Clinical trial NCT02655419: Determine the PK and Safety and Tolerability of ATM-AVI for the Treatment of cIAIs in Hospitalized Adults (REJUVENATE)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Complicated Intra-Abdominal Infections, cIAIs
Keywords: cIAIs in hospitalized adults
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Innovative Medicines Initiative
First posted: 2016-01-14
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility 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.

Primary outcomes:
measure: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0 hr
timeFrame: Predose (0 hr) on Day 1
measure: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0.42 hr
timeFrame: 0.42 hr Post dose on Day 1
measure: Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 3.25 hr
timeFrame: 3.25 hr Post dose on Day 1
measure: Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 5 hr
timeFrame: 5 hr Post dose on Day 1
measure: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0 hr
timeFrame: Predose (0 hr) on Day 1
measure: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0.42 hr
timeFrame: 0.42 hr Post dose on Day 1
measure: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 3.25 hr
timeFrame: 3.25 hr Post dose on Day 1
measure: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 5 hr
timeFrame: 5 hr Post dose on Day 1
measure: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 0 hr
timeFrame: Predose (0 hr) on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 2.75 hr
timeFrame: 2.75 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 5 hr
timeFrame: 5 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 0 hr
timeFrame: Predose (0 hr) on Day 4
measure: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 2.75 hr
timeFrame: 2.75 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 5 hr
timeFrame: 5 hr Post dose on Day 4
measure: Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0 hr
timeFrame: Predose (0 hr) on Day 4
measure: Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0.5 hr
timeFrame: 0.5 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 1 hr
timeFrame: 1 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 2 hr
timeFrame: 2 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3 hr
timeFrame: 3 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.25 hr
timeFrame: 3.25 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.5 hr
timeFrame: 3.5 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.75 hr
timeFrame: 3.75 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 4 hr
timeFrame: 4 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 5 hr
timeFrame: 5 hr Post dose on Day 4
measure: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 6 hr
timeFrame: 6 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0 hr
timeFrame: Predose (0 hr) on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0.5 hr
timeFrame: 0.5 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 1 hr
timeFrame: 1 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 2 hr
timeFrame: 2 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3 hr
timeFrame: 3 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.25 hr
timeFrame: 3.25 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.5 hr
timeFrame: 3.5 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.75 hr
timeFrame: 3.75 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 4 hr
timeFrame: 4 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 5 hr
timeFrame: 5 hr Post dose on Day 4
measure: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 6 hr
timeFrame: 6 hr Post dose on Day 4
measure: Maximum Observed Plasma Concentration (Cmax) of Aztreonam (ATM): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Maximum Observed Plasma Concentration (Cmax) of Avibactam (AVI): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Time of Observed Maximum Concentration (Tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Aztreonam (ATM): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Avibactam (AVI): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Aztreonam (ATM): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Avibactam (AVI): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Time of Last Measured Concentration (Tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
timeFrame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
measure: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug up to the LFU visit (up to maximum of 38 days)
measure: Number of Participants With Electrocardiogram (ECG) Abnormalities
timeFrame: Baseline up to EOT (up to a maximum of 15 days)
measure: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters
timeFrame: Baseline up to LFU visit (up to maximum of 38 days)
measure: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres
timeFrame: Baseline up to LFU visit (up to maximum of 38 days)
measure: Number of Participants With Clinically Significant Vital Signs
timeFrame: From first dose of study drug up to LFU visit (up to maximum of 38 days)
measure: Number of Participants With Clinical Significant Physical Examination Findings : MITT Population
timeFrame: From first dose of study drug up to the LFU visit (up to maximum of 38 days)
Secondary outcomes:
measure: Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: MITT Population
timeFrame: Test of Cure Visit (up to a maximum of 28 days)
measure: Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Modified Intent-to-Treat (mMITT) Population
timeFrame: Test of Cure Visit (up to a maximum of 28 days)
measure: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population)
timeFrame: Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
measure: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population)
timeFrame: Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
measure: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population)
timeFrame: Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
measure: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population)
timeFrame: Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
Other outcomes:
Locations:
city: Lille Cedex
country: France
facility: University Hospital C.
city: Limoges cedex
country: France
facility: CHU Limoges
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln Innere Medizin I
city: Luebeck
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein, Klinik fuer Infektiologie und Mikrobiologie, DZIF-CTU
city: Barakaldo
country: Spain
facility: Hospital Universitario Cruces
state: Bizkaia
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: ISLA Baleares
city: Barcelona
country: Spain
facility: Hospital Universitari del Mar
city: Cordoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Terrassa
country: Spain
facility: Hospital Universitario Mutua de Tarrasa
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
affiliation: Clinical Trials Centre Cologne
name: Oliver Cornely
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jimenez-Rodriguez RM, Martin-Gutierrez G, Jimenez-Jorge S, Rosso-Fernandez CM, Tallon-Aguilar L, Roca-Oporto C, Padillo J, Luckey A, Cano A, Lopez-Ruiz J, Gomez-Zorrilla S, Bonnin-Pascual J, Boix-Palop L, Montejo JM, Torre-Cisneros J, Cisneros JM. Factors associated with recruitment success in the phase 2a study of aztreonam-avibactam development programme: a descriptive qualitative analysis among sites in Spain. BMJ Open. 2022 Feb 3;12(2):e051187. doi: 10.1136/bmjopen-2021-051187.
citation: Cornely OA, Cisneros JM, Torre-Cisneros J, Rodriguez-Hernandez MJ, Tallon-Aguilar L, Calbo E, Horcajada JP, Queckenberg C, Zettelmeyer U, Arenz D, Rosso-Fernandez CM, Jimenez-Jorge S, Turner G, Raber S, O'Brien S, Luckey A; COMBACTE-CARE consortium/REJUVENATE Study Group. Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study. J Antimicrob Chemother. 2020 Mar 1;75(3):618-627. doi: 10.1093/jac/dkz497.