Study Evaluating the Pharmacokinetics (PK), Safety, and Tolerability of Tigecycline in Patients 8 to 11 Years of Age

Study Overview
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Brief Summary
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To determine the pharmacokinetic profile and to evaluate the safety and tolerability of ascending multiple doses of tigecycline in patients aged 8 to 11 years with selected serious infections; complicated intra-abdominal infections (cIAI), complicated skin and skin structure infections (cSSSI), or community-acquired pneumonia (CAP).

Official Title
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A Multicenter, Open-Label, Ascending Multiple-Dose Study to Assess the Pharmacokinetics, Safety, and Tolerability of Tigecycline in Patients 8 to 11 Years of Age With Selected Serious Infections

Conditions
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Intra-Abdominal Infection, Bacterial Infections, Pneumonia, Bacterial, Skin Diseases, Bacterial, Skin Diseases, Infectious

Intervention / Treatment
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* Drug: Tygacil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female patients aged 8 to 11 years, inclusive, willing and able to complete all activities required for the study Have a diagnosis of a serious infection (cIAI, cSSSI or CAP) requiring hospitalization and administration of IV antibiotic therapy during greater than or equal to 5 days Other inclusion criteria apply. Exclusion criteria Patients with any concomitant condition or taking any concomitant medication that, in the opinion of the investigator, could preclude an evaluation of safety or efficacy responses or make it unlikely that the anticipated course of therapy or follow-up assessment will be completed (e.g., life expectancy < 30 days). Pregnant or breastfeeding female patients and female patients of childbearing potential who are unable or unwilling to take adequate contraceptive precautions. Previous participation in this clinical trial. Receipt of any investigational drugs or devices (defined as lacking any regulatory agency's approval within 4 weeks before administration of the first dose of tigecycline). Endocarditis; presence of an artificial heart valve or infected device that will not be removed. Known or suspected hypersensitivity to tigecycline or other compounds related to this class of antibacterial agents (i.e., tetracyclines). Known or suspected P. aeruginosa infection. Patients receiving immunosuppressive therapy that, in the opinion of the investigator, would decrease the patient's ability to eradicate the infection, including the use of high-dose corticosteroid. Receipt of an organ or bone marrow transplant. Presence of any of the following laboratory findings: Neutropenia (absolute neutrophil count < 1 × 109/L [< 1000/mm3]) , AST or ALT > 10 × the ULN or bilirubin > 3 × ULN, unless isolated hyperbilirubinemia is directly related to the acute process (for patients with cIAI). Patients with any of the following conditions: Cystic fibrosis. Active tuberculosis. Congenital immunodeficiency. Meningitis. Septic shock. Osteomyelitis (suspected or evident). Refractory shock syndrome in which hemodynamic parameters cannot be maintained despite adequate supportive therapy. Confirmed malignancy with patient receiving an active course of chemotherapeutic agents. Known or suspected infection with human immunodeficiency virus (HIV) or positive test result for HIV antibody. Known or suspected concomitant bacterial or parasitic infection requiring systemic treatment. cSSSI patients, the presence of decubitus ulcers, necrotizing fasciitis, gas gangrene, or skeletal infection; CAP patients who have been hospitalized within 14 days before the onset of symptoms; CAP Patients: Presence of any of the following for patients with pneumonia: Postobstructive pneumonia. Pulmonary abscess. Empyema. Known or suspected pulmonary infection with Pneumocystis carinii.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>0.75 mg/kg (up to a maximum dose of 50 mg for each dose) of tigecycline every 12 hours infused over approximately 30 minutes. Escalation to next dose cohort will occur only after safety and tolerability at preceding dose have been established by sponsor (after tigecycline LDOT data are received) and if at least 5 of 6 PK samples per patient have been received by central laboratory in acceptable condition for 10 to 12 patients in cohort. Treatment period of tigecycline will be a minimum of 3 days (unless patient is considered a treatment failure before this time) and a maximum of 14 days. On or after Day 4, based on investigator's decision, patients can switch to oral antibiotic therapy (to be chosen and provided by the investigator) and discharged after collection of planned PK samples. | Drug: Tygacil<br> <br> |
| Experimental: B<br>1 mg/kg (up to a maximum dose of 50 mg for each dose) of tigecycline every 12 hours infused over approximately 30 minutes. Escalation to next dose cohort will occur only after safety and tolerability at preceding dose have been established by sponsor (after tigecycline LDOT data are received) and if at least 5 of 6 PK samples per patient have been received by the central laboratory in acceptable condition for 10 to 12 patients in the cohort. Treatment period of tigecycline will be a minimum of 3 days (unless the patient is considered a treatment failure before this time) and a maximum of 14 days. On or after Day 4, based on investigator's decision, patients can switch to oral antibiotic therapy (to be chosen and provided by the investigator) and discharged after collection of planned PK samples. | Drug: Tygacil<br> <br> |
| Experimental: C<br>1.25 mg/kg (up to maximum dose of 50 mg for each dose) of tigecycline every 12 hours infused over approximately 30 minutes. Treatment period of tigecycline will be a minimum of 3 days (unless patient is considered a treatment failure before this time) and a maximum of 14 days. On or after Day 4, based on investigator's decision, patients can switch to oral antibiotic therapy (to be chosen and provided by the investigator) and discharged after collection of planned PK samples. | Drug: Tygacil<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) | Cmax: tigecycline serum concentration measured in nanograms per milliliter (ng/mL) determined by a validated liquid chromatography with mass spectrophotometric (LC/MS/MS) detection method. Peak concentration was taken directly from the observed data. | Day 3 (immediately post-dose, 0.75, and 2 hours post-dose) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Time of peak concentration taken directly from the observed data. | Day 3 (immediately post-dose, 0.75, and 2 hours post-dose) | 
| Area Under the Curve (AUCτ) From Time Zero to Time of Estimated Concentration at 12 Hours | AUCτ: AUC between doses from time zero to the time of estimated concentration at 12 hours reported in nanograms * hours divided by milliliters (ng*h/mL) was calculated using the log-trapezoidal rule for decreasing concentrations and the linear-trapezoidal rule for increasing concentrations estimating the 12 hour drug concentration if necessary. | Day 3 (just before and immediately after infusion, and 0.75, 2, and 6 hours post-dose) | 
| Weight Normalized Drug Clearance (CLW) | Weight normalized drug clearance measured in liters per hour per kilogram (L/hr/kg). Drug clearance (CL) was determined as the ratio of dose/area under the concentration-time curve from time zero (start of infusion) to 12 hours (start of next infusion) (AUCτ). CLW was determined as the ratio of CL/weight. | Day 3 (just before and immediately after infusion, and 0.75, 2, and 6 hours post-dose) | 
| Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | CR = Cure: resolution of all signs, symptoms (SS) of infection (INF) or improvement, no further antibacterial therapy (AT) necessary; Improved (IMP): SS IMP to extent that switch to oral AT deemed appropriate; Failure: lack of response, required additional AT, initial recovery then deterioration requiring further AT, death due to the INF after day 2, death due to treatment (TR)-related adverse event (AE), required non-routine surgical TR >48 hours after 1st dose of TR due to failure to IMP or clinical worsening. TOC = CR, vital signs, physical exam, laboratory results, concomitant TR, and AEs. | Day 14 or LDOT, TOC Visit (10 to 21 days after last dose of total antibiotic therapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Population Pharmacokinetic (PK) Model: Volume of Distribution | Two compartment model with linear clearance and effect of weight on clearance using pooled PK data from 2 pediatric studies. All concentration-time data were combined and analyzed using population PK methods to investigate potential influence of age, weight, and height (dose, tigecycline concentrations, times, subject weight, height, age, body surface area, serum creatinine, estimated creatinine clearance, serum bilirubin. | 3074K4-2207: Day 3 just before and immediately after infusion, and 0.75, 2, and 6 hours post-dose; 3074A1-110: just before and 0.5, 0.75, 1, 2, 3, 4, 8, 12, 24, 36, and 48 hours after start of infusion | 
| Population Pharmacokinetic (PK) Model: Clearance | Two compartment model with linear clearance and effect of weight on clearance using pooled PK data from 2 pediatric studies. All concentration-time data were combined and analyzed using population PK methods to investigate potential influence of age, weight, and height (dose, tigecycline concentrations, times, subject weight, height, age, body surface area, serum creatinine, estimated creatinine clearance, serum bilirubin. | 3074K4-2207: Day 3 just before and immediately after infusion, and 0.75, 2, and 6 hours post-dose; 3074A1-110: just before and 0.5, 0.75, 1, 2, 3, 4, 8, 12, 24, 36, and 48 hours after start of infusion | 
| Population Pharmacokinetic (PK) Model: Effect of Weight | Two compartment model with linear clearance and effect of weight on clearance using pooled PK data from 2 pediatric studies. All concentration-time data were combined and analyzed using population PK methods to investigate potential influence of age, weight, and height (dose, tigecycline concentrations, times, subject weight, height, age, body surface area, serum creatinine, estimated creatinine clearance, serum bilirubin. | 3074K4-2207: Day 3 just before and immediately after infusion, and 0.75, 2, and 6 hours post-dose; 3074A1-110: just before and 0.5, 0.75, 1, 2, 3, 4, 8, 12, 24, 36, and 48 hours after start of infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cIAI, cSSSI, CAP, Child