| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute bacterial skin and skin structure infections |
|
| E.1.1.1 | Medical condition in easily understood language |
| Bacterial infection of the skin |
|
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052891 |
| E.1.2 | Term | Skin bacterial infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 vancomycin plus aztreonam in patients with ABSSSIs, with respect to investigator-assessed clinical success at the test-of-cure (TOC) visit 15–22 days after randomization, in the co-primary ITT and Clinically Evaluable (CE) populations. |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary objectives:
To demonstrate the non-inferiority of ceftobiprole to vanco+
aztreonam in patients with ABSSSIs with respect to early clinical
response based on percentage reduction in lesion size at 48–72 h
after first treatment in ITT population.
Other secondary objectives include:
To compare ceftobiprole with vanco+aztreonam:
1. Early clinical response based on percentage reduction in lesion size at 48–72 h after first treatment (CE)
2. Clinical response based on percentage reduction in lesion size at EOT and TOC (ITT+CE)
3. Sustained reduction in lesion size at EOT and TOC (ITT)
4. Investigator-assessed clinical success evaluated at 48–72 h after first treatment, EOT, and sustained clinical success at LFU (ITT+CE)
5. ACM through D28 (±2 days) (ITT)
6. Microbiological response at D3, D5, EOT, TOC, LFU (mITT+ME)
7. Safety: incidence, type, severity and relationship to study medication of AEs and changes in lab tests.
8. PK of ceftobiprole.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients meeting all of the following:
1. Male or female, aged ≥ 18 years.
2. Diagnosis of ABSSSI, meeting at least one of the definitions in (a) to (c) below. Local symptoms must have started within the 7 days prior to the Screening visit.
(a) Cellulitis/erysipelas, defined as a diffuse skin infection characterized by all of the following within 24 h:
i. Rapidly spreading areas of erythema, edema, and/or induration with a minimum total lesion surface area of 75 cm2.
ii. No collection of pus apparent upon visual examination.
iii. At least two of the following local signs of infection:
erythema
induration
localized warmth
pain or tenderness on palpation
swelling/edema
(b) Major cutaneous abscess, defined as infection characterized by a collection of pus within the dermis or deeper that is apparent upon visual examination before or after therapeutic intervention and is accompanied by all of the following within 24 h:
i. Erythema, edema and/or induration with a minimum total lesion surface area of 75 cm2.
ii. At least two of the following local signs of infection:
fluctuance
incision and drainage required
purulent or seropurulent drainage
localized warmth
pain or tenderness on palpation
(c) Wound infection, defined as infection of any apparent break in the skin characterized by at least one of the following:
i. Superficial incision/surgical site infection meeting all of the following criteria:
involves only the skin or subcutaneous tissue around the incision (does not involve fascia).
occurs within 30 days of procedure.
purulent drainage (spontaneous or therapeutic) with surrounding erythema, edema and/or induration with a minimum total lesion surface area of 75 cm2.
ii. Post-traumatic wound (including penetrating trauma, e.g., needle, nail, knife, insect and spider bites) meeting the following criterion within 24 h:
Purulent drainage (spontaneous or therapeutic) with surrounding erythema, edema and/or induration with a minimum total lesion surface area of 75 cm2.
3. At least one of the following regional or systemic signs of infection at the Screening visit:
(a) Lymph node tenderness and volume increase, or palpable lymph node proximal to the primary ABSSSI.
(b) Fever ≥ 38°C/100.4°F measured orally, > 38.5 °C / 101.3 °F measured tympanically, , 37.5 °C /99.5 °F measured by the axillary method, or > 39 °C / 102.2 °F measured rectally.
(c) White blood cell (WBC) count > 10.0 × 109/L or < 4.0 × 109/L.
(d) > 10% immature neutrophils (band forms).
4. Requirement for intravenous (IV) antibacterial treatment.
5. Willing and able to adhere to study procedures (including prohibitions and restrictions) as specified in this protocol.
6. Willing and able to remain hospitalized (in a hospital or equivalent medical confinement or clinical research unit) until completion of the early-clinical-response assessment for the primary endpoint.
7. Informed consent signed by the patient, or their legally acceptable representative if appropriate, indicating that they understand the purpose of, and procedures required for, the study, and are willing to participate. |
|
| E.4 | Principal exclusion criteria |
Patients meeting any one of the following:
1. Use of any systemic antibacterial treatment within 14 days, or topical antibacterial administration on the primary lesion within 96 h, before first infusion of study drug.
Exception: Receipt of a single dose of a short-acting (half-life ≤ 12 h) antibacterial therapy (e.g., for surgical prophylaxis) within > 3 days before randomization (i.e., patients cannot have received any antibacterial treatment within 72 h of randomization).
2. Contraindication to the administration of either of the study treatments, including known clinically-relevant hypersensitivity to related antibacterial treatments (e.g., beta-lactam and glycopeptide antibiotics), or to metronidazole if required as adjunctive therapy.
3. Participation in any other clinical study within the 30 days prior to randomization, or any prior participation in this study.
4. The primary ABSSSI is an uncomplicated skin and skin structure infection, such as furuncles, minor abscesses (area of suppuration not surrounded by cellulitis/erysipelas), impetiginous lesions, superficial or limited cellulitis/erysipelas, or minor wound infections (e.g., stitch abscesses).
5. The primary ABSSSI is due to, or associated with, any of the following:
(a) Diabetic foot infection, gangrene, or perianal abscess.
(b) Concomitant infection at another site (e.g., septic arthritis, endocarditis, osteomyelitis), not including a secondary ABSSSI lesion.
(c) Infected burns.
(d) Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular disease (arterial or venous).
(e) Any evolving necrotizing process (e.g., necrotizing fasciitis).
(f) Infections at vascular catheter sites, or involving thrombophlebitis.
6. The primary ABSSSI is associated with, or in close proximity to, a prosthetic device.
7. Patients who are placed in a hyperbaric chamber as adjunctive therapy for the ABSSSI.
8. Patients expected to require more than two surgical interventions in the operating room for the ABSSSI.
9. Severe sepsis or septic shock.
10. Significant or life-threatening condition (e.g., endocarditis, meningitis) that would confound, or interfere with, the assessment of the ABSSSI.
11. Another severe, acute or chronic medical condition, psychiatric condition, or laboratory abnormality that may increase the risks associated with study participation or administration of the investigational product, or may interfere with the interpretation of study results, and which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
12. Receiving treatment for active tuberculosis.
13. Absolute neutrophil count < 0.5 × 109/L.
14. Recent history of opportunistic infections (i.e., within 30 days) if the underlying cause of these infections is still active (e.g., leukemia, transplant, acquired immunodeficiency syndrome [AIDS]).
15. Patients receiving systemic steroids (> 40 mg per day prednisolone, or equivalent), or receiving immunosuppressant drugs.
16. Requirement for peritoneal dialysis, plasmapheresis, hemodialysis, venovenous dialysis, or other forms of renal filtration, or expected to require such treatment before the TOC visit.
17. Alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥ 8× the upper limit of normal, OR severe hepatic disease with Child-Pugh class C.
18. Women who are pregnant or nursing.
19. Women who are of childbearing potential and unwilling to use an acceptable method of birth control during the study: female sterilization (bilateral tubal occlusion or oophorectomy, or hysterectomy) or male partner vasectomy; intrauterine device (IUD); combined (estrogen- and progesterone-containing) hormonal contraception (oral, vaginal ring, or transdermal patch) with an ethinylestradiol dose of at least 30 μg, plus use of male condoms (preferably with spermicides), female condoms, a female diaphragm or a cervical cap; or total sexual abstinence.
Women are not considered to be of childbearing potential if they are either ≥ 1 year post-menopausal (where menopause is defined as at least 12 months of amenorrhea), or have a serum follicle stimulating hormone (FSH) measurement consistent with post-menopausal status according to local laboratory thresholds. An FSH measurement at Screening is to be obtained for post-menopausal females aged < 50 years, or for those aged ≥ 50 years who have been post-menopausal for < 2 years.
20. Inability to start study-drug therapy within 24 h of Screening.
21. Patients with illcit drug use within 12 months or screening, including heroin, other opioids (unleass prescribed for medical reasons unrelated to heroin substitution), cocaine/crack cocaine, and amphetamine/methamphetamine. Exception: Cannabis use. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Investigator-assessed clinical success at the TOC visit 15–22 days after randomization. The TOC visit should be performed at least 5 days after EOT.
Clinical success is defined as complete or nearly complete resolution of baseline signs and symptoms of the primary infection, such that no further antibacterial treatment is needed.
A patient meeting this definition cannot be classified as a clinical success if any of the following criteria are met:
1. Death from any cause prior to TOC.
2. Additional antibacterial therapy received for treatment of the primary lesion.
3. Initiation of non-study antibacterial treatment of another infection, unless the antibacterial agent lacks efficacy in the treatment of ABSSSI.
4. Requirement for an unplanned surgical procedure for the ABSSSI after start of therapy, (other than debridement at bedside or local bedside wound care), with the exception of cellulitis where there is a
conversion into an abscess within 48 h of study treatment initiation, or, for post-surgery patients, when an extension of the original incision is indicated.
5. Indeterminate assessment at TOC for any reason, including but not limited to:
(a) missing TOC visit
(b) lost to follow-up
(c) patient withdrew consent
(d) missing data in relation to signs and symptoms of the ABSSSI
(e) discontinuation from the study due to the need for hemodialysis
The main secondary endpoint is to be assessed in the ITT and CE populations. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Early clinical response 48–72 h after start of treatment based on the patient meeting all of the following criteria:
1. ≥ 20% reduction from baseline in the area (length × width of erythema, edema, or induration) of the primary lesion.
2. Survival for ≥ 72 h from the time of administration of the first dose of study drug.
3. No use of concomitant systemic antibacterial treatments, or topical antibacterial administration on the primary lesion.
4. No additional unplanned surgical procedure for the ABSSSI after start of therapy (other than debridement at bedside or local bedside wound care), with the exception of cellulitis where there is a conversion into an abscess within 48 h of study treatment initiation, or, for post-surgery patients, when an extension of the original incision is indicated.
The primary endpoint is to be assessed in the ITT population.
Standardized measurement of the lesion area (i.e., erythema, edema, or induration, whichever is largest) is to be performed with a flexible plastic ruler or tape measure, by multiplying the longest length of the
lesion by the widest width perpendicular to that length.
In addition, a measurement of the maximum width of erythema or edema/induration from the edge of the wound (surgical or traumatic) or abscess will be recorded. If abscess, the measurement should be
taken from the end of the fluctuance before drainage or from the edge of the drainage site after drainage.
A digital photograph will be obtained at Screening, at the early clinical response assessment (48–72 h after first treatment), and at the EOT and TOC visit, for each patient (primary ABSSSI lesion), and will be used for documentation purposes and as source data. Digital photography will not be used for the measurement of the ABSSSI lesion size area; the determination of the ABSSSI lesion size area
will be solely based on the ruler measurements. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Bulgaria |
| Hungary |
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
