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

NCT02655419 | Completed Phase 2 Results FDA Drug

• 3 other identifiers: D4910C00009C36010012015-002726-39
• Study Type: interventional
• Target: 40
• Locations: 3 countries
• Sites: 11

Brief Summary

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

Conditions

Complicated Intra-Abdominal Infections, cIAIs

Keywords

cIAIs in hospitalized adults

Outcome Measures

Primary Outcomes (54)

• Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0 hr

  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).

  Predose (0 hr) on Day 1

• Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0.42 hr

  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.

  0.42 hr Post dose on Day 1

• Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 3.25 hr

  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.

  3.25 hr Post dose on Day 1

• Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 5 hr

  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.

  5 hr Post dose on Day 1

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

  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).

  Predose (0 hr) on Day 1

• Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0.42 hr

  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.

  0.42 hr Post dose on Day 1

• Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 3.25 hr

  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.

  3.25 hr Post dose on Day 1

• Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 5 hr

  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.

  5 hr Post dose on Day 1

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

  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.

  Predose (0 hr) on Day 4

• Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 2.75 hr

  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.

  2.75 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 5 hr

  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.

  5 hr Post dose on Day 4

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

  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.

  Predose (0 hr) on Day 4

• Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 2.75 hr

  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.

  2.75 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 5 hr

  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.

  5 hr Post dose on Day 4

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

  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.

  Predose (0 hr) on Day 4

• Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0.5 hr

  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.

  0.5 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 1 hr

  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.

  1 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 2 hr

  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.

  2 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3 hr

  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.

  3 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.25 hr

  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.

  3.25 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.5 hr

  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.

  3.5 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.75 hr

  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.

  3.75 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 4 hr

  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.

  4 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 5 hr

  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.

  5 hr Post dose on Day 4

• Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 6 hr

  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.

  6 hr Post dose on Day 4

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

  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.

  Predose (0 hr) on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0.5 hr

  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.

  0.5 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 1 hr

  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.

  1 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 2 hr

  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.

  2 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3 hr

  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.

  3 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.25 hr

  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.

  3.25 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.5 hr

  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.

  3.5 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.75 hr

  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.

  3.75 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 4 hr

  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.

  4 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 5 hr

  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.

  5 hr Post dose on Day 4

• Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 6 hr

  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.

  6 hr Post dose on Day 4

• Maximum Observed Plasma Concentration (Cmax) of Aztreonam (ATM): Intensive Sampling at Day 4

  predose, 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 4

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

• Time of Observed Maximum Concentration (Tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4

  predose, 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 Aztreonam (ATM): Intensive Sampling at 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.

  predose, 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 4

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

  predose, 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 Aztreonam (ATM): Intensive Sampling at 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.

  predose, 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 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.

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

• Time of Last Measured Concentration (Tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4

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

• Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at 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.

  predose, 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 (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at 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.

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

• Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at 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.

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

• Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4

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

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

• Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

  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.

  From first dose of study drug up to the LFU visit (up to maximum of 38 days)

• Number of Participants With Electrocardiogram (ECG) Abnormalities

  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.

  Baseline up to EOT (up to a maximum of 15 days)

• Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters

  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.

  Baseline up to LFU visit (up to maximum of 38 days)

• Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres

  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.

  Baseline up to LFU visit (up to maximum of 38 days)

• Number of Participants With Clinically Significant Vital Signs

  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.

  From first dose of study drug up to LFU visit (up to maximum of 38 days)

• Number of Participants With Clinical Significant Physical Examination Findings : MITT Population

  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.

  From first dose of study drug up to the LFU visit (up to maximum of 38 days)

Secondary Outcomes (6)

• Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: MITT Population

  Test of Cure Visit (up to a maximum of 28 days)

• Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Modified Intent-to-Treat (mMITT) Population

  Test of Cure Visit (up to a maximum of 28 days)

• 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)

• 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)

• 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)

Study Arms (1)

ATM-AVI + Metronidazole

EXPERIMENTAL

Aztreonam-avibactam + metronidazole

Drug: ATM-AVI; Drug: Metronidazole

Interventions

ATM-AVI DRUG

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

ATM-AVI + Metronidazole

Metronidazole DRUG

Metronidazole 500mg infused over 1 hour every 8 hours

ATM-AVI + Metronidazole

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of informed consent
• Male or female from 18 to 90 years
• Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met
• 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
• 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.
• Patient must have or will have a surgical intervention within 24 hours (before or after) the administration of the first dose of study drug

You may not qualify if:

• Involvement in the planning and/or conduct of the study
• Patient has been previously enrolled in this study, previously treated with ATM-AVI or previously participated in an investigational study containing AVI
• 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.
• 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
• 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
• Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess or ischaemic/necrotic intestine without perforation
• 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
• Infection due to a pathogen that is unlikely to respond to ATM-AVI plus metronidazole
• Rapidly progressive or terminal illness
• Systemic antibacterial agents received within the 72- hour period prior to study entry, unless:
• A new infection and no more than 24 hours of prior antibiotic treatment received within the 72 hour period prior to study entry or
• Patient is considered to have failed the previous treatment
• Concurrent infection that may interfere with the evaluation of clinical cure for the study therapy
• requirement for effective concomitant systemic antibacterials or antifungals
• Creatinine clearance ≤30 ml/min or requirement for renal replacement therapy

Sponsors & Collaborators

• Pfizer: lead
• Innovative Medicines Initiative: collaborator

Study Sites (11)

University Hospital C.

Lille, 59037, France

Location

CHU Limoges

Limoges, 87042, France

Location

Universitaetsklinikum Koeln Innere Medizin I

Cologne, 50937, Germany

Location

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

Lübeck, 23538, Germany

Location

Hospital Universitario Cruces

Barakaldo, Bizkaia, 48903, Spain

Location

Hospital Universitario Son Espases

Palma de Mallorca, ISLA Baleares, 07010, Spain

Location

Hospital Universitari del Mar

Barcelona, 08003, Spain

Location

Hospital Universitario Reina Sofia

Córdoba, 14004, Spain

Location

Hospital Universitario Virgen Macarena

Seville, 41009, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, 41013, Spain

Location

Hospital Universitario Mutua de Tarrasa

Terrassa, 08221, Spain

Location

Related Publications (3)

• Das S, Riccobene T, Carrothers TJ, Wright JG, MacPherson M, Cristinacce A, McFadyen L, Xie R, Luckey A, Raber S. Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for Phase IIa and Phase III evaluation. Eur J Clin Pharmacol. 2024 Apr;80(4):529-543. doi: 10.1007/s00228-023-03609-x. Epub 2024 Jan 22.

  PMID: 38252170 DERIVED

• 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.

  PMID: 35115349 DERIVED

• 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.

  PMID: 31828337 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Interventions

Metronidazole

Intervention Hierarchy (Ancestors)

Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

• Oliver Cornely

  Clinical Trials Centre Cologne

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2015
• First Posted: January 14, 2016
• Study Start: May 19, 2016
• Primary Completion: October 26, 2017
• Study Completion: October 26, 2017
• Last Updated: April 2, 2020
• Results First Posted: March 4, 2019

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share

Locations

ES (7); DE (2); FR (2)