| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SERIOUS INFECTIONS DUE TO MULTI-DRUG RESISTANT GRAM- NEGATIVE BACTERIA PRODUCING METALLO-Β-LACTAMASE (MBL) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021804 |
| E.1.2 | Term | Infection bacterial |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of aztreonam-avibactam (ATM-AVI) and best available therapy (BAT) at the Test of Cure (TOC) visit in the microbiological intent-to-treat (micro-ITT) population for the treatment of selected serious infections that are due to MBL-producing Gram-negative bacteria. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of ATM-AVI and BAT at the TOC in the
microbiologically evaluable (ME) population, and at the End of Treatment
(EOT) visit in the micro-ITT and ME populations.
- To assess the microbiological response to ATM-AVI at the EOT and TOC visits in the micro-ITT ME populations.
- To assess 28-day all cause mortality.
- To evaluate the safety and tolerability profile of ATM-AVI and to BAT. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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. If a subject is unable to consent for themselves at Screening, the subject’s legally acceptable representative may provide written consent, in accordance with the country-specific regulations. Those subjects who are unconscious or considered by the investigator clinically unable to consent at Screening and who are entered into the study by the consent of a legally acceptable representative should provide their own written informed consent for continuing to participate in the study as soon as possible on recovery, as applicable in accordance with local regulations .
3. Subjects must have a confirmed diagnosis of serious bacterial infection, specifically cIAI, HAP/VAP, cUTI, or BSI requiring administration of IV antibacterial therapy (see additional Inclusion Criteria on HAP/VAP, cIAI, cUTI, or BSI for minimum disease criteria).
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 (the study qualifying pathogen, which was determined to be the causative agent of entry infection and which is available to be sent to the central laboratory). Prior to screening, genotypic confirmation of an MBL-positive pathogen at the local laboratory is required. If this is not possible then selected phenotypic tests may be acceptable with prior approval of the sponsor. In the case of
mixed infection, the subject is allowed to participate in the study if the species are deemed susceptible to ATM-AVI or the investigator considers that the additional species are colonizers which do not warrant specific treatment.
5. Female subjects of nonchildbearing potential must meet at least 1 of the following criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or
physiological cause; and status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c. Have medically confirmed ovarian failure.
Note: All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
6. Female subject of childbearing potential must have a negative serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL.
7. 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):
a. Worsening or lack of improvement of objective symptoms or signs of infection after at least 48 hours of antibacterial therapy.
8. Subject must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Subject has an Acute Physiology and Chronic Health Evaluation (APACHE) II score >30.
2. Clinical judgment by the investigator that the subject has a high likelihood of dying within the specified study treatment period despite delivery of adequate antibiotics for treatment of the index infection.
3. Subject has a history of serious allergy such as anaphylaxis, angioedema and
bronchospasm, hypersensitivity or any serious reactions to any systemic antibacterial which is allowed per protocol including ATM, carbapenem, monobactam or other β-lactam antibiotics, AVI, colistimethate or polymyxin B, nitroimidazoles or MTZ, vancomycin, linezolid, daptomycin, aminoglycosides (eg, amikacin, gentamicin, tobramycin), or any of the excipients of the respective (investigational) medicinal products to be administered during the study.
4. Subject is unlikely to respond to up to 14 days of study treatment.
5. Subject has a concurrent infection that may interfere with the evaluation of response to the study antibiotics.
6. Subject has a need for effective concomitant systemic antibacterials in addition to those allowed per protocol for the diagnoses under study.
7. Subject has known Clostridium difficile associated diarrhoea.
8. Subjects receiving hemodialysis or peritoneal dialysis.
9. Subject has an estimated CrCL ≤ 15 mL/min by Cockcroft-Gault formula (Cockcroft and Gault 1976), receiving or requirement for peritoneal dialysis, haemodialysis or hemofiltration.
10. Presence of hepatic disease as indicated by alanine transaminase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) at Screening. However, subjects with AST and/or ALT up to 5 × ULN are eligible if these elevations are acute and are documented as being directly related to the infectious process being treated.
11. Subject has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly related to the acute infection or due to known Gilbert's disease.
12. Subject has acute hepatitis or acute hepatic failure, cirrhosis or chronic hepatic failure (any Child-Pugh class).
13. Alkaline phosphatase >3.0 × ULN. However, subjects with values >3.0 × ULN and <5.0 x ULN are eligible if this value is acute and directly related to the infectious process being treated. This must be documented.
14. Subject has an absolute neutrophil count <500/mm3.
15. Subject has a perinephric infection.
16. Subject has previously been treated with ATM-AVI.
17. Subject has been previously enrolled in this study.
18. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study treatment and for at least 7 days after the last infusion of investigational product.
19. Subject is participating in or has participated in other studies involving investigational drug(s) within the last 30 days (or five times the half-life of the previously administered investigational compound, whichever is longer) prior to screening and/or during study participation.
20. Subject has other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study (eg, in HAP/VAP subjects with pulmonary disease such as lung cancer, active tuberculosis, cystic fibrosis, granulomatous disease, fungal pulmonary disease
or recent pulmonary embolism).
21. Subject has past or current history of epilepsy or seizure disorders excluding febrile seizures of childhood.
22. Colonisation with an MBL-producing Gram-negative bacteria without signs or symptoms.
23. Subject is unlikely to comply with protocol, eg, uncooperative attitude and
unlikelihood of completing the study.
24. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with clinical cure at the TOC visit in the micro-ITT analysis set. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Test of Cure (Day 28±3 days) |
|
| E.5.2 | Secondary end point(s) |
- Proportion of subjects with clinical cure at the TOC visit in the ME analysis set;
- Proportion of subjects with clinical cure at the EOT visit in the micro-ITT and
ME analysis sets.
- Proportion of subjects with a favourable (defined as eradication or presumed
eradication) per-subject microbiological response at the EOT and TOC visits in
the micro-ITT and ME analysis sets;
- Proportion of subjects with a favourable per-pathogen microbiological response at the EOT and TOC visits in the micro-ITT and ME analysis sets.
- Proportion of subjects who died on or before 28 days from randomization in the Intent-To-Treat (ITT) and micro-ITT analysis sets.
- Safety and tolerability as assessed by adverse events, physical examination, vital signs, electrocardiograms, and laboratory assessments in the safety analysis set. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Test of Cure (Day 28±3 days) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| China |
| India |
| Malaysia |
| Peru |
| Philippines |
| Romania |
| Russian Federation |
| Taiwan |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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