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

Last updated on November 20, 2019

FOR MORE INFORMATION
Study Location
University Hospital C.
Lille Cedex, , 59037 France
Contact
1-800-718-1021
Eligibility criteria
Condition
The disease, disorder, syndrome, illness, or injury that is being studied.
cIAIs Complicated Intra-Abdominal Infections
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18-90 years
Inclusion criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

1. Provision of informed consent prior to any study-specific procedures.

2. Male or female from 18 to 90 years of age inclusive.

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 (presence of pus
within the abdominal cavity) of an intra-abdominal infection associated with
peritonitis. Surgical intervention includes open laparotomy, percutaneous drainage of
an abscess, or laparoscopic surgery. Specimens from the surgical intervention must be
sent for culture. Patients who undergo a surgical procedure with complete fascial
closure are appropriate for the trial. The skin incision may be left open for purposes
of wound management as long as complete fascial closure is accomplished. The patient
has at least 1 of the following diagnosed during the surgical intervention:

1. Cholecystitis with gangrenous rupture or perforation or progression of the
infection beyond the gallbladder wall

2. Diverticular disease with perforation or abscess

3. Appendiceal perforation or peri-appendiceal abscess

4. Acute gastric or duodenal perforations, only if operated on >24 hours after
diagnosis

5. Traumatic perforation of the intestines, only if operated on >12 hours after
diagnosis (f) Secondary peritonitis (but not spontaneous bacterial peritonitis
associated with cirrhosis and chronic ascites)

(g) Intra abdominal abscess (including of liver or spleen provided that there is
extension beyond the organ with evidence of intraperitoneal involvement) OR
Preoperative enrollment where the following clinical criteria are met with
confirmation of infection by surgical intervention within 24 hours of entry:

1. Requirement for surgical intervention, defined per protocol as open laparotomy,
percutaneous drainage of an abscess, or laparoscopic surgery

2. Evidence of systemic inflammatory response, with at least one of the following:

- Fever (defined as body temperature >38°C) or hypothermia with a core body
temperature

- Elevated white blood cells (>12000 cells/μL)

- Systolic blood pressure systolic blood pressure decrease of >40 mmHg Increased heart rate ( >90 bpm)
and respiratory rate (>20 breaths/min)

- Hypoxemia (defined as oxygen saturation

- Altered mental status.

3. Physical findings consistent with intra-abdominal infection, such as:

- Abdominal pain and/or tenderness, with or without rebound

- Localized or diffuse abdominal wall rigidity

- Abdominal mass.

4. Supportive radiologic imaging findings of intra-abdominal infection such as
perforated intraperitoneal abscess detected on computed tomography scan, magnetic
resonance image, or ultrasound.

5. Specimens from the surgical intervention will be sent for culture for isolation
of both aerobic and anaerobic bacteria.

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 while assuming the organism is known to be sensitive to ATM-AVI.

- 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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details

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 investigation study containing AVI

3. Patient has participated or intends to participate in any other clinical study that
involves the administration of an investigational medication at the time of
presentation, during the course of the study, or during the 30 days prior to study
start.

4. Patient has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any
serious reaction to aztreonam, carbapenem, monobactam or other ?-lactam antibiotics,
avibactam, nitroimidazoles or metronidazole, or any of the excipients of the
respective (investigational) medicinal products to be administered during the study

5. Patient has a 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 (these are considered situations of peritoneal soiling before infection
has become established); another intra-abdominal process in which the primary etiology
is not likely to be infectious

6. Patient has a simple cholecystitis, gangrenous cholecystitis without rupture, simple
appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis,
pancreatic abscess or ischaemic/necrotic intestine without perforation

7. Patient has a cIAI managed by staged abdominal repair (STAR), open abdomen technique
or any situation where infection source control is not likely to be achieved or in
whom the abdomen is left open, particularly those for whom re-operation is planned, or
those unlikely to solely respond to antimicrobial therapy

8. At screening, if it is known the patient has an infection due to a pathogen that is
unlikely to respond to ATM-AVI plus metronidazole treatment

9. Patient has a rapidly progressive (expected to die in including acute hepatic failure, respiratory failure or septic shock with a high risk
of mortality due to other causes than cIAI

10. Patient has received systemic antibacterial agents within the 72- hour period prior to
study entry, unless either of the following pertains:

1. Patient has a new infection (not considered a treatment failure) and the
following is met:

- Patient received no more than 24 hours within the 72 hour period prior to study
entry

2. Patient is considered to have failed the previous treatment regimen

11. Patient has a concurrent infection that may interfere with the evaluation of clinical
cure for the study therapy

12. Patient needs effective concomitant systemic antibacterials (oral, IV, or
intramuscular) or antifungals in addition to the investigational product and
metronidazole

13. Patient has creatinine clearance ?50 ml/min. Note: following review of PK and safety
data from the first 10 enrolled patients, and the confirmation of a provisional dose
schedule, patients with a creatinine clearance of 31 - 50 mL/min may be included.

14. Patient has had acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis
(any Child-Pugh class), acute hepatic failure, or acute decompensation of chronic
hepatic failure

15. Presence of hepatic disease as indicated by aspartate aminotransferase (AST) or
alanine transaminase (ALT) >3 × upper limit of normal (ULN) at Screening. Patients
with AST and/or ALT >3 × ULN and not accompanied by a total bilirubin ? 2xULN and documented by the investigator as
being directly related to the infectious process being treated

16. Patient has a total bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly
related to the acute infection or due to known Gilbert's disease

17. Alkaline phosphatase (ALP) >3 × ULN. Patients with values >3 × ULN and eligible if this value is acute and directly related to the infectious process being
treated.

18. Patients with an immunocompromising illness

19. Known active Clostridium difficile associated diarrhoea

20. Any other condition that, in the opinion of the investigator, may confound the results
of the study or pose additional risks

21. Patient with a do not resuscitate order

22. Patient has an absolute neutrophil count

23. Patient has a hematocrit

24. Patient has a platelet count are permitted if the reduction is historically stable

25. Patient is currently receiving treatment with probenecid.

26. Patient is pregnant or breastfeeding or if of child bearing potential,

27. Patient is unlikely to comply with protocol,

28. Patient is currently receiving anti-convulsant therapy to prevent recurrence of a past
history of seizures.

29. Patient has a prior liver, pancreas or small-bowel transplant.

NCT02655419
Pfizer
Recruiting
Determine the PK and Safety and Tolerability of ATM-AVI for the Treatment of cIAIs in Hospitalized Adults (REJUVENATE)

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cIAIs Complicated Intra-Abdominal Infections
NCT02655419
All Genders
18+
Years
Multiple Sites
Descriptive Information
Brief Title  ICMJE Determine the PK and Safety and Tolerability of ATM-AVI for the Treatment of cIAIs in Hospitalized Adults (REJUVENATE)
Official Title  ICMJE 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
Brief SummaryDetermine the PK and safety and tolerability of aztreonam-avibactam (ATM-AVI) in the treatment of hospitalized adults with cIAI
Detailed DescriptionA 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Complicated Intra-Abdominal Infections, cIAIs
Intervention  ICMJE
  • 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
Study Arms  ICMJE Experimental: ATM-AVI + Metronidazole
Aztreonam-avibactam + metronidazole
Interventions:
  • Drug: ATM-AVI
  • Drug: Metronidazole
Publications *Not Provided


*   Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 12, 2016)
40
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 26, 2017
Actual Primary Completion DateOctober 26, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ?-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/?L
  23. Hematocrit <25% or hemoglobin <8 gm/dL.
  24. Platelet count <75,000/?L.
  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.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Germany,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02655419
Other Study ID Numbers  ICMJE D4910C00009
C3601001 ( Other Identifier: Alias Study Number )
2015-002726-39 ( EudraCT Number )
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD:Yes
Responsible PartyPfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Innovative Medicines Initiative (IMI) COMBACTE-CARE
Investigators  ICMJE
Study Director:Pfizer CT.gov Call CenterPfizer
Principal Investigator:Oliver CornelyClinical Trials Centre Cologne
PRS AccountPfizer
Verification DateApril 2019

ICMJE     Data element required by the

International Committee of Medical Journal Editors
and the
World Health Organization ICTRP

FOR MORE INFORMATION

Contact a representative by phone, email, or visiting the study website. Please see the references below:

BY PHONE

Pfizer Clinical Trials Contact Center

1-800-718-1021

BY EMAIL

Contact

[email protected]

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