Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria
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.
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 5 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 appropriate prior systemic antibiotic[s] for a carbapenem
 non-susceptible pathogen must meet the following criteria (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):

 1. Worsening or lack of improvement of objective symptoms or signs of infection
 after at least 48 hours of antibacterial therapy Note: Symptomatic subjects (see
 inclusion criteria 3 and 4) with an isolated causative pathogen that was not
 susceptible to the prior systemic therapy are eligible for this trial.

 7. Subject must be willing and able to comply with scheduled visits, treatment plan,
 laboratory tests, and other study procedures.

 Additional Inclusion Criteria- cIAI Subjects

 1. Subject must have a specimen obtained from an abdominal source during a surgical
 intervention within 5 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 5 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 5 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 5 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

 1. Subject has a confirmed diagnosis of primary BSI or catheter related BSI (CR- BSI).

 2. Consecutive positive duplicate blood cultures (n=2) within 5 days prior to screening
 indicating presence of a carbapenem non- susceptible, MBL-producing Gram- negative
 bacteria. Subjects with polymicrobial blood infections may be included in the study.

 3. Signs and symptoms of systemic infection characterised by at least one of the
 following:

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

 Exclusion Criteria All Subjects 1. Subject has an Acute Physiology and Chronic Health
 Evaluation (APACHE) II score >30.

 2. Subjects unlikely to respond to up to 14 days of study treatment. 3. History of serious
 allergic reaction (anaphylaxis, angioedema, bronchospasm, hypersensitivity) to any systemic
 antibacterial allowed per protocol.

 4. Subject has previously been treated with ATM-AVI Subject with known Clostridium
 difficile associated diarrhea. 5. Subjects with perinephric infection. 6. Colonization with
 an MBL-producing Gram-negative bacteria without signs or symptoms.

 7. Estimated CrCL ≤15 mL/min or anticipated requirement for dialysis during the study.

 8. Hepatic disease as indicated by ALT or AST >3 x ULN at Screening. Exception: AST and/or
 ALT up to 5 x ULN if these elevations are acute and directly related to the infectious
 process.

 9. Bilirubin >2 x ULN, unless related to the acute infection or due to known Gilbert's
 disease.

 10. Alkaline phosphatase (ALP) >3 x ULN. Exception: up to <5 x ULN if this value is acute
 and related to the infectious process.

 11. Absolute neutrophil count <500/mm3.

 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.

 4. Subject who has prior liver, pancreas or small bowel transplant.

 Additional Exclusion Criteria - HAP/VAP Subjects 1. APACHE II score <10. 2. Subjects with
 lung abscess, pleural empyema, or post obstructive pneumonia. 3. Subject is a recipient of
 a lung or heart transplant. 4. Subjects with myasthenia gravis.

 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. Subjects with renal transplantation.

 3. Subjects with a permanent urinary diversion (eg, with ileal loops, cutaneous
 ureterostomy or vesicoureteral reflux).

 4. Subjects who are likely to receive ongoing antibacterial drug prophylaxis after
 treatment of cUTI (eg, subjects with vesico-ureteric reflux).

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

 6. Subjects with uncomplicated urinary tract infections (generally female subjects with
 urinary frequency, urgency, or pain or discomfort without systemic symptoms or signs
 of infection).

 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).