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| Name | Class |
|---|---|
| Instituto Mexicano del Seguro Social | OTHER_GOV |
| Hospital Infantil de Mexico Federico Gomez | OTHER |
| Hospital Regional de Alta Especialidad del Bajio | OTHER |
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This study evaluates the efficacy and safety of the administration of betalactam antibiotics in prolonged infusion compared to intermittent infusion in children with sepsis. Half of participants will receive piperacillin/tazobactam, imipenem or meropenem in continuous or extended infusion, while the other half will receive piperacillin/tazobactam, imipenem or meropenem in intermittent infusion.
Sepsis is the leading cause of morbidity and mortality in hospitalised patients globally. Betalactams are time-dependent antibiotics, and so, the duration of time for which the free drug plasma concentration remains above the minimum inhibitory concentration (fT > MIC) is the pharmacokinetic/pharmacodynamic index associated with bacterial killing and clinical improvement. Numerous studies have demonstrated that continuous infusion (infusion in 24 hours) and extended infusion (through prolonging the infusion time to greater than 3 hours) allows the maintenance of concentrations above the MIC for a longer period of time within the dosing interval (30 minute or 1 hour), and so, capitalises on the pharmacodynamic properties of betalactams and maximises bacterial killing, therefore potentially improving clinical outcomes. In adult patients, the several studies suggest that prolonged infusion may offer clinical benefits and significant reduction in mortality without increasing the risk of toxicity, however, there is limited information about these dosing strategies in pediatric patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intermittent Piperacillin/tazobactam | Active Comparator | Piperacillin/tazobactam 300mg/kg/day, divided into 4 doses/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 30 minutes infusion every 6 hours. |
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| Continuous Piperacillin/tazobactam | Experimental | Piperacillin/tazobactam initial doses 75mg/kg in 30 minutes infusion, immediately thereafter continue 300mg/kg/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 24 hours infusion every 24 hours, as determined by antibiotic stability at room temperature. |
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| Intermittent Imipenem | Active Comparator | Imipenem 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes infusion every 6 hours. |
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| Extended Imipenem | Experimental | Imipenem initial doses 20mg/kg in 60 minutes infusion, immediately thereafter continue 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 6 hours infusion every 6 hours, as determined by antibiotic stability at room temperature. |
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| Intermittent Meropenem |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intermittent Piperacillin/tazobactam | Drug | Piperacillin/tazobactam administered in 30 minutes infusion. |
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| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Clinical Response | Resolution. Disappearance of all signs and symptoms related to the infection. Failure. Insufficient lessening of the signs and symptoms of infection to qualify as improvement, including death or indeterminate (no evaluation possible, for any reason). | Number of participants with clinical response at 14 days after antibiotic cessation, up to an average of 28 days or the day of your discharge if this occurred before 14 days after antibiotic cessation. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Adverse Events | Any harmful, undesirable, potentially serious and life threatening effects occurring during or after administration of the antibiotics proposed in this study (piperacillin / tazobactam, imipenem or meropenem), was evaluated as: none or adverse event classified according to the intensity of the clinical manifestation (severity) as: mild, moderate or severe and for each antibiotic. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| YazmÃn del Carmen Fuentes | Instituto Mexicano del Seguro Social | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Infantil de México Federico Gómez | Mexico City | Mexico City | 06720 | Mexico | ||
| Instituto Mexicano del Seguro Social |
Identified individual participant data for all primary and secondary outcome measures will be made available within six months of study completion
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the pre-specified intent was to only compare "Intermittent" and "Prolonged" Arm/Groups with the grouping of betalactam antibiotics (imipenem, meropenem and piperacillin/tazobactam)
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| ID | Title | Description |
|---|---|---|
| FG000 | Intermittent. Piperacillin/Tazobactam, Imipenem, Meropenem | Piperacillin/tazobactam 300mg/kg/day, divided into 4 doses/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 30 minutes infusion every 6 hours. Intermittent Piperacillin/tazobactam: Piperacillin/tazobactam administered in 30 minutes infusion. Imipenem 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes infusion every 6 hours. Intermittent Imipenem: Imipenem administered in 60 minutes infusion. Meropenem 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes every 8 hours. Intermittent Meropenem: Meropenem administered in 60 minutes infusion. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 20, 2020 |
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Open Label
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| Active Comparator |
Meropenem 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes every 8 hours. |
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| Extended Meropenem | Experimental | Meropenem initial doses 35mg/kg in 60 minutes infusion, immediately thereafter continue 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution at a concentration of 7mg/ml, to be administered in 8 hours infusion every 8 hours, as determined by antibiotic stability at room temperature. |
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| Continuous Piperacillin/tazobactam | Drug | Piperacillin/tazobactam administered in 24 hours infusion. |
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| Intermittent Imipenem | Drug | Imipenem administered in 60 minutes infusion. |
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| Extended Imipenem | Drug | Imipenem administered in 6 hours infusion. |
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| Intermittent Meropenem | Drug | Meropenem administered in 60 minutes infusion. |
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| Extended Meropenem | Drug | Meropenem administered in 8 hours infusion. |
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| Number of participants with adverse events evaluated by an physician at the time of administration of antibiotics, up to an average to 24 hours after the study drug cessation. |
| Mexico City |
| Mexico City |
| 06720 |
| Mexico |
| FG001 | Prolonged Infusion. Continuous Piperacillin/Tazobactam, Extended Imipenem, Extended Meropenem | Piperacillin/tazobactam initial doses 75mg/kg in 30 minutes infusion, immediately thereafter continue 300mg/kg/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 24 hours infusion every 24 hours, as determined by antibiotic stability at room temperature. Continuous Piperacillin/tazobactam: Piperacillin/tazobactam administered in 24 hours infusion. Imipenem initial doses 20mg/kg in 60 minutes infusion, immediately thereafter continue 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 6 hours infusion every 6 hours, as determined by antibiotic stability at room temperature. Extended Imipenem: Imipenem administered in 6 hours infusion. Meropenem initial doses 35mg/kg in 60 minutes infusion, immediately thereafter continue 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution at a concentration of 7mg/ml, to be administered in 8 hours infusion every 8 hours, as determined by antibiotic stability at room temperature. Extended Meropenem: Meropenem administered in 8 hours infusion. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Intermittent. Piperacillin/Tazobactam, Imipenem, Meropenem | Piperacillin/tazobactam 300mg/kg/day, divided into 4 doses/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 30 minutes infusion every 6 hours. Intermittent Piperacillin/tazobactam: Piperacillin/tazobactam administered in 30 minutes infusion. Imipenem 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes infusion every 6 hours. Intermittent Imipenem: Imipenem administered in 60 minutes infusion. Meropenem 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes every 8 hours. Intermittent Meropenem: Meropenem administered in 60 minutes infusion. |
| BG001 | Prolonged Infusion. Continuous Piperacillin/Tazobactam, Extended Imipenem, Extended Meropenem | Piperacillin/tazobactam initial doses 75mg/kg in 30 minutes infusion, immediately thereafter continue 300mg/kg/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 24 hours infusion every 24 hours, as determined by antibiotic stability at room temperature. Continuous Piperacillin/tazobactam: Piperacillin/tazobactam administered in 24 hours infusion. Imipenem initial doses 20mg/kg in 60 minutes infusion, immediately thereafter continue 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 6 hours infusion every 6 hours, as determined by antibiotic stability at room temperature. Extended Imipenem: Imipenem administered in 6 hours infusion. Meropenem initial doses 35mg/kg in 60 minutes infusion, immediately thereafter continue 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution at a concentration of 7mg/ml, to be administered in 8 hours infusion every 8 hours, as determined by antibiotic stability at room temperature. Extended Meropenem: Meropenem administered in 8 hours infusion. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Median | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Comorbidity | Count of Participants | Participants |
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| Comorbid conditions | Comorbidity only was in 196 patients in intermittent infusion group and 187 patients in prolonged infusion group. | Count of Participants | Participants |
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| Hospital stay prior to enrollment to the study protocol | number of participants who had been hospitalized for at least 24 hours prior to enrollment to the study protocol | Count of Participants | Participants |
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| septic shock at enrollment | Count of Participants | Participants |
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| B-lactam antibiotic | Count of Participants | Participants |
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| type of infection | Count of Participants | Participants |
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| Number of participants with organisms identified | Count of Participants | Participants |
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| 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Number of Participants With Clinical Response | Resolution. Disappearance of all signs and symptoms related to the infection. Failure. Insufficient lessening of the signs and symptoms of infection to qualify as improvement, including death or indeterminate (no evaluation possible, for any reason). | The efficacy of the maneuver was evaluated by frequency of clinical response and calculation of the absolute risk reduction and the number needed to treat. | Posted | Count of Participants | Participants | Number of participants with clinical response at 14 days after antibiotic cessation, up to an average of 28 days or the day of your discharge if this occurred before 14 days after antibiotic cessation. |
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| Secondary | Number of Participants With Adverse Events | Any harmful, undesirable, potentially serious and life threatening effects occurring during or after administration of the antibiotics proposed in this study (piperacillin / tazobactam, imipenem or meropenem), was evaluated as: none or adverse event classified according to the intensity of the clinical manifestation (severity) as: mild, moderate or severe and for each antibiotic. | evaluation of the safety of the intervention with analysis of the frequency of adverse events by treatment group | Posted | Count of Participants | Participants | Number of participants with adverse events evaluated by an physician at the time of administration of antibiotics, up to an average to 24 hours after the study drug cessation. |
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adverse events by the mode of administration: intermittent or prolonged, evaluated during the time of administration, up to an average 24 hours after administration of the antibiotics proposed.
pre-specified intent was to only compare "Intermittent" and "Prolonged" Arm/Groups with the grouping of antibiotics betalactam (imipenem, meropenem and piperacillin/tazobactam)
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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 | Intermittent. Piperacillin/Tazobactam, Imipenem, Meropenem | Piperacillin/tazobactam 300mg/kg/day, divided into 4 doses/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 30 minutes infusion every 6 hours. Intermittent Piperacillin/tazobactam: Piperacillin/tazobactam administered in 30 minutes infusion. Imipenem 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes infusion every 6 hours. Intermittent Imipenem: Imipenem administered in 60 minutes infusion. Meropenem 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes every 8 hours. Intermittent Meropenem: Meropenem administered in 60 minutes infusion. | 17 | 201 | 0 | 201 | 1 | 201 |
| EG001 | Prolonged Infusion. Continuous Piperacillin/Tazobactam, Extended Imipenem, Extended Meropenem | Piperacillin/tazobactam initial doses 75mg/kg in 30 minutes infusion, immediately thereafter continue 300mg/kg/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 24 hours infusion every 24 hours, as determined by antibiotic stability at room temperature. Continuous Piperacillin/tazobactam: Piperacillin/tazobactam administered in 24 hours infusion. Imipenem initial doses 20mg/kg in 60 minutes infusion, immediately thereafter continue 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 6 hours infusion every 6 hours, as determined by antibiotic stability at room temperature. Extended Imipenem: Imipenem administered in 6 hours infusion. Meropenem initial doses 35mg/kg in 60 minutes infusion, immediately thereafter continue 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution at a concentration of 7mg/ml, to be administered in 8 hours infusion every 8 hours, as determined by antibiotic stability at room temperature. Extended Meropenem: Meropenem administered in 8 hours infusion. | 19 | 202 | 0 | 202 | 3 | 202 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| moderate adverse event | Gastrointestinal disorders | Cofepris | Systematic Assessment | vomiting, diarrhea |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. YazmÃn Fuentes | CISMexico | 55276900 | 22462 | yazmin_fuentes@hotmail.com |
| May 28, 2021 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000078142 | Tazobactam |
| D000077731 | Meropenem |
| ID | Term |
|---|---|
| D010397 | Penicillanic Acid |
| D010406 | Penicillins |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013457 | Sulfur Compounds |
| D013450 | Sulfones |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D013845 | Thienamycins |
| D015780 | Carbapenems |
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| Between 18 and 65 years |
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| >=65 years |
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| Prolonged Infusion. Continuous Piperacillin/Tazobactam, Extended Imipenem, Extended Meropenem |
Piperacillin/tazobactam initial doses 75mg/kg in 30 minutes infusion, immediately thereafter continue 300mg/kg/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 24 hours infusion every 24 hours, as determined by antibiotic stability at room temperature. Continuous Piperacillin/tazobactam: Piperacillin/tazobactam administered in 24 hours infusion. Imipenem initial doses 20mg/kg in 60 minutes infusion, immediately thereafter continue 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 6 hours infusion every 6 hours, as determined by antibiotic stability at room temperature. Extended Imipenem: Imipenem administered in 6 hours infusion. Meropenem initial doses 35mg/kg in 60 minutes infusion, immediately thereafter continue 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution at a concentration of 7mg/ml, to be administered in 8 hours infusion every 8 hours, as determined by antibiotic stability at room temperature. Extended Meropenem: Meropenem administered in 8 hours infusion. |
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