Trial Outcomes & Findings for Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria (NCT NCT03580044)

Participants who were hospitalized with a diagnosis of complicated intra-abdominal infection (cIAI), nosocomial pneumonia (NP) including hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), complicated urinary tract infection (cUTI), or bloodstream infections (BSI) due to Metallo-beta-Lactamase (MBL)- producing Gram-negative bacteria were enrolled. This study was conducted across 9 countries from 25 Dec-2020 to 23-Jan-2023.

A total of 15 participants signed the informed consent form and were randomized in the study. The study was terminated as recruitment of participants with serious infections caused by gram-negative bacteria producing MBL was challenging.

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

Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% confidence interval (CI) was calculated using Jeffrey's method.

Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% CI was calculated using Jeffrey's method.

Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% CI was calculated using Jeffrey's method.

Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% CI was calculated using Jeffrey's method.

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 colony forming units per milliliter \[CFU/mL\] for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants).

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 colony forming units per milliliter \[CFU/mL\] for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants).

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants).

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants).

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants).

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants).

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). ME analysis set comprised of participants from micro-ITT who received at least 48 hours or \<48 hours of study therapy before discontinuation due to AE, no concomitant antibiotics against baseline MBL positive pathogens between 1st dose and TOC (excluding those with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing (except when locally confirmed); no indeterminate clinical outcomes at TOC.

Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification \<10\^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). ME analysis set comprised of participants from micro-ITT who received at least 48 hours or \<48 hours of study therapy before discontinuation due to AE, no concomitant antibiotics against baseline MBL positive pathogens between 1st dose and TOC (excluding those with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing (except when locally confirmed); no indeterminate clinical outcomes at TOC.

Percentage of participants who died due to any cause on or before 28 days after randomization were reported in this outcome measure.

Percentage of participants who died due to any cause on or before 28 days after randomization were reported in this outcome measure.

An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/ incapacity; resulted in congenital anomaly/birth defect; considered an important medical event. Treatment-emergent adverse event (TEAE) was any AE that started after the study medication start date and time.

Vital signs included blood pressure and heart rate and were measured in a supine position after at least 10 minutes of rest for the participants. Criteria for vital sign abnormalities included: systolic blood pressure (SBP): value \>150 millimeters of mercury (mmHg) and increase from baseline \>=30 mmHg and value \<90 and decrease from baseline ≥30. Diastolic BP (mm Hg) Value \>100 and increase from baseline \>= 20 and Value \<50 and decrease from baseline \>=20. Heart Rate (beats per minute \[BPM\]): Value \<40 or \>120.

Physical examination included assessment of the following: abdomen, cardiovascular, ears, eyes, general appearance, head, lungs, lymph nodes, musculoskeletal, neurological, nose, skin and throat. Number of participants with abnormal physical examination findings for each body system is reported in this outcome measure.

Potential clinically significant criteria included: Hematocrit \<0.7\*lower limit of normal (LLN) and \>30% Decrease from Baseline or \>1.3\*upper limit of normal (ULN) and \>30% Increase from Baseline; Hemoglobin: \<0.7\*LLN and \>30% Decrease from Baseline and\>1.3\*ULN and \>30% Increase from Baseline;;Erythrocytes: \<0.7\*LLN and \>30% Decrease from Baseline or \>1.3\*ULN and \>30% Increase from Baseline; Leukocytes: \<0.65\*LLN and \>60% Decrease from Baseline or \>1.5\*ULN and \>100% Increase from Baseline; Basophils/Leukocytes, Eosinophils/Leukocytes and Monocytes/Leukocytes: \>4.0\*ULN and\>300% Increase from Baseline; Lymphocytes/Leukocytes \<0.25\*LLN and \>75% Decrease from Baseline and \>1.5\* ULN and \>100% Increase from Baseline; Neutrophils/Leukocytes: \<0.65\*LLN and \>75% Decrease from Baseline or \>1.6\*ULN and \>100% Increase from Baseline; Platelets\<0.65\*LLN and \>50% Decrease from Baseline or \>1.5\*ULN and \>100% Increase from Baseline.

Criteria for potential clinically significant results were: Aspartate Aminotransferase and Alanine Aminotransferase: \>3.0\* ULN and \>100% increase from baseline (IFB); Bilirubin: \>1.5\* ULN and \>100% IFB; Direct Bilirubin: \>2.0\* ULN and \>150% IFB; Alkaline Phosphatase: 80% decrease from baseline (DFB) and \>3.0\* ULN and \>100% IFB; Urea Nitrogen:100% DFB and \>3.0\* ULN and \>200% IFB; Creatinine \>2.0\* ULN and \>100% IFB; Sodium :10% DFB or \>1.1\* ULN and \>10% IFB; Potassium: 20% DFB or \>1.2\* ULN and \>20% IFB; Chloride: 20% DFB or \>1.2\*ULN and \>20% IFB; Bicarbonate: 40% DFB or \>1.3\* ULN and \>40% IFB; Calcium: 30% DFB or \>1.3\* ULN and \>30% IFB; Albumin: 50% DFB or \>1.5\* ULN and \>50% IFB; Glucose: 40% DFB or \>3.0\*ULN and \>200% IFB.

A standard 12-lead ECG was recorded with the participant in a supine position after at least 10 minutes of rest. The following ECG parameters were recorded: heart rate, PR-interval, QRS-duration, QT-interval, QTc-interval, RR interval. Clinical significance of ECG abnormalities was judged by Investigator.