estimates for Peripheral Volume of Distribution (Vp) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Vp was estimated from the structural two-compartment population PK model with constant fraction unbound (fub), which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
  • Population Mean PK Parameter Estimates for Total-drug Clearance (CL) [ Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose ]
    Total-drug clearance (CL) was estimated from the structural two-compartment population PK model with constant fraction unbound (fub), which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
Original Primary Outcome Measures  ICMJE
 (submitted: December 7, 2017)
  • Calculated Exposure Measures for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24) [ Time Frame: 0 to 24 hours ]
  • Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Free-drug Concentrations [ Time Frame: 0 to 48 hours ]
  • Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Total-drug Concentrations [ Time Frame: 0 to 48 hours ]
  • Calculated Exposure Measures for Area Under the Curve to the Last Quantifiable Sample (AUC0-last) [ Time Frame: 0 to 48 hours ]
  • Calculated Exposure Measures for Maximum Plasma Concentration (Cmax) [ Time Frame: 0 to 48 hours ]
  • Calculated Exposure Measures for Plasma Concentration at 24 Hours After Dose (C24) [ Time Frame: 24 hours ]
  • Individual Post-hoc PK Parameter Estimates for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24) [ Time Frame: 0 to 24 hours ]
  • Individual Post-hoc PK Parameter Estimates for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Free-drug Concentrations [ Time Frame: 0 to 48 hours ]
  • Individual Post-hoc PK Parameter Estimates for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Total-drug Concentrations [ Time Frame: 0 to 48 hours ]
  • Individual Post-hoc PK Parameter Estimates for Area Under the Curve to the Last Quantifiable Sample (AUC0-last) [ Time Frame: 0 to 48 hours ]
  • Individual Post-hoc PK Parameter Estimates for Maximum Plasma Concentration (Cmax) [ Time Frame: 0 to 48 hours ]
  • Individual Post-hoc PK Parameter Estimates for Plasma Concentration at 24 Hours After Dose (C24) [ Time Frame: 24 hours ]
  • Magnitude of the Inter-individual Variability for Central Volume of Distribution (Vc) [ Time Frame: 0 to 48 hours ]
  • Magnitude of the Inter-individual Variability for Distribution Clearance (CLd) [ Time Frame: 0 to 48 hours ]
  • Magnitude of the Inter-individual Variability for Free-drug Clearance (CL) [ Time Frame: 0 to 48 hours ]
  • Magnitude of the Inter-individual Variability for Peripheral Volume of Distribution (Vp) [ Time Frame: 0 to 48 hours ]
  • Magnitude of the Inter-individual Variability for Total-drug Clearance (CL) [ Time Frame: 0 to 48 hours ]
  • Population Mean PK Parameter Estimates for Central Volume of Distribution (Vc) [ Time Frame: 0 to 48 hours ]
  • Population Mean PK Parameter Estimates for Distribution Clearance (CLd) [ Time Frame: 0 to 48 hours ]
  • Population Mean PK Parameter Estimates for Free-drug Clearance (CL) [ Time Frame: 0 to 48 hours ]
  • Population Mean PK Parameter Estimates for Peripheral Volume of Distribution (Vp) [ Time Frame: 0 to 48 hours ]
  • Population Mean PK Parameter Estimates for Total-drug Clearance (CL) [ Time Frame: 0 to 48 hours ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Minocycline Pharmacokinetics (ACUMIN)
Official Title  ICMJE A Phase IV Open-Label Pharmacokinetic Study of Minocycline for Injection Following a Single Infusion in Critically-Ill Adults (ACUMIN)
Brief Summary This is a Phase IV, multi-center open-label pharmacokinetic trial studying the pharmacokinetics and pharmacodynamics of a single dose of Minocin IV. Up to 67 subjects will be enrolled to obtain 50 evaluable, ICU patients who are already receiving antimicrobial therapy for a known or suspected Gram-negative infection. The entire study duration will be approximately 16 months and each subject participation duration will be approximately 2 days. The study will be conducted at approximately 13 clinical sites. Each subject will receive a single 200 mg dose of Minocin IV infused over approximately 60 minutes. Each subject will have 7 PK samples collected (1 pre-dose, 6 post-dose) at designated time points over a ~48 hour period following the start of the Minocin IV infusion. The primary objectives are: 1) To characterize minocycline PK at the population level in critically-ill adults, with illness known or suspected to be caused by infection with Gram-negative bacteria and 2) To assess patient-level and clinical covariates associated with minocycline pharmacokinetic properties in critically-ill adults, with illness known or suspected to be caused by infection with Gram-negative bacteria.
Detailed Description This is a Phase IV, multi-center open-label pharmacokinetic trial studying the pharmacokinetics and pharmacodynamics of a single dose of Minocin IV. Up to 67 subjects will be enrolled to obtain 50 evaluable, ICU patients who are already receiving antimicrobial therapy for a known or suspected Gram-negative infection. The entire study duration will be approximately 16 months and each subject participation duration will be approximately 2 days. The study will be conducted at approximately 13 clinical sites. Each subject will receive a single 200 mg dose of Minocin IV infused over approximately 60 minutes. Each subject will have 7 PK samples collected (1 pre-dose, 6 post-dose) at designated time points over a ~48 hour period following the start of the Minocin IV infusion. The primary objectives are: 1) To characterize minocycline PK at the population level in critically-ill adults, with illness known or suspected to be caused by infection with Gram-negative bacteria and 2) To assess patient-level and clinical covariates associated with minocycline pharmacokinetic properties in critically-ill adults, with illness known or suspected to be caused by infection with Gram-negative bacteria. Up to 67 subjects will be enrolled in order to obtain 50 PK evaluable subjects in the study. To be considered PK evaluable, a subject must receive the full infusion of study drug, and is required to have at least 3 PK samples collected in the first 12 hours post dose and at least 1 PK sample collected 24-48 hours post dose. Subjects who are dosed with minocycline but do not meet this PK sampling requirement will still be included in the population PK analysis, but an additional subject will be enrolled as a replacement to meet the goal of having 50 PK evaluable subjects with intensive PK sampling.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Bacterial Infection
Intervention  ICMJE Drug: Minocycline
Minocycline is a semisynthetic derivative of tetracycline and is indicated for the treatment of infections due to susceptible isolates of designated microorganisms.
Study Arms  ICMJE Experimental: Minocin® IV
200 mg minocycline hydrochloride IV infusion over approximately 60 minutes, n=50
Intervention: Drug: Minocycline
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 Completed
Actual Enrollment  ICMJE
 (submitted: August 15, 2019)
58
Original Estimated Enrollment  ICMJE
 (submitted: December 7, 2017)
67
Actual Study Completion Date  ICMJE July 20, 2019
Actual Primary Completion Date July 20, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female > / = 18 years of age.
  2. Subject is in the ICU, or is being admitted to the ICU.
  3. Known or suspected Gram-negative infection for which the subject is receiving systemic antibiotics, and which was the reason for admission to the ICU, or reason for persistent need for ICU care.
  4. Expectation, in the judgment of the investigator, that the subject will remain admitted in the hospital for at least 48 hours following enrollment and that all study procedures will be completed.
  5. Expectation that intravenous access will be sufficient for drug infusion and either intravenous or arterial access will be sufficient to allow for all protocol required blood sampling to occur.
  6. The subject, or legally authorized representative (LAR), is able and willing to provide signed informed consent.

Exclusion Criteria:

  1. History of significant hypersensitivity or allergic reaction to tetracycline antibiotics.
  2. Receipt of oral or intravenous tetracycline class drugs within 7 days of enrollment (e.g., minocycline, tetracycline, tigecycline, doxycycline).
  3. Use of isotretinoin within 2 weeks of enrollment into the study.
  4. Major surgery* within 48 hours prior to enrollment.

    *Major surgery is defined as "the opening of either a body cavity or the mesenchymal barrier, using general anesthesia".

  5. Pregnant or breastfeeding women.
  6. Patient is being treated for intracranial hypertension.
  7. Any condition that, in the judgment of the investigator, precludes participation because it could affect subject safety.*

    *Subjects on, or who may be considered for Renal Replacement Therapy (RRT) during the study period are not excluded from participating in the study.

  8. Receipt of an investigational study product within 7 days prior to enrollment. Investigator discretion should be used when longer acting agents have been used in the previous 30 days.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03369951
Other Study ID Numbers  ICMJE 16-0011
2UM1AI104681-08 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
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 Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date December 4, 2017

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