Clinical trial NCT03369951: Minocycline Pharmacokinetics (ACUMIN)
Official title: A Phase IV Open-Label Pharmacokinetic Study of Minocycline for Injection Following a Single Infusion in Critically-Ill Adults (ACUMIN)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Bacterial Infection
Keywords: ACUMIN
Infusion
Injection
Minocycline
Pharmacokinetic
PK
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2017-12-12
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Calculated Exposure Measures for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
measure: Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Free-drug Concentrations
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Total-drug Concentrations
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Calculated Exposure Measures for Area Under the Curve to the Last Quantifiable Sample (AUC0-last)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Calculated Exposure Measures for Maximum Plasma Concentration (Cmax)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Calculated Exposure Measures for Plasma Concentration at 24 Hours After Dose (C24)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
measure: Individual Post-hoc PK Parameter Estimates for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
measure: Individual Post-hoc PK Parameter Estimates for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Free-drug Concentrations
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Individual Post-hoc PK Parameter Estimates for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Total-drug Concentrations
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Individual Post-hoc PK Parameter Estimates for Area Under the Curve to the Last Quantifiable Sample (AUC0-last)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Individual Post-hoc PK Parameter Estimates for Maximum Plasma Concentration (Cmax)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Individual Post-hoc PK Parameter Estimates for Plasma Concentration at 24 Hours After Dose (C24)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
measure: Magnitude of the Inter-individual Variability for Central Volume of Distribution (Vc)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Magnitude of the Inter-individual Variability for Distribution Clearance (CLd)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Magnitude of the Inter-individual Variability for Free-drug Clearance (CL)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Magnitude of the Inter-individual Variability for Peripheral Volume of Distribution (Vp)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Magnitude of the Inter-individual Variability for Total-drug Clearance (CL)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Population Mean PK Parameter Estimates for Central Volume of Distribution (Vc)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Population Mean PK Parameter Estimates for Distribution Clearance (CLd)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Population Mean PK Parameter Estimates for Free-drug Clearance (CL)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Population Mean PK Parameter Estimates for Peripheral Volume of Distribution (Vp)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
measure: Population Mean PK Parameter Estimates for Total-drug Clearance (CL)
timeFrame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Secondary outcomes:
Other outcomes:
Locations:
city: Decatur
country: United States
facility: Emory Decatur Hospital - Clinical Trials - Immunology/Infectious Disease
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital - ICU
state: Illinois
city: Chicago
country: United States
facility: Northwestern Medicine - Department of Obstetrics and Gynecology - Division of Female Pelvic Medicine and Reconstructive Surgery
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky - UK Albert B Chandler Hospital
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville School of Medicine - Surgery
state: Kentucky
city: Detroit
country: United States
facility: Henry Ford Health System - Henry Ford Hospital
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital - Royal Oak Campus - Infectious Disease
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis - Infectious Diseases
state: Missouri
city: Durham
country: United States
facility: Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit
state: North Carolina
city: Durham
country: United States
facility: Duke University Hospital - Duke Medicine Pavilion - MICU
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University - Infectious Diseases and Tropical/Travel Medicine Clinic
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati College of Medicine - Division of Infectious Diseases
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University School of Medicine - Medicine - Infectious Diseases and HIV Medicine
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University - Division of Pulmonary and Critical Care Medicine
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh - Medicine - Infectious Diseases
state: Pennsylvania
Study officials:
References: