Bacterial Infections, Intra-Abdominal Infection, Pneumonia, Bacterial, Skin Diseases, Bacterial, Skin Diseases, Infectious
Conditions
Keywords
cIAI, cSSSI, CAP, Child
Brief summary
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).
Interventions
DRUGTygacil
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to 11 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Day 14 or LDOT, TOC Visit (10 to 21 days after last dose of total antibiotic therapy) | 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. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Day 3 (immediately post-dose, 0.75, and 2 hours post-dose) | Time of peak concentration taken directly from the observed data. |
| Area Under the Curve (AUCτ) From Time Zero to Time of Estimated Concentration at 12 Hours | Day 3 (just before and immediately after infusion, and 0.75, 2, and 6 hours post-dose) | 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. |
| Weight Normalized Drug Clearance (CLW) | Day 3 (just before and immediately after infusion, and 0.75, 2, and 6 hours post-dose) | 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. |
| Maximum Observed Plasma Concentration (Cmax) | Day 3 (immediately post-dose, 0.75, and 2 hours post-dose) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Population Pharmacokinetic (PK) Model: Clearance | 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 | 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. |
| Population Pharmacokinetic (PK) Model: Effect of Weight | 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 | 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. |
| Population Pharmacokinetic (PK) Model: Volume of Distribution | 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 | 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. |
Countries
Belgium, Mexico, South Africa, Taiwan, Ukraine, United States
Participant flow
Pre-assignment details
Fifty-nine participants were screened and enrolled in the study, and 58 participants received at least 1 dose of tigecycline.
Participants by arm
| Arm | Count |
|---|---|
| Tigecycline 0.75 mg/kg 0.75 milligram per kilogram (mg/kg) intravenous (IV) infusion every 12 hours | 17 |
| Tigecycline 1 mg/kg 1 milligram per kilogram (mg/kg) IV infusion every 12 hours | 21 |
| Tigecycline 1.25 mg/kg 1.25 milligram per kilogram (mg/kg) IV infusion every 12 hours | 20 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 |
| Overall Study | Institutional Review Board review | 0 | 0 | 1 |
| Overall Study | Parent/legal guardian request | 0 | 1 | 1 |
| Overall Study | Surgical team recommendation | 0 | 1 | 0 |
| Overall Study | Unable to administer antibiotics at home | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Tigecycline 1.25 mg/kg | Total | Tigecycline 0.75 mg/kg | Tigecycline 1 mg/kg |
|---|---|---|---|---|
| Age Continuous | 9.72 years STANDARD_DEVIATION 0.94 | 10.04 years STANDARD_DEVIATION 1.05 | 10.21 years STANDARD_DEVIATION 1.15 | 10.20 years STANDARD_DEVIATION 1.06 |
| Selected Serious Infections Community Acquired Pneumonia | 4 participants | 19 participants | 7 participants | 8 participants |
| Selected Serious Infections Complicated Intra-abdominal Infection | 12 participants | 24 participants | 6 participants | 6 participants |
| Selected Serious Infections Complicated Skin and Skin Structure Infection | 4 participants | 15 participants | 4 participants | 7 participants |
| Sex: Female, Male Female | 8 Participants | 27 Participants | 9 Participants | 10 Participants |
| Sex: Female, Male Male | 12 Participants | 31 Participants | 8 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 17 | 16 / 21 | 17 / 20 |
| serious Total, serious adverse events | 1 / 17 | 1 / 21 | 1 / 20 |
Outcome results
Primary
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.
Time frame: Day 3 (just before and immediately after infusion, and 0.75, 2, and 6 hours post-dose)
Population: mITT; N = number of participants with sufficient reported tigecycline concentration data to estimate AUC.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tigecycline 0.75 mg/kg | Area Under the Curve (AUCτ) From Time Zero to Time of Estimated Concentration at 12 Hours | 1650 ng*h/mL | Standard Deviation 529 |
| Tigecycline 1 mg/kg | Area Under the Curve (AUCτ) From Time Zero to Time of Estimated Concentration at 12 Hours | 2557 ng*h/mL | Standard Deviation 1196 |
| Tigecycline 1.25 mg/kg | Area Under the Curve (AUCτ) From Time Zero to Time of Estimated Concentration at 12 Hours | 3196 ng*h/mL | Standard Deviation 1704 |
Primary
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.
Time frame: Day 3 (immediately post-dose, 0.75, and 2 hours post-dose)
Population: Modified intent to treat (mITT) population: participants who were screened, assigned to study medication and received at least one dose of study medication. N = number of participants with evaluable tigecycline concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tigecycline 0.75 mg/kg | Maximum Observed Plasma Concentration (Cmax) | 456 ng/mL | Standard Deviation 347 |
| Tigecycline 1 mg/kg | Maximum Observed Plasma Concentration (Cmax) | 1515 ng/mL | Standard Deviation 1457 |
| Tigecycline 1.25 mg/kg | Maximum Observed Plasma Concentration (Cmax) | 2599 ng/mL | Standard Deviation 3643 |
Primary
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.
Time frame: Day 14 or LDOT, TOC Visit (10 to 21 days after last dose of total antibiotic therapy)
Population: mITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tigecycline 0.75 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Improved: LDOT | 17.6 percentage of participants |
| Tigecycline 0.75 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Cure: TOC | 94.1 percentage of participants |
| Tigecycline 0.75 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Indeterminate: LDOT | 0.0 percentage of participants |
| Tigecycline 0.75 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Cure: LDOT | 82.4 percentage of participants |
| Tigecycline 0.75 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Indeterminate: TOC | 0.0 percentage of participants |
| Tigecycline 0.75 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Failure: TOC | 5.9 percentage of participants |
| Tigecycline 0.75 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Failure: LDOT | 0.0 percentage of participants |
| Tigecycline 1 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Indeterminate: LDOT | 19.0 percentage of participants |
| Tigecycline 1 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Cure: LDOT | 52.4 percentage of participants |
| Tigecycline 1 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Improved: LDOT | 28.6 percentage of participants |
| Tigecycline 1 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Failure: LDOT | 0.0 percentage of participants |
| Tigecycline 1 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Cure: TOC | 76.2 percentage of participants |
| Tigecycline 1 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Failure: TOC | 4.8 percentage of participants |
| Tigecycline 1 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Indeterminate: TOC | 19.0 percentage of participants |
| Tigecycline 1.25 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Cure: TOC | 75.0 percentage of participants |
| Tigecycline 1.25 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Improved: LDOT | 55.0 percentage of participants |
| Tigecycline 1.25 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Indeterminate: TOC | 15.0 percentage of participants |
| Tigecycline 1.25 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Failure: TOC | 10.0 percentage of participants |
| Tigecycline 1.25 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Indeterminate: LDOT | 15.0 percentage of participants |
| Tigecycline 1.25 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Failure: LDOT | 0.0 percentage of participants |
| Tigecycline 1.25 mg/kg | Percentage of Participants With Clinical Response (CR) to Tigecycline at Last Day of Therapy (LDOT) and Test-of-Cure (TOC) Assessment | Cure: LDOT | 30.0 percentage of participants |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time of peak concentration taken directly from the observed data.
Time frame: Day 3 (immediately post-dose, 0.75, and 2 hours post-dose)
Population: mITT; N = number of participants with evaluable tigecycline concentration data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tigecycline 0.75 mg/kg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0.6 hours | Standard Deviation 0.2 |
| Tigecycline 1 mg/kg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0.5 hours | Standard Deviation 0.1 |
| Tigecycline 1.25 mg/kg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0.8 hours | Standard Deviation 0.6 |
Primary
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.
Time frame: Day 3 (just before and immediately after infusion, and 0.75, 2, and 6 hours post-dose)
Population: mITT; N = number of participants with sufficient reported tigecycline concentration data to estimate AUC.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tigecycline 0.75 mg/kg | Weight Normalized Drug Clearance (CLW) | 0.490 L/hr/kg | Standard Deviation 0.13 |
| Tigecycline 1 mg/kg | Weight Normalized Drug Clearance (CLW) | 0.498 L/hr/kg | Standard Deviation 0.335 |
| Tigecycline 1.25 mg/kg | Weight Normalized Drug Clearance (CLW) | 0.528 L/hr/kg | Standard Deviation 0.384 |
Secondary
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.
Time frame: 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: Separate population pharmacokinetic analysis results are not available for the current study as more than 1 study was involved in this analysis based on pooled data from pediatric studies 3074A1-110 and 3074K4-2207.
Secondary
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.
Time frame: 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: Separate population pharmacokinetic analysis results are not available for the current study as more than 1 study was involved in this analysis based on pooled data from pediatric studies 3074A1-110 and 3074K4-2207.
Secondary
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.
Time frame: 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: Separate population pharmacokinetic analysis results are not available for the current study as more than 1 study was involved in this analysis based on pooled data from pediatric studies 3074A1-110 and 3074K4-2207.