Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria

Phase 3 study to determine the efficacy, safety, and tolerability of aztreonam- avibactam (ATM- AVI) versus best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections (cIAI), nosocomial pneumonia (NP) including hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), complicated urinary tract infections (cUTI), or bloodstream infections (BSI) due to metallo-β-lactamase (MBL)- producing Gram-negative bacteria.

This is a prospective, randomized, multicenter, open-label, parallel group, comparative study to determine the efficacy, safety, and tolerability of aztreonam- avibactam (ATM- AVI) versus best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections (cIAI), nosocomial pneumonia (NP) including hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), complicated urinary tract infections (cUTI), or bloodstream infections (BSI) due to metallo-β-lactamase (MBL)- producing Gram-negative bacteria.

The study will randomize approximately 60 subjects in a 2:1 randomization scheme (ATM-AVI: BAT) with infections due to MBL-producing Gram-negative bacteria. Molecular testing at the central microbiology laboratory will be performed to confirm the MBL status of the organism upon study completion or at pre-designated intervals.

The study will consist of a Screening Visit (Visit 1), a Baseline visit (Visit 2) on Day 1 of the study treatment, ongoing treatment visits (Visits 3 to 15) from Day 2 to Day 14, an End of Treatment (EOT) visit (Visit 16) within 24 hours after the last infusion, a Test of Cure (TOC) visit (Visit 17) on Day 28 (±3 days) and a Late Follow Up (LFU) visit (Visit 18) on Day 45 (±3 days).

Subjects will be stratified at randomization based on infection type (cIAI, HAP/VAP, cUTI or BSI). The number of subjects with cUTI will be no more than approximately 75% of the study population.

After obtaining written informed consent and confirming eligibility, subjects will be randomized in a 2:1 ratio to the ATM AVI treatment arm or the BAT treatment arm according to a central randomization schedule (approximately 40 (ATM AVI) and approximately 20 (BAT) subjects per group).

The duration of treatment is 5 to 14 days for cIAI, cUTI and BSI and 7 to 14 days for HAP/VAP. Each subject is expected to complete the study, including the LFU visit. The precise duration of treatment will be determined by the investigator based on the subject's severity of infection and subsequent response to treatment.

For subjects randomized to ATM AVI treatment arm, sparse blood samples will be collected for population pharmacokinetic (PK) assessments and PK/pharmacodynamic (PD) relationships will be evaluated in subjects where plasma samples and microbiological response data have been collected.

Eligibility Criteria:
Inclusion Criteria All Subjects

1. Subject must be ≥18 years of age.
2. Evidence of a personally signed and dated informed consent document indicating that the subject or a legally acceptable representative has been informed of all pertinent aspects of the study.
3. Subjects must have a confirmed diagnosis of serious bacterial infection, specifically cIAI, HAP/VAP, cUTI, or BSI requiring administration of IV antibacterial therapy.
4. Subjects must have an MBL- positive Gram- negative bacteria (an Enterobacteriaceae and/or Stenotrophomonas maltophilia for which the imipenem or meropenem MIC is ≥ 4 µg/mL), that was isolated from an appropriate specimen obtained within 7 days prior to screening.
5. Female subject of childbearing potential must have a negative serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL.
6. Subjects who have received more than 48 hours of an appropriate prior systemic antibiotic\[s\] for a carbapenem non -susceptible pathogen may be enrolled if they demonstrate worsening or lack of improvement of objective symptoms or signs of infection (Note: antibiotic\[s\] is considered appropriate if microbiological susceptibility test results show that all carbapenem non -susceptible pathogens are susceptible to the systemic antibiotic\[s\] received).

Additional Inclusion Criteria- cIAI Subjects

1. Subject must have a specimen obtained from an abdominal source during a surgical intervention within 7 days prior to screening from which a study qualifying pathogen was isolated upon culture. Surgical intervention includes open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery.
2. The subject has at least 1 of the following diagnosed during the surgical intervention:

   • Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall;

   • Diverticular disease with perforation or abscess;
   * Appendiceal perforation or peri-appendiceal abscess;
   * Acute gastric or duodenal perforations, only if operated on \>24 hours after diagnosis;
   * Traumatic perforation of the intestines, only if operated on \>12 hours after diagnosis;
   * Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis associated with cirrhosis or chronic ascites);
   * Intra abdominal abscess (including of the liver and spleen provided that there is extension beyond the organ with evidence of intra peritoneal involvement).
3. Subject has at least 1 of the following signs / symptoms from each of the following 2 groups:

   • Group A: Evidence of systemic inflammatory response:

   • Documented fever (defined as body temperature ≥38°C) or hypothermia (with a rectal core body temperature ≤35°C);

   • Elevated white blood cells (WBC) (\>12000 cells/µL);

   • Systolic blood pressure (SBP) \<90 mmHg or mean arterial pressure (MAP) \<70 mmHg, or a SBP decrease of \>40 mmHg;

   • Increased heart rate ( \>90 beats per minute \[bpm\]) and respiratory rate (\>20 breaths/min);

   • Hypoxemia (defined as oxygen \[O2\] saturation \<95% by pulse oximetry);

   • Altered mental status.

   • Group B: 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.

Additional Inclusion Criteria - HAP/VAP Subjects

1. Onset of symptoms \>48 hours after admission or \<7 days after discharge from an inpatient care facility (for which the duration of admission was \>3 days).
2. New or worsening infiltrate on chest X- ray (or computerized tomography \[CT\]- scan) obtained within 48 hours prior to randomization.
3. At least 1 of the following:

   * Documented fever (temperature ≥38°C) or hypothermia (rectal/core temperature ≤35°C);
   * WBC ≥10,000 cells/mm3, leukopenia with total WBC ≤4500 cells/mm3, or \>15% immature neutrophils (bands) noted on peripheral blood smear.
4. At least 2 of the following:

   • A new cough (or worsening of cough at Baseline);

   • Production of purulent sputum or purulent endotracheal secretions;

   • Auscultatory finding consistent with pneumonia/pulmonary consolidation (eg, rales, rhonchi, bronchial breath sounds, dullness on percussion, egophony);

   • Dyspnea, tachypnea, or hypoxemia (O2 saturation \<90% or partial pressure of O2 \[pO2\]\<60 mmHg while breathing room air);

   • Need for acute changes in the ventilator support status/system to enhance oxygenation, as determined by worsening oxygenation (arterial blood gas \[ABG\] or pO2 in arterial blood \[PaO2\]/fraction of inspired O2 \[FiO2\]) or needed changes in the amount of positive end expiratory pressure.
5. Subjects must have a respiratory specimen obtained within 7 days prior to screening for Gram stain and culture from which a study qualifying pathogen was isolated upon culture. This includes culture of either an expectorated sputum or a specimen of respiratory secretions obtained by endotracheal aspiration in intubated subjects, or by bronchoscopy with bronchoalveolar lavage (BAL), mini BAL or protected specimen brush (PSB) sampling.

Additional Inclusion Criteria - cUTI Subjects

1. Subject had urine within 7 days prior to screening that cultured positive; containing ≥10\^5 colony forming unit (CFU)/mL of at least 1 carbapenem non susceptible, MBL positive Gram-negative bacteria, ie, the isolate from the study qualifying culture.
2. Subject had pyuria in the 7 days prior to screening as determined by a midstream clean catch or catheterized urine specimen with ≥10 white blood cells (WBCs) per HighPower Field (HPF) on standard examination of urine sediment or ≥10 WBCs/mm3 in unspun urine.
3. Subject demonstrates either acute pyelonephritis or complicated lower UTI without pyelonephritis as defined by the following criteria:

   a. Acute pyelonephritis indicated by flank pain (which must have onset or worsened within 7 days of enrollment) or costovertebral angle tenderness on examination and at least 1 of the following: i) Fever, defined as body temperature ≥38°C (with or without patient symptoms of rigor, chills, or warmth); ii) Nausea and/or vomiting. OR b. Complicated lower UTI, as indicated by qualifying symptoms plus at least 1 complicating factor as follows: i) Qualifying symptoms: subject must have at least 2 of the following symptoms with at least 1 symptom from Group A:

   • Group A symptoms include dysuria, urgency, frequency, and or suprapubic pain;

   • Group B symptoms include fever (defined as body temperature ≥38°C with or without patient symptoms of rigor, chills, warmth), nausea, and/or vomiting.

   ii) Complicating factors: subject must have at least 1 of the following complicating factors:

   • Documented history of urinary retention (male subjects);

   • Obstructive uropathy that is scheduled to be medically or surgically relieved during study therapy and before the EOT;

   • Functional or anatomical abnormality of the urogenital tract, including anatomic malformations or neurogenic bladder, or with a postvoid residual urine volume of at least 100 mL;

   • Use of intermittent bladder catheterization or presence of an indwelling bladder catheter for at least 48 hours;

   • Urogenital procedure (such as cystoscopy or urogenital surgery) within the 7 days prior to obtainment of the specimen used for the study qualifying culture.

   Additional Inclusion Criteria - BSI Subjects

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1. Subject has a confirmed diagnosis of primary BSI or catheter related BSI (CR- BSI).
2. Signs and symptoms of systemic infection characterized by at least one of the following:

   1. Chills, rigors, or fever (temperature of ≥38.0°C or ≥100.4°F);
   2. Elevated white blood cell count (≥10,000/mm3) or left shift (\>15% immature polymorphonuclear leukocytes (PMNs)).

Exclusion Criteria All Subjects

1. History of serious allergic reaction (anaphylaxis, angioedema, bronchospasm, hypersensitivity) to any systemic antibacterial allowed per protocol.
2. Subject has a concurrent infection that may interfere with the evaluation of response to the study antibiotics.
3. Subject has a need for effective concomitant systemic antibacterials in addition to those allowed per protocol for the diagnoses under study.
4. Estimated CrCL ≤15 mL/min or anticipated requirement for dialysis during the study.

Additional Exclusion Criteria - cIAI Subjects

1. Subject has infections limited to the hollow viscous, such as simple cholecystitis, gangrenous cholecystitis without rupture, and simple appendicitis, or has acute suppurative cholangitis, infected necrotizing pancreatitis, or pancreatic abscess.
2. Subject has abdominal wall abscess or small bowel obstruction without perforation or ischemic bowel without perforation.
3. Subject has a cIAI managed by staged abdominal repair (STAR), or "open abdomen" technique, or marsupialization. This criterion is intended to exclude subjects in whom the abdomen is left open, particularly those for whom re operation is planned.

Additional exclusion criteria - cUTI Subjects 1. Subjects with suspected or confirmed complete obstruction of any portion of the urinary tract, perinephric or intrarenal abscess, or prostatitis, or history of any illness that, in the opinion of the investigator, may confound the results of the study or pose additional risk in administering the study therapy to the subject.

2. Any recent history of trauma to the pelvis or urinary tract.

Additional exclusion criteria - BSI Subjects

1. Subject has a prosthetic cardiac valve or synthetic endovascular graft. 2. Subject has a suspected or documented medical condition with well-defined requirement for prolonged antibiotic treatment (eg, infectious endocarditis, osteomyelitis/septic arthritis, undrainable/undrained abscess, unremoveable/unremoved prosthetic associated infection).