CTRI/2019/06/019884 [Registered on: 26/06/2019] Trial Registered Prospectively
Last Modified On:
29/06/2021
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Active Controlled Trial
Public Title of Study
A Study to Determine the Effect of Aztreonam-Avibactam for the Treatment of Serious Infections Due to Resistant (MBL-producing) Gram Negative Bacteria.
Scientific Title of Study
A PROSPECTIVE, RANDOMIZED, OPEN-LABEL, COMPARATIVE STUDY TO ASSESS THE EFFICACY, SAFETY AND TOLERABILITY OF AZTREONAM-AVIBACTAM (ATM-AVI) AND BEST AVAILABLE THERAPY FOR THE TREATMENT OF SERIOUS INFECTIONS DUE TO MULTI-DRUG RESISTANT GRAM- NEGATIVE BACTERIA PRODUCING METALLO-Î’-LACTAMASE (MBL)
Trial Acronym
ASSEMBLE
Secondary IDs if Any
Secondary ID
Identifier
2017-004544-38
EudraCT
C3601009 Amendment 1 dated 05-Jul-2018
Protocol Number
NCT03580044
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Artemis Health Sciences Institutional Ethics Committee
Approved
Ethics Committee of Bangalore Medical College and Research Institute. K.R.Road, Fort, Bangalore 560002, Karnataka, INDIA
Approved
Institutional Ethics Committee, Government Medical College
Approved
Institutional Ethics Committee, Lata Mangeshkar Medical Foundation’s, Deenanath Mangeshkar Hospital and Centre,Off Karve Road, Erandawane, Pune 411004
S.R.Kalla Memorial Ethical Committee for Human,Research, S.R.Kalla Memorial Gastro & General Hospital 78-79 Dhuleshwar Garden,Behind HSBC Bank Sardar Patel Marg C-Scheme Jaipur-302001 Rajasthan India
ATM-AVI doses (loading, extended loading and maintenance) and the dosing frequency of the
maintenance dose are dependent on renal function. Subjects will be given a loading dose of
500 mg ATM plus 167 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 30 minutes. This treatment will immediately be followed by an extended loading dose of 1500 mg ATM plus 500 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 3 hours. Then there will be a 3 hour or 5 hour gap. Subjects will receive a maintenance dose of 1500 mg ATM plus 500 mg AVI
every 6 hours or 750 mg ATM plus 250 mg AVI every 6 hours, or 675 mg ATM plus 225 mg AVI every 8 hours.
Subjects with cIAI will also receive Metronidazole (MTZ) 500 mg IV q8h over 60 minutes. The first dose of MTZ will be started immediately after the extended loading dose of ATM-AVI has completed and treatment will be continued until the end of the treatment period.
Comparator Agent
Best Available Therapy (BAT)
The comparator treatments in this study are to be the best available therapy (BAT) based upon site practice and local epidemiology. The choice of BAT for each subject must be recorded prior to randomization. Acceptable BAT may include but not limit to the following Aminoglycoside;
Colistin (or polymixin B if colistin not available /accessible); Fosfomycin; Meropenem; Tigecycline. If the chosen BAT does not provide adequate anaerobic coverage for cIAI subjects
MTZ is to be administered as a co therapy. BAT dose, frequency, dose adjustments with renal impairment will be based on per local package inserts.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
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 nonsusceptible
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 to the power of 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).
ExclusionCriteria
Details
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 greater than 2 X ULN, unless related to the acute infection or due to known Gilberts 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).
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
Proportion of subjects with clinical cure in the microbiological Intent-To-Treat (micro-ITT) analysis set
Up to 31 days
Secondary Outcome
Outcome
TimePoints
Proportion of subjects with clinical cure in the Microbiologically Evaluable (ME) analysis set
up to 31 days
Proportion of subjects with clinical cure in the micro-ITT and ME analysis sets
within 24 hours after the completion of the last infusion of IV study treatment
Proportion of subjects with a favorable per subject microbiological response in the micro ITT and
ME analysis sets
within 24 hours after the completion of the last infusion of IV
study treatment and up to 31 days
Proportion of subjects with a favorable per pathogen microbiological response in the micro ITT and ME analysis sets
Time Frame: within 24 hours after the completion of the last infusion of IV
study treatment and up to 31 days
Proportion of subjects who died on or before 28 days in the Intent-To-Treat (ITT) and micro-ITT analysis sets
from randomization up to 31 days
Incidence and severity of adverse events
from first dose up to 48 days
Incidence of abnormalities in physical examination
Total Sample Size="60" Sample Size from India="14" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
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.
Due to the Character Limitation we could not capture the below few point in the Inclusion criteria. Hence, we are providing the same here:
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)).