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Trial record 2 of 3 for:    aztreonam-avibactam

Determine the PK and Safety and Tolerability of ATM-AVI for the Treatment of cIAIs in Hospitalized Adults (REJUVENATE)

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ClinicalTrials.gov Identifier: NCT02655419
Recruitment Status : Completed
First Posted : January 14, 2016
Last Update Posted : November 17, 2017
Sponsor:
Collaborator:
Innovative Medicines Initiative (IMI) COMBACTE-CARE
Information provided by (Responsible Party):
Pfizer

Brief Summary:
Determine the PK and safety and tolerability of aztreonam-avibactam (ATM-AVI) in the treatment of hospitalized adults with cIAI

Condition or disease Intervention/treatment Phase
Complicated Intra-Abdominal Infections, cIAIs Drug: ATM-AVI Drug: Metronidazole Phase 2

Detailed Description:
A Phase IIa prospective, open-label, multicenter study to determine the pharmacokinetics (PK) and safety and tolerability of aztreonam-avibactam (ATM-AVI) for the treatment of complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Iia Prospective, Open-label, Multicenter Study To Determine The Pharmacokinetics (pk) And Safety And Tolerability Of Aztreonam-avibactam (Atm-avi) For The Treatment Of Complicated Intra-abdominal Infections (Ciais) In Hospitalized Adults
Actual Study Start Date : May 19, 2016
Actual Primary Completion Date : October 26, 2017
Actual Study Completion Date : October 26, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ATM-AVI + Metronidazole
Aztreonam-avibactam + metronidazole
Drug: ATM-AVI

Cohort 1:

(Creatinine clearance > 50 mL/min)6500mg ATM/1777mg AVI on day 1 followed by total daily dose of 6000mg ATM/1640mg AVI

Cohorts 2 and 3:

(Creatinine clearance > 50 mL/min) As above, or: 6500 mg ATM/2167 mg on Day 1 followed by a total daily dose of 6000 mg ATM/2000 m AVI

(Creatinine clearance 31 - 50 mL/min) 4250 mg ATM/1162 mg AVI on Day 1 followed by total daily dose 3000 mg ATM/820 mg AVI, or:

4250 mg ATM/1417 mg AVI on Day 1 followed by total daily dose 3000 mg ATM/1000 mg AVI


Drug: Metronidazole
Metronidazole 500mg infused over 1 hour every 8 hours




Primary Outcome Measures :
  1. Concentrations of ATM and AVI in plasma [ Time Frame: sample collected at day 1 and day 4 ]
    Sparse sampling will be taken from all patients at Day 1; intensive sampling will be taken from first 25 patients on Day 4 and remaining 15 patients take sparse sampling.

  2. Description of ATM-AVI PK profile in terms of Cmax [ Time Frame: sample collected at day 4 ]
    For patient undergoing intensive sampling on Day 4 .

  3. Description of ATM-AVI PK profile in terms of tmax [ Time Frame: sample collected at day 4 ]
    For patient undergoing intensive sampling on Day 4.

  4. Description of ATM-AVI PK profile in terms of AUC(0-6) [ Time Frame: For patient undergoing intensive sampling on Day 4. ]
    sample collected at day 4

  5. Description of ATM-AVI PK profile in terms of AUC(0-last) [ Time Frame: For patient undergoing intensive sampling on Day 4. ]
    sample collected at day 4

  6. Description of ATM-AVI PK profile in terms of tlast [ Time Frame: sample collected at day 4 ]
    For patient undergoing intensive sampling on Day 4.

  7. Description of ATM-AVI PK profile in terms of t1/2 [ Time Frame: sample collected at day 4 ]
    For patient undergoing intensive sampling on Day 4.

  8. Description of ATM-AVI PK profile in terms of Vss [ Time Frame: sample collected at day 4 ]
    For patient undergoing intensive sampling on Day 4.

  9. Description of ATM-AVI PK profile in terms of Vz [ Time Frame: sample collected at day 4 ]
    For patient undergoing intensive sampling on Day 4.

  10. Description of ATM-AVI PK profile in terms of CL [ Time Frame: sample collected at day 4 ]
    For patient undergoing intensive sampling on Day 4.

  11. Description of safety in terms of adverse events [ Time Frame: from screening to last visit (about 35 +/-3day) ]
  12. Description of safety profile in terms of physical examination [ Time Frame: from screening to last visit (about 35 +/-3day) ]
  13. Description of safety profile in terms of vital signs [ Time Frame: from screening to last visit (about 35 +/-3day) ]
  14. Description of safety profile in terms of ECG [ Time Frame: from screening to last visit (about 35 +/-3day) ]
  15. Description of safety profile in terms of laboratory assessments [ Time Frame: from screening to last visit (about 35 +/-3day) ]

Secondary Outcome Measures :
  1. Proportion of patients with clinical cure [ Time Frame: at TOC (test of cure) visit, day 22-28 ]
    Proportion of patients with clinical cure at TOC (day 22-28). Clinical Response will be assessed as 'Cure', based on resolution or significant improvement of signs and symptoms of cIAI such that no further antimicrobial therapy, drainage or surgical intervention is necessary and the patient does not meet any criteria for 'Failure' (death related to cIAI, received treatment with additional antibiotics for ongoing cIAI, evidence of persisting or recurrent infection at surgical re-intervention, or post-operative wound infection) or 'Indeterminate' (study data not available for evaluation of efficacy for any reason, including 'lost to follow up' or 'assessment not undertaken').

  2. Correlation of derived PK parameters and clinical cure [ Time Frame: at TOC (test of cure) visit (Day 22-28) ]

    Clinical Response will be assessed as 'Cure', based on resolution or significant improvement of signs and symptoms of cIAI such that no further antimicrobial therapy, drainage or surgical intervention is necessary and the patient does not meet any criteria for 'Failure' (death related to cIAI, received treatment with additional antibiotics for ongoing cIAI, evidence of persisting or recurrent infection at surgical re-intervention, or post-operative wound infection) or 'Indeterminate' (study data not available for evaluation of efficacy for any reason, including 'lost to follow up' or 'assessment not undertaken').

    The relationship between exposure to ATM-AVI and efficacy (clinical cure) will be explored graphically.




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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of informed consent
  2. Male or female from 18 to 90 years
  3. Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met
  4. Diagnosis of cIAI

    EITHER:

    Intra-operative/postoperative enrolment with visual confirmation of cIAI. OR Preoperative enrollment with evidence of systemic inflammatory response, physical and radiological findings consistent with cIAI; confirmation of cIAI at time of surgery within 24 hours of study entry

  5. Patients who failed prior antibacterial treatment for their current cIAI can be enrolled but must:

    • Have a known or suspected pathogen causing cIAI that is resistant to the prior therapy
    • Require surgical intervention.
  6. Patient must have or will have a surgical intervention within 24 hours (before or after) the administration of the first dose of study drug

Exclusion criteria:

  1. Involvement in the planning and/or conduct of the study
  2. Patient has been previously enrolled in this study, previously treated with ATM-AVI or previously participated in an investigational study containing AVI
  3. Patient has participated or intends to participate in any other clinical study that involves the administration of a study drug during the course of the study, or during the 30 days prior to study start.
  4. History of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to aztreonam, carbapenem,monobactam or other β-lactam antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of the study drugs
  5. Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours of diagnosis; perforation of gastroduodenal ulcer with surgery within 24 hours of diagnosis primary etiology is not likely to be infectious
  6. Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess or ischaemic/necrotic intestine without perforation
  7. Staged abdominal repair (STAR), open abdomen technique or where infection source control is not likely to be achieved; unlikely to solely respond to antimicrobial therapy
  8. Infection due to a pathogen that is unlikely to respond to ATM-AVI plus metronidazole
  9. Rapidly progressive or terminal illness
  10. Systemic antibacterial agents received within the 72- hour period prior to study entry, unless:

    1. A new infection and no more than 24 hours of prior antibiotic treatment received within the 72 hour period prior to study entry or
    2. Patient is considered to have failed the previous treatment
  11. Concurrent infection that may interfere with the evaluation of clinical cure for the study therapy
  12. requirement for effective concomitant systemic antibacterials or antifungals
  13. Creatinine clearance ≤30 ml/min or requirement for renal replacement therapy
  14. Acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis, acute hepatic failure, or acute decompensation of chronic hepatic failure
  15. Hepatic disease as indicated by AST or ALT >3 × ULN. Patients with AST and/or ALT >3 × ULN and < 5 × ULN are eligible if acute, not accompanied by a total bilirubin ≥ 2xULN and documented by the investigator as being directly related to cIAI.
  16. Patient has a total bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly related to cIAI or due to known Gilbert's disease
  17. ALP >3 × ULN. Patients with values >3 × ULN and <5 x ULN are eligible if acute and directly related to the infectious process being treated.
  18. Immunocompromising illness
  19. Active Clostridium difficile associated diarrhoea
  20. Any other condition that may confound the results of the study or pose additional risks
  21. Do not resuscitate order
  22. Absolute neutrophil count <1000/μL
  23. Hematocrit <25% or hemoglobin <8 gm/dL.
  24. Platelet count <75,000/μL.
  25. Currently receiving probenecid.
  26. Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control.
  27. Unlikely to comply with protocol,
  28. Currently receiving anti-convulsant therapy to prevent recurrence of a past history of seizures.
  29. Prior liver, pancreas or small-bowel transplant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02655419


Locations
France
Nouveau CHU Amiens Picardie
AMIENS Cedex, France, 80054
CHU de Clermont-Ferrand
Clermont-Ferrand, France, 63003
University Hospital C.
Lille Cedex, France, 59037
CHU Limoges
Limoges cedex, France, 87042
CHU de la Miletrie
POITIERS Cedex, France, 86021
Germany
Universitaetsklinikum Freiburg, Department Chirurgie
Freiburg, Germany, 79106
Universitaetsklinikum Koeln Innere Medizin I
Koeln, Germany, 50937
Universitaetsklinikum Schleswig-Holstein, Klinik fuer Infektiologie und Mikrobiologie, DZIF-CTU
Luebeck, Germany, 23538
Klinikum rechts der Isar der Technischen Universitaet Muenchen
Muenchen, Germany, 81675
Universitaetsklinikum Regensburg Klinik und Poliklinik fuer Chirurgie
Regensburg, Germany, 93053
Spain
Hospital Universitario Cruces
Barakaldo, Bizkaia, Spain, 48903
Hospital Universitario Son Espases
Palma de Mallorca, ISLA Baleares, Spain, 07010
Hospital Universitari del Mar
Barcelona, Spain, 08003
Hospital Universitari Vall d'Hebron
Barcelona, Spain, 08035
Hospital Clinic de Barcelona
Barcelona, Spain, 08036
Servicio Andaluz de Salud- Reina Sofia University Hospital
Cordoba, Spain, 14004
Hospital Universitario Virgen Macarena
Sevilla, Spain, 41009
Hospital Universitario Virgen del Rocio
Sevilla, Spain, 41013
University Hospital Mutua
Terrassa, Spain, 08221
Hospital Clinico Universitario Zaragoza
Zaragoza, Spain, 50012
Sponsors and Collaborators
Pfizer
Innovative Medicines Initiative (IMI) COMBACTE-CARE
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
Principal Investigator: Oliver Cornely Clinical Trials Centre Cologne

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02655419     History of Changes
Other Study ID Numbers: D4910C00009
C3601001 ( Other Identifier: Alias Study Number )
2015-002726-39 ( EudraCT Number )
First Posted: January 14, 2016    Key Record Dates
Last Update Posted: November 17, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
URL: http://

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Pfizer:
cIAIs in hospitalized adults

Additional relevant MeSH terms:
Infection
Intraabdominal Infections
Avibactam
Metronidazole
Aztreonam
Anti-Infective Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Bacterial Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action