| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of Patients with acute bacterial skin and skin structure infections |
|
| E.1.1.1 | Medical condition in easily understood language |
| skin and skin structure infections |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065240 |
| E.1.2 | Term | Wound infection bacterial |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040872 |
| E.1.2 | Term | Skin infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10042343 |
| E.1.2 | Term | Subcutaneous abscess |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066409 |
| E.1.2 | Term | Staphylococcal skin infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10007882 |
| E.1.2 | Term | Cellulitis |
| 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 |
| The primary objective is to determine the non-inferiority (as defined by the cessation of spread or reduction in size of the baseline lesion at Early Clinical Evaluation (ECE) at 48 to 72 hours and no rescue medication with single-dose intravenous (IV) oritavancin diphosphate (oritavancin) compared with IV vancomycin for 7 to 10 days in the modified intent-to-treat (mITT) population. |
|
| E.2.2 | Secondary objectives of the trial |
Clinical response [CR] (clinical cure [CC]) of single-dose IV oritavancin (ORI) vs 7-10 days IV vancomycin (VAN) treatment at End of Therapy (EOT) visit, sustained to Day 10 (D10) & post therapy evaluation (PTE) visit in mITT population
CR (cessation of spread/reduction in size of the baseline lesion at 48-72h [CSBL]) of ORI vs VAN in clinically evaluable (CE) population
CR (CC) of treatment with ORI vs VAN at EOT visit, D10 & PTE visit in CE population
Efficacy: CR (CSBL & CC) endpoints by pathogen vs VAN treatment in the microbiologically ITT (MITT) & microbiologically evaluable (ME) populations
Microbiological response [MR] of ORI vs VAN treatment in the MITT & ME populations
Incidence of microbiological relapse or recurrence rates at PTE visit in MITT & ME populations
CR & MR in patients in CE & ME populations meeting systemic inflammatory response syndrome
criteria at screening/with +ve blood cultures
Safety & tolerability
PK & PK/PD |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females ≥18 years old
2. Diagnosis of ABSSSI suspected or confirmed to be caused by a Gram-positive pathogen requiring at least 7 days of IV therapy. A specimen for culture must be obtained whenever possible by an approved protocol method 24 hours before the first dose of study drug. Final culture results are not required prior to initiation of study drug.
3. An ABSSSI which includes one of the following infections:
a. Wound infections: that are either traumatic or surgical in origin defined as an infection characterized by purulent drainage from a wound with surrounding erythema, oedema, and/or induration of a minimum surface area of 75 cm2 (eg, the shortest distance of erythema, oedema, and/or induration extending at least 5 cm from the peripheral margin of the wound), accompanied by signs and systemic inflammation symptoms as listed below. Onset of this infection must have occurred within 7 days prior to randomization and no later than 30 days following the trauma or surgical procedure.
b. Cellulitis/erysipelas: a diffuse skin infection characterized by spreading areas of erythema, oedema, and/or induration of a minimum surface area of 75 cm2 (eg, minimum length of 10 cm and width of 7.5 cm), accompanied by signs and systemic inflammation symptoms as listed below. Onset of cellulitis must be within 7 days prior to randomization.
c. Major cutaneous abscess: an infection characterized by a collection of pus within the dermis or deeper that is accompanied by erythema, oedema, and/or induration of a minimum surface area of 75 cm2 (eg, the shortest distance of erythemia, oedema, and/or induration extending at least 5 cm from the peripheral margin of the abscess), accompanied by signs and systemic inflammation symptoms as listed below.
4. ABSSSI must present with at least two of the following signs and symptoms:
a. Purulent drainage or discharge
b. Erythema
c. Fluctuance
d. Heat or localized warmth
e. Oedema/induration
f. Pain or tenderness to palpation
AND At least one of the following signs of systemic inflammation*:
a. Proximal lymph node swelling and tenderness
b. Increased temperature (38.0°C [100.4°F]) (oral route; temperature should not be obtained by rectal, axillary or tympanic routes)
c. Decreased temperature (<36.0°C or [<96.8°F]) (oral route; temperature should not be obtained by rectal, axillary or tympanic routes)
d. Increased WBC (10,000/mm3)
e. Bandemia > 10%
f. C-reactive protein (CRP) > upper limit of normal (ULN)
* If a patient does not have any of the noted signs of systemic inflammation, they may still be enrolled if they meet any of the following conditions:
a. Age >70 years
b. Diabetes mellitus requiring treatment with insulin and/or oral hypoglycaemic medications
c. Treatment with immunosuppressive or chemotherapy in the prior 3 months
5. Able to give informed consent and willing to comply with all required study procedures (if necessary informed consent may be obtained from the patient’s legal representative, with a witness present). |
|
| E.4 | Principal exclusion criteria |
1. Prior systemic or topical antibacterial therapy with activity against suspected or proven Gram-positive pathogens within the preceding 14 days unless: a. The causative Gram-positive pathogen(s) isolated from the ABSSSI site is resistant in vitro to the antibacterial(s) that was administered with documented clinical progression, or b. Documented failure to previous ABSSSI antibiotic therapy is available. Documentation of treatment failure must be recorded (eg, record in patient’s medical chart of wound size prior to initial treatment with demonstration of progression on therapy, discussion with prior treating physician, consultation of patient’s medical records, and/or consultation of available documentation of treatment (eg, prescription) before study randomization, c. Patient received a single dose of a short-acting antibacterial therapy (eg, surgical prophylaxis) three or more days before randomization (ie, patients cannot have received any antibiotic treatment within 72 hours of randomization). 2. Infections associated with, or in close proximity to, a prosthetic device 3. Severe sepsis or refractory shock 4. Known or suspected bacteraemia at time of screening
5. ABSSSI due to or associated with any of the following: a. Infections suspected or documented to be caused by Gram-negative pathogens (ie, human or animal bites, injuries contaminated with fresh or salt water, external malignant otitis) b. Wound infections (surgical or traumatic) and abscesses with only Gram-negative pathogens c. Diabetic foot infections (infection extending distal to the malleoli in a patient with diabetes mellitus and peripheral neuropathy and/or vascular insufficiency or any ulceration of their foot) d. Concomitant infection at another site not including a secondary ABSSSI lesion (eg, septic arthritis, endocarditis, osteomyelitis) e. Infected burns f. A primary infection secondary to a pre-existing skin disease with associated inflammatory changes such as atopic dermatitis, eczema or hidradenitis suppurativa g. Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular disease (arterial or venous) h. Any evolving necrotizing process (ie necrotizing fasciitis), gangrene or infection suspected or proven to be caused by Clostridium species (eg, crepitance on examination of the ABSSSI site and/or surrounding tissue(s) or radiographic evidence of subcutaneous gas in proximity to the infection) i. Infections known to be caused by a Gram-positive organism with a vancomycin minimum inhibitory concentration (MIC) >2 mcg/mL or clinically failing prior therapy with glycopeptides j. Catheter site infections 6. Allergy or intolerance to aztreonam or metronidazole in a patient with suspected or proven polymicrobial wound infection involving Gram-negative and/or anaerobic bacteria 7. Currently receiving chronic systemic immunosuppressive therapy such as chemotherapy or prednisone (prednisone at non-immunosuppressive doses of ≤15 mg/day is permitted) 8. Last known cluster of differentiation 4 (CD4) count <200 cells/mm3 in patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) 9. Neutropenia with absolute neutrophil count (ANC) <500 cells/mm3 10. Significant or life-threatening condition (eg, endocarditis) that would confound or interfere with the assessment of the ABSSSI 11. Women who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 2 acceptable methods of birth control: (eg, prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, barrier method(s) or male partner sterilization). Women ≥2 years postmenopausal or surgically sterile are exempt from this exclusion 12. History of immune-related hypersensitivity reaction to glycopeptides (such as vancomycin, televancin, daptomycin, or teicoplanin) or any of their excipients. Note: patients who have had histamine-like infusion reactions to a glycopeptide are not excluded 13. Patients that require anticoagulant monitoring with an activated partial thromboplastin time (aPTT) 14. Contraindication to vancomycin administration 15. Patients unwilling to forego blood and/or blood product donation for at least 3 months from initiation of first study drug 16. Treatment with investigational medicinal product within 30 days before enrollment and for the duration of the study 17. Investigational device present, or removed within 30 days before enrollment, or presence of device-related infection 18. Patients who the investigator considers unlikely to adhere to the protocol, comply with study drug administration, or complete the clinical study (eg, unlikely to survive 90 days from initiation of study drug) 19. Liver function tests (LFTs) ≥3-times the ULN or total bilirubin ≥2-times ULN 20. Presence or history of hyperuricemia and gouty arthritis 21. Unwilling to refrain from chronic use of any medication with antipyretic properties
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The efficacy outcome is cessation of spread or reduction in size of baseline lesion, absence of fever, and no rescue antibiotic medication at ECE (48 to 72 hours). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Early Clinical Evaluation (ECE) at 48 to 72 hours (Hour 48 to Hour 72) from initiation of first study drug infusion |
|
| E.5.2 | Secondary end point(s) |
Efficacy outcomes:
• Clinical cure determined by the investigator at the End of therapy (EOT), Day 10, and post-therapy evaluation (PTE) visits
• Clinical cure, determined by the investigator, overall and by pathogen, at the EOT visit, Day 10, and at the (PTE) visit
Microbiological outcomes:
• The microbiological response, overall and by pathogen, at the EOT visit, at Day 10, and at the PTE visit
• The microbiological relapse (or recurrence) at the PTE visit
• The clinical response (cessation of spread or reduction in size of baseline lesion/absence of fever and no rescue antibiotic medication and clinical cure) and microbiological response within the CE population and MicroE population respectively meeting SIRS criteria at screening (defined as two of the following: temperature >38°C, pulse >90 bpm, respiratory rate >20 breaths per minute, WBC count >12,000 mm3 or <4,000 mm3 or >10% bandemia) OR with positive blood cultures |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- End of Therapy (EOT) at Day 7 to Day 10 or the day the patient stops study drug or changes to non–study drug therapy for primary ABSSSI
- Day 10 Evaluation defined as 10 days from initiation of the first study drug infusion
- Post therapy evaluation (PTE) at 7 to 14 days from EOT Safety follow up at 60 days (+ 7 days) post first administration of study drug |
|
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Canada |
| Czech Republic |
| France |
| Germany |
| India |
| Israel |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Ukraine |
| United Kingdom |
| 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
|
| Last visit (Day 60) of the last patient |
|
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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