E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Complicated Urinary Tract Infections (cUTIs) |
Infecciones del tracto urinario complicadas |
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E.1.1.1 | Medical condition in easily understood language |
Urinary Tract Infection |
Infección del tracto urinario |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the noninferiority of ceftazidime-avibactam compared with doripenem with respect to symptomatic resolution of UTI-specific symptoms and resolution of, or improvement in, flank pain based on the patient-reported symptom assessment |
Evaluar la ausencia de inferioridad de ceftazidima avibactam en comparación con doripenem con respecto a la resolución de los síntomas específicos de IU y la resolución de, o mejora del dolor de costado en función de la respuesta sintomática comunicada por el paciente. |
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E.2.2 | Secondary objectives of the trial |
?To deter. the efficacy(Ef) of CAZ-AVI compared w/ dori wrt the per pt & per-pathogen MR at the EoIVT,ToC,& LFU visits in pts who are in the mmITT,ME,& eME analysis sets(AS) ?To deter. the Ef of CAZ-AVI compared to dori wrt the symptomatic resolution of UTI-specific symptoms based on pt-reported symptom assessment at ToC, & LFU visits in mmITT AS ?To deter. the Ef of CAZ-AVI compared w/ dori wrt the investigatordetermined CC at the EoIVT,ToC,& LFU visits in pts who are in the mmITT,ME,eME,& CE AS ?To eval the Ef of CAZ-AVI vs dori in pathogens resistant to ceftazidime ?To comp the time to 1st defervescence of CAZ-AVI vs dori in pts who are on IV study therapy & who have fever at study entry in the mmITT,ME,eME,& CE AS ?To eval the safety & toler. profile of CAZ-AVI compared w/ dori in the tx of pts w/ a cUTI in the safety AS ?To eval the pk of the ind. components of CAZ-AVI(avibactam & ceftazidime) ?To eval CAZ-AVI exposure & the antimicrobial response relationship |
Determinar la eficacia de CAZ AVI en comparación con doripenem con respecto a:- RM por pac. y por patógeno en las visitas final ttr. IV [FDT (IV)], CDC y seguimiento tardío (ST) en los pacientes incluidos en los grupos de análisis ITMm, EM y EM ampliado.- la resolución (o regreso a la situación premórbida) de todos los síntomas específicos de IU en función de la respuesta sintomática comunicada por el paciente en las visitas CDC y ST, en los pac. incluidos en el grupo de análisis ITMm.- la CC determinada por el investigador en las visitas FDT (IV), CDC y ST en los pac. incluidos en los grupos de análisis ITMm, EM, EM ampliado y evaluable clínicamente. -los patógenos resistentes a la ceftazidima.- tiempo hasta la 1era desaparición de fiebre durante el tto. IV en los pac. que tengan fiebre al entrar en el estudio en los grupos de análisis ITMm, EM, EM ampliado y EC.-Perfil de seguridad tolerabilidad de CAZ AVI en comparación con doripenem.-FC de los componentes individuales de CAZ AVI |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 18 to 90 years of age, inclusive. 2. Female patients can participate if they are surgically sterile or completed menopause or females capable of having children and agree not to attempt pregnancy while receiving IV study therapy and for a period of 28 days after. 3.Has pyuria >/= 10 WBCs and has a positive urine culture within 48 hours of enrollment containing >/=10 to the fifth CFU/ml of a recognized uropathogen known to be susceptible to IV study therapy (CAZ-AVI and doripenem). 4.Demonstrates either acute pyelonephritis or complicated lower UTI without pyelonephritis |
1. 18 a 90 años, ambos inclusive. 2. Las mujeres están autorizadas si han sido esterilizadas quirúrgicamente o finalizado la menopausia o estár en edad fértil y estar dispuestas a no intentar quedarse embarazada mientras reciba el tratamiento IV del estudio y durante un periodo de 28 días después. 3. Tiene piuria >=10 leucocitos y tiene un cultivo de orina positivo en las 48 horas posteriores al reclutamiento que contiene >/=10 al quinto UFC/ml de un uropatógeno reconocido que se sepa que es susceptible al tratamiento IV (CAZ-AVI y doripenem). 4. Presenta pielonefritis aguda o infección urinaria baja complicada sin pielonefritis |
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E.4 | Principal exclusion criteria |
1. Urine pathogen is a Gram-positive pathogen or a uropathogen resistant to CAZ-AVI or doripenem. 2. Patient's urine culture at study entry isolates more than 2 microorganisms regardless of the colony count or patient has a confirmed fungal UTI. 3.Patient is receiving hemodialysis or peritoneal dialysis or had a renal transplant. 4.Patient is immunocompromised. 5.Patient is considered unlikely to survive the 6 to 8 week study period or have a rapidly progressive or terminal illness. |
1. El patógeno en el urocultivo es un patógeno grampositivo o un uropatógeno resistente a un cultivo de CAZ-AVI o de doripenem. 2. Se aíslan más de 2 microorganismos con independencia del recuento de colonias en el urocultivo del paciente al entrar en el estudio o el paciente tiene una IU fúngica confirmada. 3. El paciente está recibiendo hemodiálisis o diálisis peritoneal o se sometió a un transplante renal. 4. Paciente inmunosuprimido. 5. Se considera improbable que el paciente sobreviva el período del estudio de 6 a 8 semanas o el paciente presenta una enfermedad rápidamente progresiva o terminal |
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E.5 End points |
E.5.1 | Primary end point(s) |
- The proportion of patients with resolved (or return to premorbid) UTI symptoms except flank pain and resolution or improvement in flank pain based on patient-reported symptom assessment response at Day 5 visit. Timeframe: Day 5 after start of study drug - The proportion of patients with a per patient microbiological eradication and resolution (or return to premorbid) of all UTI-specified symptoms based on patient-reported symptom assessment response. Timeframe: 21 to 25 days after start of study drug |
- Proporción de pacientes con resolución (o regreso a la situación premórbida) de los síntomas específicos de IU, salvo dolor de costado y resolución o mejoría del dolor de costado, en función de la respuesta sintomática comunicada por el paciente en la visita del día 5. Periodo: Día 5 después del inicio del fármaco del estudio. - Proporción de pacientes con erradicación microbiológica por paciente y con resolución (o regreso a la situación premórbida) de todos los síntomas específicos de IU, en función de la respuesta sintomática comunicada por el paciente. Periodo: 21 a 25 días después del fármaco del estudio. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Outcome measure 1 - Day 5 after start of study drug Primary Outcome measure 2 - Day 21-25 after start of study drug |
Medida 1 del resultado primario: Día 5 después del inicio del fármaco del estudio. Medida 2 del resultado primario: 21 a 25 días después del inicio del fármaco del estudio. |
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E.5.2 | Secondary end point(s) |
- The proportion of pts w/ a favorable per pt MR in the mmITT analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after study drug start(SDS) - The proportion of pts w/ a favorable per pt MR in the ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after SDS - The proportion of pts w/ a favorable per pt MR in the extended ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after SDS - The proportion of pts w/ resolution (or return to premorbid) of all UTIspecific symptoms based on the pt-reported symptom assessment response in the mmITT analysis set. Outcome measured at the following timepoints: 21-25 days & 45-52 days after SDS - The proportion of favorable per-pathogen MR in the mmITT analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after study drug start - The proportion of favorable per-pathogen MR in the ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the start of study drug(SoSD) - The proportion of favorable per-pathogen MR in the extended ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the SoSD - The proportion of pts w/ an investigator-determined CC in the mmITT analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the SoSD - The proportion of pts w/ an investigator-determined CC in the ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the SoSD - The proportion of pts w/ an investigator-determined CC in the extended ME analysis set. Timeframe: w/in 24 hrs after IV completion, 21 ~ 25 days & 45 ~ 52 days after the SoSD - The proportion of pts w/ an investigator-determined CC in the CE analysis set. Timeframe: w/in 24 hrs after IV completion, 21-25 days & 45-52 days after the SoSD - The favorable per pathogen MR by categories of minimum inhibitory concentration in the mmITT analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25 days & 45- 52 days after the SoSD - The favorable per pathogen MR by categories of minimum inhibitory concentration in the ME analysis set. Outcome measured at the following timepoints: w/in 24 hrs after IV completion, 21-25days & 45-52 days after the SoSD - The favorable per pathogen MR by categories of minimum inhibitory concentration in the extended ME analysis set. Outcome measured at the following timepoints: 24 hrs after completion of study drug, 21-25 days & 45-52 days after the SoSD - The proportion of pts w/ favorable investigator clinical response assessment in pts infected w/ a ceftazidime resistant pathogen in the mmITT analysis set. Outcome measured at the following timepoint: 21- 25 days after study drug start - The proportion of pts w/ an investigator-determined CC in pts infected w/ a ceftazidime resistant pathogen in the ME analysis set. Outcome measured at the following timepoint: 21-25 days after study drug start - The proportion of pts w/ an investigator-determined CC in pts infected w/ a ceftazidime resistant pathogen in the extended ME analysis set. Outcome measured at the following timepoint: 21-25 days after study drug start - The proportion of pts w/ favorable per-pt MR for pts infected w/ a ceftazidime resistant pathogen in the mmITT analysis set. Outcome measured at the following timepoint: 21-25 days after SDS - The proportion of pts w/ favorable per-pt MR for pts infected w/ a ceftazidime resistant pathogen in the ME analysis set. Timeframe: 21- 25 days after study drug start - The proportion of pts w/ favorable per-pt MR for pts infected w/ a ceftazidime resistant pathogen in the extended ME analysis set. Timeframe: 21-25 days after study drug start - The proportion of pts w/ symptomatic resolution (defined in the coprimary variables) for pts infected w/ a ceftazidime resistant pathogen in the mmITT analysis set. Outcome measured at the following timepoint: Day 5 & 21-25 days after study drug start - The time to 1st defervescence while on IV study therapy in pts in the mmITT, ME, extended ME, and CE analysis sets who have fever at study entry. Timeframe: any time after start of study drug to end of IV study therapy - Evaluation of the pk of the individual components of CAZ-AVI (avibactam & ceftazidime) - The safety & tolerability by incidence & severity of adverse events & serious adverse events, vital signs, clinical laboratory tests, ECGs & physical exams. Outcome measured at the following timepoints: study duration (screening visit (Day -1) through last follow up visit (up to 52 days) |
Proporción de pacientes con una respuesta microbiológica (RM) favorable por paciente en los grupos de análisis de intención de tratar modificada por microbiología (ITMm), evaluable microbiologicamente (EM) y EM ampliado, medido en las 24 horas después del último día de la administración IV del fármaco del estudio, 21 a 25 días y 45 a 52 días después de iniciar la administración del fármaco del estudio (SDS). - Proporción de pac. con resolución (o regreso a la situación premórbida) de todos los síntomas específicos de IU en función de la respuesta sintomática comunicada por el paciente en el grupo de análisis ITMm, medido en los siguientes momentos: 21-25 días y 45-52 días después SDS. - Proporción de pacientes con una RM favorable por patógeno en los grupos de análisis ITMm, EM y EM ampliado medido en los siguientes puntos: en 24 h después de fin ttr.IV, 21-25 días y 45-52 días después SDS. - Proporción de pacientes con curación clínica determinada por el investigador en los grupos de análisis ITMm, EM, EM ampliado y EC medido en los siguientes puntos: en 24 h después de fin ttr. IV, 21-25 días y 45-52 días después SDS - RM favorable por patógeno por categoría de concentración inhibidora mínima en los grupos de análisis ITMm, EM, EM ampliado medido en 24 h después de fin tto. IV, 21-25 días y 45-52 días después SDS -Proporción de pac. con una evaluación de respuesta clínica favorable evaluada por el investigador en los pacientes infectados por un patógeno resistente a la ceftazidima en los grupos de análisis ITMm , EM y EM ampliado medido a los 21-25 días después SDS -Proporción de pac. con RM favorable en los pac infectado por un patógeno resistente a la ceftazidima en el grupo de análisis ITMm, EM y EM ampliado medido a los 21-25 días después SDS. Proporción de pacientes con resolución sintomática (según se define en las variables principales) en los pac. infectados por un patógeno resistente a la ceftazidima en el grupo de análisis ITMm medido el día 5 y 21-25 días después SDS. -Tiempo hasta la primera desaparición de la fiebre durante el tratamiento IV del estudio en los grupos de análisis ITMm, EM, EM ampliado y EC en los pacientes con fiebre al entrar en el estudio, medido en cualquier momento después SDS hasta fin ttr.IV. -Evaluación PK de los componentes individuales de CAZ-AVI (avibactam y ceftazidima). -La seguridad y tolerabilidad se evaluarán mediante la incidencia y la intensidad de los AA y los AAG, constantes vitales,análisis de lab, ECG, exploración física medido desde la selección día -1 hasta la última visita de seguimiento (a los 52 días). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Listed in E.5.2 |
Mencionado en E.5.2 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarkers and Microbiology cultures |
Biomarcadores y cultivos de microbiología |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Belgium |
Brazil |
Bulgaria |
Canada |
Croatia |
Czech Republic |
France |
Germany |
Greece |
India |
Israel |
Italy |
Korea, Republic of |
Mexico |
Peru |
Poland |
Romania |
Russian Federation |
Spain |
Taiwan |
Ukraine |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the last visit of the last patient participating in the study. |
El final del estudio se define como la última visita del último paciente que participa en el estudio. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 28 |