MedPath

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

Phase 2
Completed
Conditions
Complicated Intra-Abdominal Infections, cIAIs
Interventions
Registration Number
NCT02655419
Lead Sponsor
Pfizer
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.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
40
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.

Exclusion Criteria

Not provided

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
ATM-AVI + MetronidazoleATM-AVIAztreonam-avibactam + metronidazole
ATM-AVI + MetronidazoleMetronidazoleAztreonam-avibactam + metronidazole
Primary Outcome Measures
NameTimeMethod
Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0 hrPredose (0 hr) on Day 1

All participants were to have sparse pharmacokinetics (PK) sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above lower limit of quantification (LLOQ). LLOQ for ATM was 0.1 microgram per milliliter (mcg/ml).

Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 2.75 hr2.75 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0.42 hr0.42 hr Post dose on Day 1

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 2.75 hr2.75 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 1 hr1 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 3.25 hr3.25 hr Post dose on Day 1

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 5 hr5 hr Post dose on Day 1

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0 hrPredose (0 hr) on Day 1

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 nanogram per milliliter (ng/ml).

Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 2 hr2 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3 hr3 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 5 hr5 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Time of Last Measured Concentration (Tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Number of Participants With Clinically Significant Vital SignsFrom first dose of study drug up to LFU visit (up to maximum of 38 days)

Vital sign parameters included: Supine systolic blood pressure (millimeters of mercury \[mmHg\]), Supine diastolic blood pressure (mmHg), Heart rate (beats per minute), Respiratory rate (breaths per minute) and body temperature (degree celsius). Criteria for clinical significance in vital signs was based on investigator's assessment. LFU visit occurred within 20 to 24 days after last infusion.

Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0.42 hr0.42 hr Post dose on Day 1

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 3.25 hr3.25 hr Post dose on Day 1

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 5 hr5 hr Post dose on Day 1

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 0 hrPredose (0 hr) on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 5 hr5 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 5 hr5 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 0 hrPredose (0 hr) on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.75 hr3.75 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 2 hr2 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3 hr3 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0 hrPredose (0 hr) on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0.5 hr0.5 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.25 hr3.25 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.25 hr3.25 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.5 hr3.5 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.75 hr3.75 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 5 hr5 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 6 hr6 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Maximum Observed Plasma Concentration (Cmax) of Aztreonam (ATM): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Maximum Observed Plasma Concentration (Cmax) of Avibactam (AVI): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Avibactam (AVI): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4

AUC(0-6) was defined as the area under the plasma concentration-time curve from time zero up to the six hours postdose.

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 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4

AUC(0-last) was defined as the area under the plasma concentration-time curve from time zero up to the time of the last measurable concentration.

Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.5 hr3.5 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 6 hr6 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0 hrPredose (0 hr) on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0.5 hr0.5 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4

Apparent volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.

Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4

Apparent volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.

Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 4 hr4 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 1 hr1 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Aztreonam (ATM): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4

AUC(0-6) was defined as the area under the plasma concentration-time curve from time zero up to the six hours postdose.

Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4

Plasma elimination half-life was defined as time measured for the plasma concentration of ATM and AVI to decrease by one half of its initial concentration.

Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology ParametersBaseline up to LFU visit (up to maximum of 38 days)

Criteria for abnormality: Hemoglobin, hematocrit, erythrocytes less than(\<) 0.7\*lower limit of normal \[LLN\] and (\&) greater than (\>) 30 percent (%) below baseline \[BB\]; \>1.3\*upper limit of normal \[ULN\] \& \>30% above baseline \[AB\], leukocytes \<0.65\*LLN \& \>60% BB; \>1.6\* ULN \& \>100% AB; platelets \<0.65\*LLN \& \>50% BB; \>1.5\*ULN \& \>100% AB; neutrophils \<0.65\*LLN \& \>75% BB; \>1.6\*ULN \& \>100% AB, lymphocytes \<0.25\*LLN \& \>75%BB; \>1.5\*ULN \& \>100% AB, basophils, eosinophils, monocytes\>4.0\*ULN \& \>300% AB. LFU visit occurred within 20 to 24 days after last infusion.

Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 4 hr4 hr Post dose on Day 4

All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.

Time of Observed Maximum Concentration (Tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
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 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4

AUC(0-last) was defined as the area under the plasma concentration-time curve from time zero up to the time of the last measurable concentration.

Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4

Clearance of a drug was measure of the rate at which a drug was metabolized or eliminated by normal biological processes.

Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)From first dose of study drug up to the LFU visit (up to maximum of 38 days)

An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAEs was an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; or was an important medical event which may jeopardise the participants or require medical intervention to prevent one of the above outcomes. Treatment-emergent were events between first infusion of study drug and up to late follow-up (LFU) visit (20 to 24 days after last infusion). AEs included both non-serious AEs and SAEs.

Number of Participants With Electrocardiogram (ECG) AbnormalitiesBaseline up to EOT (up to a maximum of 15 days)

Criteria for ECG abnormalities: QT value: greater than or equal to (\>=) 450 milliseconds (msec), \>=480 msec, \>=500 msec, \>=500 and increase from baseline \>=60 msec. Increase from baseline in QT: \>=30 msec, \>=60 msec. Decrease from baseline in QT: \>=30 msec, \>=60 msec. QTcB value: \>=450 msec, \>=480 msec, \>=500 msec, \>=500 and increase from baseline \>=60 msec. Increase from baseline in QT interval using Bazett's correction (QTcB) value: \>=30 msec, \>=60 msec. Decrease from baseline in QTcB: \>=30 msec, \>=60 msec. QT interval using Fridericia's correction (QTcF) value: \>=450 msec, \>=480 msec, \>=500 msec, \>=500 and increase from baseline \>=60 msec. Increase from baseline in QTcF value: \>=30 msec, \>=60 msec. Decrease from baseline in QTcF value: \>=30 msec, \>=60 msec. EOT (end of treatment) visit occurred within 24 hours after last infusion.

Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry ParamteresBaseline up to LFU visit (up to maximum of 38 days)

Criteria for abnormality: aspartate aminotransferase, alanine aminotransferase \>3.0\*ULN \& \>100% AB, alkaline phosphatase \<0.5 \*LLN \& \>80% BB\&; \>3.0\*ULN \& \>100% AB; bilirubin \>1.5\*ULN \& \>100% AB; direct bilirubin \>2.0\*ULN \& \>150% AB; protein \<0.5\*LLN \& \>50%BB; \>1.5\*ULN \& \>50% AB, albumin \<0.5\*LLN \& \>50% BB; \>1.5\*ULN \& \>50% AB, urea nitrogen \<0.2\* LLN \& \>100% BB; \>3.0\*ULN \& \>200% AB, creatinine \>2.0\*ULN \& \>100% AB, sodium \<0.85\*LLN \& \>10% BB;\>1.1\*ULN \&\>10% AB; potassium \<0.8\*LLN \&\>20% BB; \>1.2\*ULN \&\>20% AB, chloride \<0.8\*LLN \&\>20% BB;\>1.2\*ULN \& \>20% AB, calcium \<0.7\*LLN \& \>30% BB; \>1.3\*ULN \& \>30% AB, phosphate \<0.5\*LLN \& \>50% BB; \>3.0\*ULN \& \>200% AB, bicarbonate \<0.7\*LLN \& \>40% BB; \>1.3\*ULN \& \>40% AB, glucose \<0.6\*LLN \& \>40% BB, \>3.0\*ULN \& \>200% AB. LFU visit occurred within 20 to 24 days after last infusion.

Number of Participants With Clinical Significant Physical Examination Findings : MITT PopulationFrom first dose of study drug up to the LFU visit (up to maximum of 38 days)

Physical examinations included an assessment of abdomen, cardiovascular, general appearance, head, eyes, ears, nose, lymph nodes, skin, musculoskeletal, neurological, respiratory systems and other (edemas). Clinically significant abnormality in physical examination was based on investigator's assessment. LFU visit occured within 20 to 24 days after last infusion.

Secondary Outcome Measures
NameTimeMethod
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)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)

AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose.

Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Modified Intent-to-Treat (mMITT) PopulationTest of Cure Visit (up to a maximum of 28 days)

Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of the index infection (cIAI) such as no further antimicrobial therapy, drainage, or surgical intervention is necessary and does not meet any of the failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within the abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. TOC visit occurred up to a maximum of 28 days after first dose.

Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: MITT PopulationTest of Cure Visit (up to a maximum of 28 days)

Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of the index infection (cIAI) such as no further antimicrobial therapy, drainage, or surgical intervention is necessary and does not meet any of the failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within the abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. TOC visit occurred up to a maximum of 28 days after first dose.

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)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)

AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose.

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)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)

AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose.

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)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)

AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose.

Trial Locations

Locations (11)

CHU Limoges

🇫🇷

Limoges cedex, France

University Hospital C.

🇫🇷

Lille Cedex, France

Hospital Universitario Son Espases

🇪🇸

Palma de Mallorca, ISLA Baleares, Spain

Hospital Universitari del Mar

🇪🇸

Barcelona, Spain

Hospital Universitario Reina Sofia

🇪🇸

Cordoba, Spain

Universitaetsklinikum Schleswig-Holstein, Klinik fuer Infektiologie und Mikrobiologie, DZIF-CTU

🇩🇪

Luebeck, Germany

Hospital Universitario Cruces

🇪🇸

Barakaldo, Bizkaia, Spain

Hospital Universitario Mutua de Tarrasa

🇪🇸

Terrassa, Spain

Hospital Universitario Virgen Macarena

🇪🇸

Sevilla, Spain

Universitaetsklinikum Koeln Innere Medizin I

🇩🇪

Koeln, Germany

Hospital Universitario Virgen del Rocio

🇪🇸

Sevilla, Spain

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