| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated staphylococcus aureus bacteremia (cSAB) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated staphylococcus aureus bacteremia (cSAB) |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058887 |
| E.1.2 | Term | Staphylococcus aureus bacteremia |
| 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 demonstrate the non-inferiority of ceftobiprole to daptomycin for overall success as assessed by an independent Data Review Committee (DRC) in the treatment of S. aureus bacteremia (SAB), including infective endocarditis (IE), at the post-treatment evaluation (PTE) visit in the modified intent-to-treat (mITT) population. |
|
| E.2.2 | Secondary objectives of the trial |
To compare ceftobiprole with daptomycin with respect to:
1. All-cause mortality through Day 70 (PTE visit) and Day 28 in the intent-to-treat (ITT) and mITT populations.
2. Microbiological eradication rates (negative blood culture for S. aureus) at Day 4, Day 8, and the end-of-treatment (EOT) and PTE visits.
3. Overall success rates in the mITT, ITT, and clinically evaluable (CE) populations:
a) at the EOT and PTE visits (ITT and CE populations only)
b) at the EOT and PTE visits, for IE vs non-IE SAB
c) at the EOT and PTE visits, by renal-function status
4. Development of new metastatic foci, or other complications of SAB, after Day 7.
5. Time-to-first-blood-culture-negative for S. aureus, confirmed by a second blood-culture-negative for S. aureus, obtained at least 24 h after the first negative blood-culture.
6. Safety and tolerability (Safety population).
To assess the pharmacokinetics (PK) of ceftobiprole. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 years of age.
2. Informed consent signed by the patient (or by their legally acceptable representative, if appropriate) indicating that they understand the purpose of, and procedures required for, the study and are willing to participate in the study.
3. SAB, based on at least one S. aureus-positive blood culture obtained within the 72 h prior to randomization:
(a) identified by culture laboratory report, or
(b) positive diagnostic test for S. aureus (e.g., polymerase chain reaction [PCR], tube coagulase test and fluorescent in situ hybridization[FISH]) obtained from a blood culture.
Note: The microbiological work-up of the blood culture may:
• Occur prior to informed consent to participation in the study
• Be undertaken either on-site or in an external microbiology laboratory specifically appointed for the purposes of this study.
• Use a diagnostic test:
– routinely performed locally for the detection of S. aureus from blood cultures
or
– provided to the laboratory for the purpose of this study, if the test has regulatory approval in the country where the test is being performed.
Nevertheless, patients without a Central Microbiology Laboratory assessment may be included in the mITT population if there is unequivocal documented evidence of a baseline blood culture positive for S. aureus at the local laboratory
4. At least one of the following signs or symptoms of bacteremia within the 72 h prior to randomization (may be based on measurements obtained before or after informed consent but within the 72 h prior to randomisation):
(a) fever > 38°C/100.4°F measured orally, > 38.5 °C / 101.3 °F measured tympanically, > 37.5° C / 99.5 °F measured by axillary method, or > 39 °C / 102.2 °F measured rectally
(b) white blood cell (WBC) count > 10.0 × 109/L, or < 4.0 × 109/L, or > 10% immature neutrophils (bands)
(c) tachycardia (heart rate > 90 bpm)
(d) hypotension (systolic blood pressure < 90 mmHg)
5. Required duration of study antibacterial treatment ≤ 42 days.
6. SAB in patients undergoing chronic intermittent hemodialysis or peritoneal dialysis.
7. Persistent SAB: documented failure of bloodstream clearance, defined as a positive blood culture for S. aureus within the 72 h prior to randomization, after prior appropriate anti-staphylococcal treatment (except failure under daptomycin therapy) of at least 3 complete days.
8. Other forms of complicated SAB, including the following:
(a) Acute bacterial skin or skin-structure infections (ABSSSIs)
(b) Metastatic infection of native tissue
Examples include but are not limited to:
• Septic arthritis or bacterial joint infection/empyema
• Septic or suppurative thrombophlebitis
• Visceral soft-tissue abscesses requiring ≤ 42 days of study antibacterial treatment
• Septic pulmonary emboli/infarction
Note: The diagnosis of a septic pulmonary embolism will be made by the investigator based on clinical symptoms of fever, cough, putum/hemoptysis in the presence of an extrapulmonary infection, sepsis, or risk factors for septic emboli (e.g., intravenous drug use) and will be based on the following radiological signs:
Contrast-enhanced CT (preferred):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of cavitation) or wedgeshaped infiltrates
– with/without a feeding vessel sign (vessel leading to the nodule)
– with/without pleural effusion or features suggestive of pleural empyema
Non-contrast enhanced CT (e.g., in patients with a contraindication for contrast administration):
Peripheral and/or subpleural multifocal nodular lesions (in different stages of cavitation) or wedgeshaped infiltrates
– with/without pleural effusion or features suggestive of pleural empyema
Plain X-ray (e.g., in patients unable to undergo a CT):
Multifocal nodular densities or wedge-shaped infiltrates in varying stages of cavitation with or without pleural effusion or features suggestive of pleural empyema
9. Definite native-valve right-sided IE (RIE) by Modified Duke’s Criteria
Note: Patients with left-sided infective endocarditis (LIE) are excluded from the study. If LIE is diagnosed after onset of study therapy, patients may be maintained in the study. In the event that the investigator decides to discontinue the study therapy, the patient will be included in the mITT population and considered a failure.
The minimum requirements for a diagnosis of RIE and LIE (Modified Duke’s Criteria), and the minimum diagnostic requirements for other forms of complicated SAB, are provided in Appendix 1 and 2 of the protocol
10. Osteomyelitis (including vertebral, sternal, or long-bone osteomyelitis)
11. Epidural or cerebral abscess
|
|
| E.4 | Principal exclusion criteria |
1. Treatment with potentially effective (anti-staphylococcal) systemic antibacterial treatment for more than 48 h within the 7 days prior to randomization.
2. Bloodstream or non-bloodstream concomitant infections with Gram-negative bacteria that are known (at Screening) to be non-susceptible to either ceftobiprole or aztreonam.
3. Confirmed uncomplicated SAB (e.g., catheter-related non-persistent SAB without signs of SAB complications, unless the patient has end-stage renal disease and is on intermittent hemodialysis or peritoneal dialysis).
4. Left sided infective endocarditis (known or suspected to be present at the time of randomization).
Note: If LIE is diagnosed after onset of study therapy, patients may be maintained in the study. In the event that the investigator decides to discontinue the study therapy, the patient will be included in the mITT population and considered failure.
5. Prosthetic cardiac valves or valve support rings, cardiac pacemakers, automatic implantable cardioverter-defibrillator, or left-ventricular assist devices.
6. Complicated SAB in patients with other foreign body material that cannot be removed within the 7 days after randomization.
Exceptions:
• Patients with non-infected coronary stents may be included regardless of the time of stent implantation.
• Patients with non-infected (no signs or symptoms of clinical involvement at the time of randomization) prosthetic joints, plates, spinal hardware, or other extravascular material may be included if implantation of the foreign material was performed at least 60 days before randomization.
• Patients with non-infected (no signs or symptoms of clinical involvement at the time of randomization) intravascular prosthetic material or vena cava filters may be included if implantation of the foreign material was performed at least 90 days before randomization
7. Cardiac native-valve surgery planned within 3 days after randomization.
8. Community- or hospital-acquired pneumonia.
Note: The diagnosis of pneumonia will be made by the investigator based on respiratory complaints (e.g., cough, dyspnea, purulent secretions, and chest pain) and new or worsening infiltrates suggestive of bacterial pneumonia on a chest radiograph or a high-resolution CT. Equivocal findings on a chest radiograph should be further assessed by the conduct of a high-resolution chest CT (if feasible) and/or the
conduct of lung ultrasound to support the presence or absence of a diagnosis of pneumonia.
9. High probability of death within 7 days due to the underlying SAB or SAB-associated disease, or high probability of death within 28 days from an unrelated underlying disease.
10. Clinically-relevant hypersensitivity to beta-lactam antibacterials or daptomycin.
11. Known infection due to Staphylococcus aureus that exhibits reduced susceptibility to daptomycin (minimum inhibitory concentration[MIC] > 1 mg/L), or ceftobiprole (MIC > 2 mg/L).
12. Absolute neutrophil count < 0.5 × 109/L.
13. Either: a) a history of opportunistic infections (e.g., invasive fungal infections or cytomegalovirus [CMV]) within 30 days prior to randomization, where the underlying cause of these infections is still active (e.g., leukemia, transplant, acquired immunodeficiency Syndrome [AIDS]); or b) CD4 count < 100 cells/mm3 in patients with AIDS; or c) patients treated with cotrimoxazole as prophylaxis for pneumocystis pneumonia.
14. Requirement or expected requirement between randomization and the PTE visit for potentially effective (anti-staphylococcal) systemic antibacterial treatment that is unrelated to the Treatment of SAB, e.g., in the context of planned surgery, gynecological or other procedures requiring antibacterial prophylaxis or other anticipated uses of antibacterials such as treatment for acne vulgaris.
15. Requirement for continuous renal-replacement therapy at the time of randomization, or high likelihood of requirement for continuous renal-replacement therapy during the study period.
Note: Patients undergoing chronic intermittent hemodialysis or peritoneal dialysis are permitted to participate in the study.
16. Alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥ 8 × the upper limit of normal, or severe hepatic disease with Child-Pugh class C.
17. Women who are pregnant or nursing.
18. Women who are of childbearing potential and unwilling to use an acceptable method of birth control during the study:
19. Use of an investigational drug in a Phase I study within the 30 days prior to the study start of study treatment.
Note: Use of investigational drugs in Phase 2 or Phase 3 studies within the 30 days prior to the start of study drug treatment is allowed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall success at the PTE visit (Day 70±5 days post-randomization) in the mITT analysis set, as assessed by the DRC.
The primary endpoint will be tested for the non-inferiority of ceftobiprole versus daptomycin using a non-inferiority margin of 15%.
Overall success is defined as all of the following criteria being met:
1. Patient alive at Day 70 (±5 days) post-randomization.
2. No new metastatic foci or complications of the SAB infection.
3. Resolution or improvement of SAB-related clinical signs and symptoms.
4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus):
• at least one while the patient is on active study treatment; AND
confirmed by at least one subsequent negative blood culture for S. aureus,
- either in the period between 7 days after the EOT visit and the PTE visit
-or at the PTE visit
Treatment failure is defined as any of the following:
1. Premature discontinuation of study treatment due to DRC-assessed lack of efficacy (as assessed by the DRC) or for adverse events (AEs) that represent manifestation of disease progression or relapse, at any time between first dose of study drug and the PTE visit.
2. Development of new metastatic or other complications related to SAB between Day 8 and the PTE visit. Development of new metastatic or other complications of SAB prior to Day 8 will be assessed by the DRC on a case-by-case basis to assess whether These constitute a delayed manifestation of the baseline disease or new complications.
3. SAB relapse or reinfection based on evidence from a blood culture positive for S. aureus (after documented clearance of S. aureus from the bloodstream and clinical improvement) between the EOT and PTE visits.
4. Receipt of systemic non-study antibacterial treatment, other than those permitted under the protocol, for the treatment of SAB. This includes patients who are prematurely discontinued from study therapy due to an AE, but who require continuation of antibacterial treatment for SAB.
5. Treatment of infections other than SAB with systemic non-study antibacterial treatment which is potentially effective against S. aureus , and which is considered by the DRC to have a relevant impact on the primary endpoint
6. Death for any reason between first administration of study drug and the PTE visit.
7. Indeterminate outcome, defined as any data needed to determine whether the outcome is success or failure missing at the PTE visit, including but not limited to:
a) missing PTE visit, or missing key data to evaluate the primary endpoint
b) lost-to-follow-up, or patients who withdrew consent prior to the PTE visit
c) patients not meeting the criteria for Success or Failure, or patients not meeting all criteria for overall success
8. Requirement for systemic antibacterial treatment for SAB beyond EOT. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 70 (±5 days) post-randomization, day 8, beyond EOT |
|
| E.5.2 | Secondary end point(s) |
1. All-cause mortality (mITT population) at Day 70 (PTE visit)
All-cause mortality will also be assessed at Day 28, and in the ITT population, and will be assessed descriptively.
2. Microbiological eradication (mITT population) at Day 70 (PTE visit)
Microbiological eradication will also be assessed in the CE population, and at Day 4, Day 8, and the EOT visit, and will be assessed descriptively.
Eradication: No growth of the baseline pathogen(s), secondary to an adequate clinical response based on a negative blood culture while the patient is on active study treatment which is confirmed by at least one subsequent negative blood culture for S. aureus, either in the period between 7 days after EOT and the PTE visit, or at the PTE visit.
Failure: Persistence relapse, or reinfection of S. aureus infection, defined as one or more of:
• Ongoing positive blood cultures leading to discontinuation for the study drug ,
Subsequent isolation of S. aureus from a blood culture after clearance of bacteremia and clinical improvement,
Relapse bloodstream infection with same pathogen isolated at baseline based on genotyping
Reinfection: blood stream infection with a different S. aureus strain to that isolated at baseline based on genotyping.
• Absence of at least two negative blood cultures (at least one negative blood culture on active study treatment, and at least one post-treatment) to confirm eradication.
Relapse or reinfection between EOT and PTE that is reported to the investigator from a healthcare provider not involved in the study (e.g., from another hospital), needs to be thoroughly documented and will be reviewed by the investigator and the DRC for determination.
3. Overall success rate at PTE (CE population)
The overall success rate will also be assessed at the EOT visit in the mITT, ITT and CE populations, and in the ITT population at the PTE visit, and will be assessed descriptively.
4. Development of new metastatic foci or other complications of SAB after Day 7 (mITT population)
Development of new metastatic foci or other complications of SAB after Day 7 will also be assessed in the CE population, and will be assessed descriptively.
Timepoints: Day 8–EOT, and PTE
Newly diagnosed IE or complicated SAB with metastatic foci or other complications of S. aureus infection, including metastatic foci in the vertebral column (vertebral abscess, osteomyelitis, discitis or epidural abscess), cerebral abscess/infarction, splenic abscess/infarction, renal abscess/infarction, psoas abscess or other deep-tissue abscess, other metastatic infection of native tissue, septic Arthritis (or bacterial joint infection/empyema), septic or suppurative thrombophlebitis and septic pulmonary emboli/infarction.
5. Time to S. aureus bloodstream clearance (mITT and CE populations)
Timepoints: Day 3–EOT
Time-to-first-blood-culture-negative for S. aureus, confirmed by a second blood-culture-negative for S. aureus obtained at least 24 h after the first negative blood-culture.
6. Safety/Tolerability (Safety population)
Timepoints: First dose of study drug–PTE
Incidence, type, severity, and relationship to study medication of AEs; and changes in laboratory tests (hematology, biochemistry including haptoglobin, urinalysis, and Coombs-test).
7. Pharmacokinetics of ceftobiprole (PK population)
Plasma levels of ceftobiprole and the beta-lactam ring-open product BAL1029
Sparse PK sampling (all patients)
• Day 3: predose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
• Day 12: predose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
Rich PK sampling (selected sites, N=40 ceftobiprole-treated patients [i.e., approximately 80 patients overall])
• Day 3: predose before the first BPR/PBO infusion, 2 h (end of infusion), 3 h, 4 h, 6 h
• Day 12: predose before the first BPR/PBO infusion, 2 h (end of infusion), 4 to 6 h
Plasma-concentration data will be analyzed at each time point and will be presented as individual concentrations with descriptive statistics (mean, SD, CV%, min, median, max). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 3, Day 4, Day 7, Day 8, Day 12, Day 28, Day 35, Day 42, Day 70, Day 3-EOT, EOT |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Bulgaria |
| Georgia |
| Germany |
| Hungary |
| Israel |
| Italy |
| Mexico |
| Russian Federation |
| South Africa |
| Spain |
| 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
|
| The End of Study is defined as the completion of the last study-related contact with any patient, referred to as the date of ‘Last Patient, Last Visit’ (LPLV). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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