Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria
- Conditions
- Serious Bacterial Infection
- Interventions
- Combination Product: ATM-AVIDrug: BAT
- Registration Number
- NCT03580044
- Lead Sponsor
- Pfizer
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 15
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description ATM- AVI Aztreonam- Avibactam (ATM-AVI) Active Treatment Arm ATM-AVI - Best Available Therapy (BAT) Comparator Treatment Arm BAT -
- Primary Outcome Measures
Name Time Method Percentage of Participants With Clinical Cure at the Test of Cure (TOC) Visit -Microbiological Intent to Treat (Micro-ITT) Analysis Set 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Clinical Cure at the EOT Visit- ME Analysis Set 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.
Percentage of Participants With a Favorable Per Participant Microbiological Response at TOC Visit-Micro-ITT Analysis Set 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).
Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the TOC Visit-ME Analysis Set 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 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 With a Favorable Per Participant Microbiological Response at EOT Visit-ME Analysis Set 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).
Percentage of Participants Who Died Within 28 Days From Randomization- Micro ITT Analysis Set From randomization up to Day 28 Percentage of participants who died due to any cause on or before 28 days after randomization were reported in this outcome measure.
Number of Participants With Abnormal Physical Examination Findings Baseline (last non-missing value observed before start of treatment on Day 1), EOT (Up to 24 hours after the last infusion on Day 14), TOC (Day 28) 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.
Percentage of Participants With Clinical Cure at the TOC Visit-Microbiologically Evaluable (ME) Analysis Set 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.
Percentage of Participants With Clinical Cure at the End of Treatment (EOT) Visit- Micro-ITT Analysis Set 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.
Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the EOT Visit-ME Analysis Set 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 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.
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events From first dose of study treatment (Day 1) until late follow-up visit (Up to Day 45) 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.
Percentage of Participants With a Favorable Per Participant Microbiological Response at EOT Visit-Micro-ITT Analysis Set 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).
Percentage of Participants With a Favorable Per Participant Microbiological Response at TOC Visit-ME Analysis Set 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).
Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the EOT Visit-Micro-ITT Analysis Set 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).
Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the TOC Visit-Micro-ITT Analysis Set 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).
Percentage of Participants Who Died Within 28 Days From Randomization-ITT Analysis Set From randomization up to Day 28 Percentage of participants who died due to any cause on or before 28 days after randomization were reported in this outcome measure.
Number of Participants With Vital Sign Abnormalities From first dose of study treatment (Day 1) until TOC (Up to Day 28) 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.
Number of Participants With Clinically Significant Abnormalities in Hematology Assessments From first dose of study treatment (Day 1) until TOC (Up to Day 28) 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.
Number of Participants With Clinically Significant Abnormalities in Clinical Chemistry Assessments From first dose of study treatment (Day 1) until TOC (Up to Day 28) 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.
Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) From first dose of study treatment (Day 1) until TOC (Up to Day 28) 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.
Trial Locations
- Locations (41)
The First Affiliated Hospital of Shantou University Medical College
🇨🇳Shantou, Guangdong, China
Hunan Province People's Hospital
🇨🇳Changsha, Hunan, China
The First Hospital of Kunming
🇨🇳Kunming, China
Huashan Hospital Fudan University
🇨🇳Shanghai, Shanghai, China
Banner University Medical Center Tucson
🇺🇸Tucson, Arizona, United States
Hospital San Roque
🇦🇷Cordoba, Argentina
Baotou Central Hospital
🇨🇳Baotou, Inner Mongolia Autonomous Region, China
General Hospital of Athens "Evangelismos"
🇬🇷Athens, Greece
General and Chest Diseases Hospital "Sotiria"
🇬🇷Athens, Greece
General Hospital of Athens "Laiko",
🇬🇷Athens, Greece
University General Hospital "ATTIKON", Medicine and Infectious Diseases
🇬🇷Athens, Greece
University General Hospital of Heraklion
🇬🇷Heraklion, Crete, Greece
University General Hospital of Larissa
🇬🇷Larissa, Greece
Government medical College
🇮🇳Kozhikode, Kerala, India
Apollo Hospitals Enterprise Limited
🇮🇳Chennai, Tamil NADU, India
Victoria Hospital, Bangalore Medical College and Research Institute
🇮🇳Bangalore, India
Hospital Kuala Lumpur
🇲🇾Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
University Malaya Medical Centre
🇲🇾Kuala Lumpur, Malaysia
Hospital Civil de Guadalajara "Fray Antonio Alcalde"
🇲🇽Guadalajara, Jalisco, Mexico
Davao Doctors Hospital
🇵🇭Davao City, Philippines
Makati Medical Center
🇵🇭Makati City, Philippines
Manila Doctors Hospital
🇵🇭Manila, Philippines
St. Luke's Medical Center
🇵🇭Quezon City, Philippines
Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"
🇷🇴Bucuresti, Romania
Spitalul Clinic de Boli Infectioase si Tropicale "Dr. Victor Babes"
🇷🇴Bucuresti, Romania
Spitalul Clinic de Boli Infectioase Cluj Napoca
🇷🇴Cluj-Napoca, Romania
Spitalul Clinic Judetean de Urgenta "Pius Brinzeu"
🇷🇴Timisoara, Romania
Spitalul Clinic de Boli Infectioase "Sf. Parascheva" Iasi
🇷🇴Iasi, Romania
SBHI of the city of Moscow "N.I.Pirogov City Clinical Hospital # 1"
🇷🇺Moscow, Russian Federation
OGBUZ "Smolensk Regional Clinical Hospital"
🇷🇺Smolensk, Russian Federation
SRI of Antimicrobial Chemotherapy
🇷🇺Smolensk, Russian Federation
FSBEI of HE "Smolensk State Medical University" of the Ministry of Health of the RF
🇷🇺Smolensk, Russian Federation
Kaohsiung Veterans General Hospital
🇨🇳Kaohsiung, Taiwan
National Taiwan University Hospital
🇨🇳Taipei City, Taiwan
Bamrasnaradura Infectious Disease Institute (BIDI)
🇹🇭Muang, Nonthaburi, Thailand
Srinagarind Hospital, Division of lnfectious Disease and Tropical Medicine
🇹🇭Muang, Khonkaen, Thailand
Faculty of Medicine Siriraj Hospital
🇹🇭Bangkoknoi, Bangkok, Thailand
Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳Kaohsiung City, Taiwan
Deenanath Mangeshkar Hospital And Research Centre
🇮🇳Pune, Maharashtra, India
S.R.Kalla Memorial Gastro & General Hospital
🇮🇳Jaipur, Rajasthan, India
Songklanagarind Hospital, Prince of Songkla University
🇹🇭Hat Yai, Songkhla, Thailand