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    Summary
    EudraCT Number:2011-002119-27
    Sponsor's Protocol Code Number:CXA-cIAI-10-08
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-11-18
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2011-002119-27
    A.3Full title of the trial
    A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, PHASE 3 STUDY TO
    COMPARE THE EFFICACY AND SAFETY OF INTRAVENOUS CXA-201 WITH THAT OF MEROPENEM IN COMPLICATED INTRAABDOMINAL INFECTIONS
    ESTUDIO DE FASE 3, MULTICÉNTRICO, DOBLE CIEGO, ALEATORIZADO, PARA COMPARAR LA EFICACIA Y LA SEGURIDAD DE CXA 201 INTRAVENOSO CON LA DE MEROPENEM EN INFECCIONES INTRAABDOMINALES COMPLICADAS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial to test a new antibiotic given by vein to be used for Complicated Intra-abdominal infections.
    Un ensayo para probar un antibiotico intravenoso en infecciones intra-abdominales complicadas.
    A.4.1Sponsor's protocol code numberCXA-cIAI-10-08
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCubist Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCubist Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPRA International
    B.5.2Functional name of contact pointPaul Starkey
    B.5.3 Address:
    B.5.3.1Street AddressDynamostr. 13 - 15
    B.5.3.2Town/ cityMannheim
    B.5.3.3Post codeD-68165
    B.5.3.4CountryGermany
    B.5.4Telephone number+491792525608
    B.5.5Fax number+496218782181
    B.5.6E-mailMedicEU@PRAIntl.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCXA-201
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCXA-201
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Meropenem 1 g Powder for Solution for Injection or Infusion
    D.2.1.1.2Name of the Marketing Authorisation holderOrchid Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMeropenem 1 g
    D.3.4Pharmaceutical form Powder for solution for injection or infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMEROPENEM
    D.3.9.1CAS number 96036-03-2
    D.3.9.4EV Substance CodeSUB08778MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Flagyl 500mg/100ml Solution for Infusion (Metronidazole)
    D.2.1.1.2Name of the Marketing Authorisation holderWinthrop Pharmaceuticals UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFlagyl 500mg/100ml Solution for Infusion
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETRONIDAZOLE
    D.3.9.1CAS number 443-48-1
    D.3.9.4EV Substance CodeSUB08922MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Complicated Intraabdominal Infections
    Infecciones Intraabdominales Complicadas
    E.1.1.1Medical condition in easily understood language
    Intraabdominal infections in complicated conditions like Peritonitis
    Infecciones intraabdominales en condiciones complicadas como Peritonitis
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the non-inferiority of CXA-201 and metronidazole vs. meropenem in adult subjects with complicated intraabdominal infection (cIAI) based on the 95% confidence interval (CI) around the difference in clinical cure rates at the TOC visit (26 to 30 days after the initiation of study drug administration) in the microbiological intent-to-treat (MITT) population.
    Demostrar la no inferioridad de CXA-201 y metronidazol frente a meropenem en pacientes adultos con infección intraabdominal complicada (IIAc) basado en un intervalo de confianza (IC) del 95% alrededor de la diferencia en las tasas de curación clínica en la visita de PDC (de 26 a 30 días después del inicio de la administración del fármaco del estudio) en la población de intención de tratar microbiológica (ITM).
    E.2.2Secondary objectives of the trial
    ? To demonstrate the non-inferiority of CXA-201 and metronidazole vs. meropenem in adult subjects with cIAI based on the 95% CI around the difference in clinical cure rates at the TOC visit (26 to 30 days after the initiation of study drug administration) in the microbiologically evaluable (ME) population .
    ? To compare the clinical response of CXA-201 and metronidazole to that of meropenem at the TOC visit in the clinically evaluable (CE) population.
    ? To compare the microbiological response of CXA-201 and metronidazole to that of meropenem at the TOC visit.
    ? To compare the clinical and microbiological responses of CXA-201 and metronidazole versus meropenem at the EOT (within 24 hours of last dose of treatment) and LFU visit (38-45days post
    first dose of study drug)
    ? To evaluate the safety and tolerability of CXA-201 in adult subjects with cIAI.
    ?Demostrar la no inferioridad de CXA-201 y metronidazol frente a meropenem en pacientes adultos con IIAc de acuerdo con un IC del 95% alrededor de la diferencia en las tasas de curación clínica en la visita de PDC (de 26 a 30 días después del inicio de la administración del fármaco del estudio) en la población evaluable microbiológicamente (EM).
    ?Comparar la respuesta clínica de CXA-201 y metronidazol con la de meropenem en la visita de PDC en la población evaluable clínicamente (EC).
    ?Comparar la respuesta microbiológica de CXA-201 y metronidazol con la de meropenem en la visita de PDC.
    ?Comparar las respuestas clínicas y microbiológicas de CXA-201 y metronidazol frente a meropenem en el FDT (en el plazo de 24 horas después de la última dosis de tratamiento) y en la visita de SGT (38-45 días después de la primera dosis del fármaco del estudio).
    ?Evaluar la seguridad y tolerabilidad de CXA-201 en pacientes adultos con IIAc.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects MUST satisfy all of the following entry criteria before they will be allowed to participate in the study:
    1. Provide written informed consent prior to any study-related procedure not part of normal medical care (a legally acceptable representative may provide consent if the subject is unable to do so, provided this is approved by local country and institution specific guidelines).
    2. Be males or females ? 18 years of age.
    3. If female, subject is non-lactating, and is either:
    a. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or
    b. Of childbearing potential and is practicing a barrier method of birth control (e.g., a diaphragm or contraceptive sponge) along with 1 of the following methods: oral or parenteral contraceptives (for 3 months prior to study drug administration), or a vasectomized partner. Or, the subject is practicing abstinence from sexual intercourse. Subjects must be willing to practice these methods for the duration of the trial and for at least 35 days after last dose of study medication.
    4. Males are required to practice reliable birth control methods (condom or other barrier device) during the conduct of the study and for at least 35 days after last dose of study medication.
    5. One of the following diagnoses (in which there is evidence of intraperitoneal infection) including:
    a. Cholecystitis (including gangrenous cholecystitis) with rupture, perforation, or progression of the infection beyond the gallbladder wall;
    b. Diverticular disease with perforation or abscess;
    c. Appendiceal perforation or periappendiceal abscess;
    d. Acute gastric or duodenal perforation, only if operated on > 24 hours after perforation occurs;
    e. Traumatic perforation of the intestine, only if operated on > 12 hours after perforation occurs;
    f. Peritonitis due to other perforated viscus or following a prior operative procedure;
    i. Subjects with inflammatory bowel disease or ischemic bowel disease are eligible provided there is bowel perforation.
    g. Intraabdominal abscess (including liver or spleen).
    6. Subject requires surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous draining of an abscess) within 24 hours of (before or after) the first dose of study drug.
    7. If subject is to be enrolled preoperatively, the subject should have radiographic evidence of bowel perforation or intraabdominal abscess.
    8. Subjects who failed prior antibacterial treatment for the current cIAI can be enrolled but must: (a) have a positive culture (from an intraabdominal site) and (b) require surgical intervention. Such
    subjects can be enrolled before the results of the culture are known; however, if the culture is negative, study drug administration must be discontinued.
    9. Willing and able to comply with all study procedures and restrictions.
    Los pacientes DEBEN cumplir todos los criterios de entrada que se indican a continuación para poder participar en el estudio:
    1. Dar su consentimiento informado por escrito antes de cualquier procedimiento relacionado con el estudio que no sea parte de la asistencia médica normal (un representante legalmente aceptable puede dar el consentimiento si el paciente es incapaz de hacerlo, siempre que esto esté aprobado por las normas específicas del país y la institución).
    2. Ser varón o mujer ? 18 años.
    3. Si es mujer, la paciente no está en periodo de lactancia y:
    a. No es potencialmente fértil, lo que se define como posmenopáusica durante al menos 1 año o quirúrgicamente estéril debido a la ligadura de trompas bilaterales, ooforectomía bilateral o histerectomía; o
    b. Es potencialmente fértil y está practicando un método anticonceptivo de barrera (p. ej., diafragma o esponja anticonceptiva) junto con 1 de los métodos siguientes: anticonceptivos orales o parenterales (durante 3 meses antes de la administración del fármaco del estudio) o pareja vasectomizada. O la paciente practica la abstinencia sexual. Las pacientes deben estar dispuestas a practicar estos métodos durante todo el ensayo y durante un mínimo de 35 días después de la última dosis de medicación del estudio.
    4. Los varones deben practicar métodos anticonceptivos fiables (preservativo u otro dispositivo de barrera) durante la realización del estudio y durante un mínimo de 35 días después de la última dosis de medicación del estudio.
    5. Uno de los siguientes diagnósticos (en los que haya pruebas de infección intraperitoneal) incluidos:
    a. Colecistitis (incluida la colecistitis gangrenosa) con rotura, perforación o progresión de la infección más allá de la pared de la vesícula biliar;
    b. Enfermedad diverticular con perforación o absceso;
    c. Perforación del apéndice o absceso periapendicular;
    d. Perforación gástrica o duodenal aguda, sólo si se operó > 24 horas después de que se produjese la perforación;
    e. Perforación traumática del intestino, sólo si se operó > 12 horas después de que se produjese la perforación;
    f. Peritonitis debido a otra víscera perforada o después de un procedimiento quirúrgico anterior;
    i. Los pacientes con enfermedad inflamatoria intestinal o enfermedad isquémica intestinal son elegibles siempre que exista perforación intestinal.
    g. Absceso intraabdominal (incluidos de hígado o de bazo).
    6. El paciente precisa intervención quirúrgica (p. ej., laparotomía, cirugía laparoscópica o drenaje percutáneo de un absceso) en el plazo de 24 horas (antes o después) de la primera dosis del fármaco del estudio.
    7. Si el paciente va a ser incluido preoperatoriamente, debe tener pruebas radiográficas de perforación intestinal o absceso intraabdominal.
    8. Los pacientes en los que haya fracasado un tratamiento antibacteriano previo para la IIAc actual pueden ser reclutados pero deben: (a) tener un cultivo positivo (de una localización intraabdominal) y (b) precisar intervención quirúrgica. Dichos pacientes pueden ser incluidos antes de que se conozcan los resultados del cultivo; sin embargo, si el cultivo es negativo, debe suspenderse la administración del fármaco del estudio.
    9. Dispuestos a y capaces de cumplir todos los procedimientos y limitaciones del estudio.
    E.4Principal exclusion criteria
    1. Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation.
    2. Simple appendicitis; acute suppurative cholangitis; infected necrotizing pancreatitis; pancreatic abscess; or pelvic infections.
    3. Spontaneous [primary] bacterial peritonitis associated with cirrhosis and chronic ascites.
    4. Complicated intraabdominal infection managed by staged abdominal repair (STAR), open abdomen technique including temporary closure of the abdomen, or any situation where infection source control is not likely to be achieved.
    5. Known prior to randomization to have an IAI or postoperative infection caused by pathogen(s) resistant to meropenem.
    6. Use of systemic antibiotic therapy for IAI for more than 24 hours prior to the first dose of study drug, unless there is a documented treatment failure with such therapy.
    7. More than one dose of an active non-study antibacterial regimen given postoperatively. For subjects enrolled preoperatively, no postoperative non-study antibacterial therapy is allowed.
    8. Subjects who previously received imipenem, meropenem, doripenem or cefepime for the current intraabdominal infection.
    9. Have a concomitant infection at the time of randomization, which requires non-study systemic antibacterial therapy in addition to IV study drug therapy. (Drugs with only gram-positive activity [e.g., daptomycin, vancomycin, linezolid] are allowed).
    10. Severe impairment of renal function (estimated creatinine clearance [CrCl] < 30 mL/min), or requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (< 20 mL/h urine output over 24 hours).
    11. The presence of hepatic disease at baseline as defined by any of the following:
    a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 4 x upper limit of normal (ULN)
    b. Total bilirubin > 2 x ULN, unrelated to cholecystitis
    c. Alkaline phosphatase > 4 x ULN. Subjects with a value > 4 x ULN and < 5 x ULN are eligible if this value is historically stable
    d. Acute or chronic hepatitis, cirrhosis, acute hepatic failure, acute decompensation of chronic hepatic failure.
    12. Hematocrit < 25% or hemoglobin < 8 gm/dL.
    13. Neutropenia with absolute neutrophil count < 1000 /mm3.
    14. Platelet count < 75,000 /mm3. Subjects with a platelet count as low as 50,000 /mm3 are permitted if the reduction is historically stable.
    15. Considered unlikely to survive the 4- to 5-week study period.
    16. Any rapidly-progressing disease or immediately life-threatening illness (including respiratory failure and septic shock).
    17. Immunocompromising condition, including established Acquired Immune Deficiency Syndrome (AIDS), hematological malignancy, or bone marrow transplantation, or immunosuppressive therapy
    including cancer chemotherapy, medications for prevention of organ transplantation rejection, or the administration of corticosteroids equivalent to or greater than 40 mg of prednisone per day administered continuously for more than 14 days preceding randomization.
    18. Have a documented history of any moderate or severe hypersensitivity or allergic reaction to any ?-lactam antibacterial (a history of a mild rash followed by uneventful re-exposure is not a
    contraindication to enrollment), including cephalosporins, carbapenems, penicillins, or ß-lactamase inhibitors, or metronidazole, or nitroimidazole derivatives.
    19. Any condition or circumstance that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of study data.
    20. Participation in any clinical study of an investigational product within days prior to the proposed first day of study drug.
    21. Previous participation in any study of CXA-101 or CXA-201.
    22. Subjects who have received disulfiram in the past 14 days or who are currently receiving probenecid.
    23. Women who are pregnant or nursing.
    1. Diagnóstico de absceso de la pared abdominal, obstrucción del intestino delgado o enfermedad isquémica intestinal sin perforación.
    2. Apendicitis simple; colangitis supurativa aguda; pancreatitis necrotizante infectada; absceso pancreático o infecciones pélvicas.
    3. Peritonitis bacteriana espontánea [primaria] asociada a cirrosis y ascitis crónica.
    4. Infección intraabdominal complicada manejada mediante reparación abdominal en etapas (STAR), técnica de abdomen abierto que incluye el cierre temporal del abdomen, o cualquier situación en la que no sea probable que se consiga el control de la fuente de infección.
    5. Conocimiento previo a la aleatorización de que se trata de una IIA o infección posoperatoria causada por patógeno(s) resistente(s) al meropenem.
    6. Uso de tratamiento antibiótico sistémico para la IIA durante más de 24 horas antes de la primera dosis del fármaco del estudio, a menos que exista un fracaso documentado del tratamiento con dicha terapia.
    7. Más de una dosis de un régimen antibacteriano activo que no sea del estudio administrada posoperatoriamente. En los pacientes reclutados preoperatoriamente, no se permite ningún tratamiento antibacteriano posoperatorio que no sea del estudio.
    8. Los pacientes que hayan recibido previamente imipenem, meropenem, doripenem o cefepima para la infección intraabdominal actual.
    9. Tener una infección concomitante en el momento de la aleatorización, que precise terapia antibiótica sistémica distinta a la del estudio además del tratamiento IV con fármacos del estudio. (Se permiten fármacos que sólo tienen actividad frente a gram positivos [p. ej., daptomicina, vancomicina, linezolida]).
    10. Deterioro intenso de la función renal (estimación de aclaramiento de creatinina [CrCl] < 30 ml/min) o requisitos de diálisis peritoneal, hemodiálisis o hemofiltración u oliguria (< 20 ml/h de producción de orina a lo largo de 24 horas).
    11. Presencia de enfermedad hepática en el momento basal definida por cualquiera de las siguientes circunstancias:
    a. Alanina aminotransferasa (ALT) o aspartato aminotransferasa (AST) > 4 x límite superior de lo normal (LSN)
    b. Bilirrubina total > 2 x LSN, no relacionada con colecistitis
    c. Fosfatasa alcalina > 4 x LSN. Los pacientes con un valor > 4 x LSN y < 5 x LSN son elegibles si este valor es históricamente estable
    d. Hepatitis aguda o crónica, cirrosis, insuficiencia hepática aguda, descompensación aguda de insuficiencia hepática crónica.
    12. Hematocrito < 25% o hemoglobina < 8 g/dl.
    13. Neutropenia con un recuento absoluto de neutrófilos < 1.000 /mm3.
    14. Recuento de plaquetas < 75.000 /mm3. Se admiten pacientes con un recuento de plaquetas de sólo 50.000/mm3 si la reducción es históricamente estable.
    15. Se considera poco probable que sobrevivan al periodo de 4 a 5 semanas del estudio.
    16. Cualquier enfermedad de progresión rápida o enfermedad potencialmente mortal de forma inmediata (como insuficiencia respiratoria o shock séptico).
    17. Enfermedad que supone inmunosupresión, como el síndrome de inmunodeficiencia adquirida (SIDA) establecido, neoplasia maligna hematológica o trasplante de médula ósea o tratamiento inmunosupresor incluida la quimioterapia para el cáncer, medicamentos para la prevención del rechazo de trasplantes de órganos o administración de corticosteroides equivalentes a 40 mg de prednisona al día o más administrados de forma continua durante más de 14 días antes de la aleatorización.
    18. Tener antecedentes documentados de cualquier hipersensibilidad o reacción alérgica moderada o grave a cualquier antibacteriano ? lactámico (los antecedentes de una erupción leve seguida de una nueva exposición sin problemas no son contraindicación para el reclutamiento), incluidas las cefalosporinas, los carbapenems, las penicilinas o los inhibidores de la ß-lactamasa o metronidazol o derivados del nitroimidazol.
    19. Cualquier problema o circunstancia que, en opinión del investigador, comprometería la seguridad del paciente o la calidad de los datos del estudio.
    20. Participación en cualquier estudio clínico de un producto en investigación dentro de los 30 días previos al primer día propuesto de administración del fármaco del estudio.
    21. Participación previa en cualquier estudio de CXA 101 o CXA-201.
    22. Pacientes que hayan recibido disulfiram en los últimos 14 días o que estén recibiendo actualmente probenecid.
    23. Mujeres embarazadas o en periodo de lactancia materna.
    E.5 End points
    E.5.1Primary end point(s)
    Clinical cure rate at the TOC visit in the primary MITT population.
    Tasa de curación clínica en la visita de PDC en la población principal de ITM.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary statistical goal of this study is to establish non-inferiority of CXA-201 plus metronidazole to meropenem with respect to proportion of subjects in the MITT primary analysis population who achieve clinical cure at TOC visit. A 95% CI (normal approximation to the binomial distribution) around the difference in clinical cure rate (CXA-201 minus meropenem) will be calculated. CXA-201 plus metronidazole will be considered non-inferior to meropenem if the lower limit of the 95% CI if the difference in cure rate (CXA-201 minus meropenem) at TOC among subjects in the MITT population is greater than minus 12.5%.
    El principal objetivo estadístico de este estudio es establecer la no inferioridad de CXA-201 más metronidazol frente a meropenem con respecto a la proporción de pacientes de la población del análisis principal de ITM que alcanzan curación clínica en la visita de PDC. Se calculará un IC del 95% (aproximación normal a la distribución binomial) alrededor de la diferencia en las tasas de curación clínica ([CXA-201 más metronidazol] menos meropenem). Se considerará que CXA 201 más metronidazol son no inferiores a meropenem si el límite inferior del IC del 95% de la diferencia en las tasas de curación ([CXA-201 más metronidazol] menos meropenem) entre los pacientes en la ITM en la visita de PDC es mayor que menos 12,5%.
    E.5.2Secondary end point(s)
    Additional secondary goals are to compare CXA-201 plus metronidazole to meropenem with respect to following end points:
    (1) clinical cure rate at TOC in the CE population,
    (2) microbiological eradication rate (per-subject) at TOC in the ME population,
    (3) perpathogen microbiological eradication rate at TOC in the ME population, and
    (4) proportion of subjects with superinfections or new infections in the MITT population. A 95% CI will be obtained for the difference in rates between CXA-201 and meropenem.
    Otros objetivos secundarios son comparar CXA-201 más metronidazol con meropenem con respecto a las siguientes variables: (1) tasa de curación clínica en la PDC en la población EC, (2) tasa de erradicación microbiológica (por paciente) en la PDC en la población EM, (3) tasa de erradicación microbiológica por patógeno en la PDC en la población EM y (4) proporción de pacientes con superinfecciones o nuevas infecciones en la población de ITM. Se obtendrá un IC del 95% para las diferencias en las tasas entre CXA-201 más metronidazol y meropenem.
    E.5.2.1Timepoint(s) of evaluation of this end point
    For the secondary statistical goal, a 95% CI will also be obtained for the difference in the clinical cure rate at TOC in the ME population. CXA-201 plus metronidazole will be considered non-inferior to meropenem if the lower limit of the 95% CI if the difference in cure rate (CXA-201 minus meropenem) at TOC among subjects in the ME population is greater than minus 12.5%.
    Para el objetivo estadístico secundario, se obtendrá también un IC del 95% para la diferencia en la tasa de curación clínica en la visita de PDC en la población EM. Se considerará que CXA-201 más metronidazol son no inferiores a meropenem si el límite inferior del IC del 95% de la diferencia en las tasas de curación ([CXA-201 más metronidazol] menos meropenem) entre los pacientes en la población EM en la visita de PDC es mayor que menos 12,5%.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA39
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Brazil
    Georgia
    Mexico
    Peru
    Romania
    Russian Federation
    South Africa
    Spain
    Ukraine
    United States
    E.8.7Trial 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
    The study will be stopped when the last subject completes the study or when the last ongoing subject has discontinued treatment, whichever occurs first.
    El estudio finalizará cuando el último sujeto complete el mismo o bien cuando el último sujeto participante haya discontinuado el tratamiento, lo que antes ocurra.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months20
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months20
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 780
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 377
    F.4.2.2In the whole clinical trial 780
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The Investigator must ensure that the investigational product will be used only in accordance with the protocol. It is forbidden to use investigational drug material for purposes other than as defined in this
    protocol.

    All subjects who discontinue the study medication should be offered alternative treatment if applicable. Treatment should be given according to normal clinical practice, after a termination visit.
    El investigador debe asegurarse de que el producto en investigación será usado solamente de acuerdo con el protocolo. Está prohibido usar material relacionado con el producto en investigación para otros propósitos diferentes a los definidos en el protocolo.
    Debe ofrecerse tratamiento alternativo a todos los sujetos que discontinúen de la medicación en estudio si aplica. Este tratamiento será proporcionado de acuerdo con la práctica clínica habitual tras la visita de finalización.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-01-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-01-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-09-10
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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