NCT03580044

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

Terminated Phase 3 Results posted Last updated 2 February 2024

What this trial tests

Phase 3 trial testing ATM-AVI in Serious Bacterial Infection in 15 participants. Terminated before completion.

Timeline

25 December 2020

Primary endpoint
23 January 2023

23 January 2023

Quick facts

Lead sponsor	Pfizer
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	15
Start date	25 December 2020
Primary completion	23 January 2023
Estimated completion	23 January 2023
Sites	42 locations across Russia, Greece, Malaysia, Taiwan, Mexico, Philippines, Argentina, Romania

Drugs / interventions tested

• ATM-AVI (atm-avi) — full drug profile →
• BAT (bat) — full drug profile →

Conditions studied

• Serious Bacterial Infection — all drugs for Serious Bacterial Infection →

Sponsor

Pfizer — full company profile →

Who can join

18 and older, any sex, with Serious Bacterial Infection. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Clinical Cure at the Test of Cure (TOC) Visit -Microbiological Intent to Treat (Micro-ITT) Analysis Set Primary · Day 28

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.

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	41.7	18.0 – 68.8
Best Available Therapy (BAT)	0.0	NA – NA

Percentage of Participants With Clinical Cure at the TOC Visit-Microbiologically Evaluable (ME) Analysis Set Secondary · Day 28

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.

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	55.6	25.4 – 82.7
Best Available Therapy (BAT)	0.0	NA – NA

Percentage of Participants With Clinical Cure at the End of Treatment (EOT) Visit- Micro-ITT Analysis Set Secondary · Up to 24 hours after the last infusion on Day 14

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.

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	58.3	31.2 – 82.0
Best Available Therapy (BAT)	0.0	NA – NA

Percentage of Participants With Clinical Cure at the EOT Visit- ME Analysis Set Secondary · Up to 24 hours after the last infusion on Day 14

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.

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	66.7	34.8 – 89.6
Best Available Therapy (BAT)	0.0	NA – NA

Percentage of Participants With a Favorable Per Participant Microbiological Response at EOT Visit-Micro-ITT Analysis Set Secondary · Up to 24 hours after the last infusion on Day 14

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).

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	81.82
Best Available Therapy (BAT)	0.0

Percentage of Participants With a Favorable Per Participant Microbiological Response at TOC Visit-Micro-ITT Analysis Set Secondary · Day 28

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).

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	60.00
Best Available Therapy (BAT)	0.0

Percentage of Participants With a Favorable Per Participant Microbiological Response at EOT Visit-ME Analysis Set Secondary · Up to 24 hours after the last infusion on Day 14

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).

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	66.67
Best Available Therapy (BAT)	0.00

Percentage of Participants With a Favorable Per Participant Microbiological Response at TOC Visit-ME Analysis Set Secondary · Day 28

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).

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	66.7
Best Available Therapy (BAT)	0.00

Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the EOT Visit-Micro-ITT Analysis Set Secondary · Up to 24 hours after the last infusion on Day 14

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).

Enterobacterales

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	75.0
Best Available Therapy (BAT)	0.0

Pseudomonas aeruginosa

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	50.0

Stenotrophomonas maltophilia

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	66.7

Enterococcus faecium

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	100.0

Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the TOC Visit-Micro-ITT Analysis Set Secondary · Day 28

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).

Enterobacterales

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	50.0
Best Available Therapy (BAT)	0.00

Pseudomonas aeruginosa

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	0.0

Stenotrophomonas maltophilia

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	33.3

Enterococcus faecium

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	0.0

Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the EOT Visit-ME Analysis Set Secondary · Up to 24 hours after the last infusion on Day 14

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

Enterobacterales

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	80.0
Best Available Therapy (BAT)	0.0

Stenotrophomonas maltophilia

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	100.0

Enterococcus faecium

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	100.0

Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the TOC Visit-ME Analysis Set Secondary · Day 28

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

Enterobacterales

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	60.0
Best Available Therapy (BAT)	0.0

Stenotrophomonas maltophilia

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	50.0

Enterococcus faecium

Group	Value	95% CI
Aztreonam- Avibactam (ATM- AVI)	0.0

Adverse events — posted to ClinicalTrials.gov

Time frame: All-cause mortality: From randomization up to late follow-up visit (up to 45 days); SAEs and non-SAEs: From first dose of study drug up to the late follow-up visit (up to maximum of 45 days). Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Aztreonam- Avibactam (ATM- AVI)

Serious: 5/12 (42%)

Deaths: 2/12

Best Available Therapy (BAT)

Serious: 2/2 (100%)

Deaths: 1/3

Serious adverse events (12 terms)

Reaction	System	Aztreonam- Avibactam (ATM-…	Best Available Therapy (BAT)
Cardiac arrest	Cardiac disorders	—	—
Multiple organ dysfunction syndrome	General disorders	—	—
Pyelonephritis	Infections and infestations	—	—
Sepsis	Infections and infestations	—	—
Urinary tract infections	Infections and infestations	—	—
Bacterial test positive	Investigations	—	—
Enterococcus test positive	Investigations	—	—
Neoplasm progession	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Urinary tract obstruction	Renal and urinary disorders	—	—
Acute pulmonary oedema	Respiratory, thoracic and mediastinal disorders	—	—
Thrombophlebitis	Vascular disorders	—	—

Other adverse events (26 terms — click to expand)

Reaction	System	Aztreonam- Avibactam (ATM-…	Best Available Therapy (BAT)
Hypokalaemia	Metabolism and nutrition disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Ocular hypertension	Eye disorders	—	—
Frequent bowel movements	Gastrointestinal disorders	—	—
Chest discomfort	General disorders	—	—
Pyrexia	General disorders	—	—
Hepatic function abnormal	Hepatobiliary disorders	—	—
Bacteraemia	Infections and infestations	—	—
Intervertebral discitis	Infections and infestations	—	—
Abdominal wound dehiscence	Injury, poisoning and procedural complications	—	—
Stoma prolapse	Injury, poisoning and procedural complications	—	—
Alanine aminotransferase increased	Investigations	—	—
Aspartate aminotransferase increased	Investigations	—	—
Blood alkaline phosphatase increased	Investigations	—	—
Blood creatinine increased	Investigations	—	—
Catheter culture positive	Investigations	—	—
Gamma-glutamyltransferase increased	Investigations	—	—
Platelet count increased	Investigations	—	—
Staphylococcus test positive	Investigations	—	—
Device occlusion	Product Issues	—	—
Intensive care unit delirium	Psychiatric disorders	—	—
Ureterolithiasis	Renal and urinary disorders	—	—
Decubitus ulcer	Skin and subcutaneous tissue disorders	—	—
Skin maceration	Skin and subcutaneous tissue disorders	—	—
Haematoma	Vascular disorders	—	—
Phlebitis	Vascular disorders	—	—

Most-reported serious reactions: Cardiac arrest, Multiple organ dysfunction syndrome, Pyelonephritis, Sepsis, Urinary tract infections, Bacterial test positive, Enterococcus test positive, Neoplasm progession.

Data from ClinicalTrials.gov NCT03580044 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Bloodstream infections in critically ill patients: an expert statement.
   Timsit JF, Ruppé E, Barbier F, Tabah A, et al · · 2020 · cited 287× · PMID 32047941 · DOI 10.1007/s00134-020-05950-6
2. Treatment of Infections Due to MDR Gram-Negative Bacteria.
   Bassetti M, Peghin M, Vena A, Giacobbe DR. · · 2019 · cited 209× · PMID 31041313 · DOI 10.3389/fmed.2019.00074
3. Metallo-β-Lactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline.
   Boyd SE, Livermore DM, Hooper DC, Hope WW. · · 2020 · cited 206× · PMID 32690645 · DOI 10.1128/aac.00397-20
4. Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections: Despite Progress, More Action Is Needed.
   Butler MS, Gigante V, Sati H, Paulin S, et al · · 2022 · cited 165× · PMID 35007139 · DOI 10.1128/aac.01991-21
5. The urgent need for metallo-β-lactamase inhibitors: an unattended global threat.
   Mojica MF, Rossi MA, Vila AJ, Bonomo RA. · · 2022 · cited 159× · PMID 34246322 · DOI 10.1016/s1473-3099(20)30868-9
6. New Carbapenemase Inhibitors: Clearing the Way for the β-Lactams.
   Vázquez-Ucha JC, Arca-Suárez J, Bou G, Beceiro A. · · 2020 · cited 87× · PMID 33291334 · DOI 10.3390/ijms21239308
7. Defining the Role of Novel β-Lactam Agents That Target Carbapenem-Resistant Gram-Negative Organisms.
   Tamma PD, Hsu AJ. · · 2019 · cited 55× · PMID 30793757 · DOI 10.1093/jpids/piz002
8. In vitro selection of aztreonam/avibactam resistance in dual-carbapenemase-producing Klebsiella pneumoniae.
   Niu S, Wei J, Zou C, Chavda KD, et al · · 2020 · cited 40× · PMID 31722380 · DOI 10.1093/jac/dkz468