| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Bacterial Skin and Skin Structure Infections |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040872 |
| E.1.2 | Term | Skin infection |
|
| 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 noninferiority (NI) in the early clinical response rate of 6-day oral TR-701 free acid (FA) compared with that of 10-day oral linezolid treatment at 48-72 hours in the Intent-to-Treat (ITT) analysis set in patients with ABSSSI. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives include the following:
To compare the early clinical response of 6-day TR-701 FA and 10-day linezolid treatment at 48-72 hours that is sustained at the End of Therapy (EOT) Visit (Day 11) in the ITT and Clinically Evaluable at EOT (CE-EOT) analysis sets
♦ To compare the Investigator’s assessment of clinical success at the Post-Treatment Evaluation (PTE) Visit (7-14 days after the EOT Visit) in the ITT and Clinically Evaluable at PTE (CEPTE) analysis sets
♦ To compare the Investigator’s assessment of clinical response at the 48-72 Hour and Day 7 Visits in the ITT analysis set
♦ To compare patient-reported pain, by study visit
♦ To evaluate the safety profile of TR-701 FA in comparison with that of linezolid
♦ To assess the population pharmacokinetic profile of TR-700 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females ≥ 18 years old
2. ABSSSI meeting at least 1 of the clinical syndrome definitions listed below and requiring systemic oral antibiotic therapy. Local symptoms must have started within 7 days before the Screening Visit.
A. Cellulitis/erysipelas defined as a diffuse skin infection, characterized by all of the
following within 24 hours:
♦ Rapidly spreading areas of erythema of a minimum surface area of 75 cm2
♦ No collection of pus apparent upon visual examination (diagnosis still consistent with cellulitis/erysipelas if pus is collected from the lesion)
♦ At least 1 of the following signs of infection:
◊ Induration
◊ Localized warmth
◊ Pain or tenderness on palpation
◊ Swelling
♦ At least 1 of the following systemic signs of infection:
◊ Lymph node tenderness and increase in volume or palpable proximal to the
primary ABSSSI
◊ Fever, defined as body temperature ≥ 38°C (100.4°F) oral, ≥ 38.5°C (101.2°F)
tympanic, or ≥ 39°C (102.2°F) rectal (observed by a health care provider)
◊ White blood cell (WBC) count ≥ 10,000 cells/mm3 or < 4000 cells/mm3
◊ > 10% immature neutrophils
B. Major cutaneous abscess defined as an infection characterized by a collection of pus within the dermis or deeper that is accompanied by all of the following within 24 hours:
♦ Erythema extending at least 5 cm from the peripheral margin of the abscess
♦ At least 1 of the following signs of infection:
◊ Fluctuance
◊ Incision and drainage required
◊ Purulent or seropurulent drainage
◊ Localized warmth
◊ Pain or tenderness on palpation
♦ At least 1 of the following systemic signs of infection:
◊ Lymph node tenderness and increase in volume or palpable proximal to the
primary ABSSSI
◊ Fever, defined as body temperature ≥ 38°C (100.4°F) oral, ≥ 38.5°C (101.2°F)
tympanic, or ≥ 39°C (102.2°F) rectal (observed by a health care provider)
◊ WBC count ≥ 10,000 cells/mm3 or < 4000 cells/mm3
◊ > 10% immature neutrophils
C. Wound Infection defined as an infection of any apparent break in the skin characterized by the following:
♦ Superficial incisional SSI meeting all of the following criteria:
◊ Follows clean surgery (elective, not emergency, nontraumatic, primarily closed,
no acute inflammation; no break in technique; respiratory, gastrointestinal,
biliary, and genitourinary tracts not entered)
◊ Involves only the skin or subcutaneous tissue around the incision, does not
involve fascia
◊ Occurs within 30 days after procedure
◊ Original surgical incision ≥ 3 cm
◊ Purulent drainage from a wound with surrounding erythema extending at least 5
cm from the peripheral margin of the wound
◊ At least 1 of the following systemic signs of infection:
- Lymph node tenderness and increase in volume or palpable proximal to the
primary ABSSSI
- Fever, defined as body temperature ≥ 38°C (100.4°F) oral, ≥ 38.5°C
(101.2°F) tympanic, or ≥ 39°C (102.2°F) rectal (observed by a health care
provider)
- WBC count ≥ 10,000 cells/mm3 or < 4000 cells/mm3
- > 10% immature neutrophils
♦ Post-traumatic wound (including penetrating trauma [needle, nail, knife])
characterized by all of the following within 24 hours:
◊ Purulent drainage from a wound with surrounding erythema extending at least 5
cm from the peripheral margin of the wound
◊ At least 1 of the following systemic signs of infection:
- Lymph node tenderness and increase in volume or palpable proximal to the
primary ABSSSI
- Fever, defined as body temperature ≥ 38°C (100.4°F) oral, ≥ 38.5°C
(101.2°F) tympanic, or ≥ 39°C (102.2°F) rectal (observed by a health care
provider)
- WBC count ≥ 10,000 cells/mm3 or < 4000 cells/mm3
- > 10% immature neutrophils
3. Suspected or documented gram-positive infection from baseline Gram stain or culture. The sample must have been collected using a valid sampling technique such as an aspirate, biopsy, incision, deep swab, etc. A superficial swab is not acceptable
4. Able to give informed consent and willing to comply with all required study procedures |
|
| E.4 | Principal exclusion criteria |
1.Uncomplicated skin and skin structure infections (SSSIs) such as furuncles, minor abscesses (area of suppuration not surrounded by cellulitis/erysipelas), impetiginous lesions, superficial or limited cellulitis/erysipelas, and minor wound infections (eg, stitch abscesses)
2. Infections associated with, or in close proximity to, a prosthetic device
3. Severe sepsis or septic shock
4. Known bacteremia at time of screening
5. ABSSSI due to or associated with any of the following:
♦ Suspected or documented gram-negative pathogens in patients with
cellulitis/erysipelas or major cutaneous abscess that require an antibiotic with specific
gram-negative coverage. Patients with wound infections where gram-negative
adjunctive therapy is warranted may be enrolled if they meet the other eligibility
criteria
♦ Diabetic foot infection, gangrene, or perianal abscess
♦ Concomitant infection at another site not including a secondary ABSSSI lesion (eg,
septic arthritis, endocarditis, osteomyelitis)
♦ Infected burns
♦ Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular disease
(arterial or venous)
♦ Any evolving necrotizing process (ie, necrotizing fasciitis)
♦ Infected human or animal bites
♦ Infections at vascular catheter sites or involving thrombophlebitis
♦ Incisional SSI with any of the following characteristics:
◊ Follows clean-contaminated surgery (urgent or emergency case that is otherwise
clean, elective opening of respiratory, gastrointestinal, biliary, or genitourinary
tract with minimal spillage [eg, appendectomy] not encountering infected urine or
bile; minor technique break)
◊ Follows contaminated surgery (nonpurulent inflammation; gross spillage from
gastrointestinal tract; entry into biliary or genitourinary tract in the presence of
infected bile or urine; major break in technique)
◊ Follows dirty surgery (purulent inflammation [eg, abscess]; preoperative
perforation of respiratory, gastrointestinal, biliary, or genitourinary tract)
◊ Extends into the fascial or muscle layers, organs, or spaces
6. Use of antibiotics as follows:
◊ Systemic antibiotic with gram-positive cocci activity for the treatment of any
infection within 96 hours before Dose 1 of study drug
◊ Patients who failed prior therapy for the primary infection site are also excluded
from enrollment
◊ Topical antibiotic on the primary lesion except for antibiotic/antiseptic-coated
dressing applied to the clean postsurgical wound
7. Administration of linezolid within 30 days before Dose 1
8. Recent history of opportunistic infections where the underlying cause of these infections is still active (eg, leukemia, transplant, acquired immunodeficiency syndrome [AIDS])
9. Receiving chronic systemic immunosuppressive therapy such as prednisone doses ≥ 20 mg per day for ≥ 3 of the last 12 months OR therapies that in the Investigator’s judgment could predispose to opportunistic infections
10. Receiving treatment for active tuberculosis
11. Last known CD4 count < 200 cells/mm3 in patients with AIDS
12. Current or anticipated neutropenia with ANC < 1000 cells/mm3
13. Severe renal disease defined as creatinine clearance (CrCl) < 30 mL/min estimated by the Cockcroft-Gault formula OR requirement for peritoneal dialysis, plasmapheresis, hemodialysis, venovenous dialysis, or other forms of renal filtration
14. ALT or AST ≥ 5 upper limit of normal OR moderate to severe hepatic disease with Child-Pugh score ≥7 defined by the following:
♦ Presence of ascites upon examination
♦ Evidence of encephalopathy upon examination
♦ Total bilirubin ≥ 2 mg/dL
♦ Serum albumin ≤ 3.5 g/dL
♦ Prothrombin time (PT) ≥ 4 seconds longer than control, or international normalized
ratio (INR) ≥ 1.7
15. Significant or life-threatening condition or organ or system condition or disease
(eg, endocarditis, meningitis) that would confound or interfere with the assessment of the ABSSSI
16. Morbid obesity with body mass index (BMI) ≥ 40 kg/m2
17. Physician-diagnosed migraine headaches within 3 years
18. ECG finding of QTc interval > 500 msec
19. Hypertensive crisis, pheochromocytoma, carcinoid syndrome, or thyrotoxicosis
20. Use of the following medications within 2 days before Dose 1, or planned use through the EOT Visit
♦ Systemic directly and indirectly acting sympathomimetic agents, vasopressive agents, or dopaminergic agents
21. Use of the following medications within 14 days before Dose 1, or planned use through the EOT Visit :
♦ Monoamino oxidase A and B inhibitors
♦ Serotonergic agents including antidepressants such as selective serotonin reuptake
inhibitors, tricyclic antidepressants, and serotonin 5-hydroxytryptamine
receptor agonists, meperidine, or buspirone
22. High tyramine diet
23. Women who are pregnant or nursing, or who are of childbearing potential and unwilling to use an acceptable method of birth control or male patient sterilization |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy outcome is the early clinical response rate at the 48-72 Hour Visit in the ITT analysis set. Early clinical response (responder [afebrile with cessation of spread from baseline of the primary ABSSSI lesion], nonresponder) will be determined programmatically from lesion measurements and temperature data recorded on the e-CRF. |
|
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 27 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 | 0 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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