| 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 |
| Acute infection of the skin or structure of the skin due to bacteria |
|
| 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 | 10040872 |
| E.1.2 | Term | Skin 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 |
| The primary objective is to determine the noninferiority (NI) in the early clinical response rate of intravenous (IV) to oral 6 day TR-701 free acid (FA) compared with that of IV to oral 10-day linezolid treatment at 48 72 hours after the first infusion of study drug in the intent-to-treat (ITT) analysis set in patients with acute bacterial skin and skin structure infections (ABSSSI). Early clinical response is defined by lesion area only. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives include the following:
• To compare the programmatic clinical response of 6-day TR-701 FA and 10 day linezolid treatment 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-Therapy Evaluation (PTE) Visit (7-14 days after the EOT Visit) in the ITT and Clinically Evaluable at PTE (CE PTE) 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 (PK) profile of TR-700
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients who meet all of the following diagnostic and inclusion criteria for ABSSSI are eligible for the study:
1. Males or females ≥ 12 years old
2. Adequate venous access for a minimum of 2 IV doses of study drug
3. ABSSSI meeting at least 1 of the clinical syndrome definitions listed below and requiring IV 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, edema, and/or induration of a minimum total lesion 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 2 of the following signs of infection:
Erythema
Induration
Localized warmth
Pain or tenderness on palpation
Swelling/edema
• At least 1 of the following regional or 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 (101.3°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 apparent upon visual examination spreading within the dermis or deeper that is accompanied by all of the following within 24 hours:
• Erythema, edema, and/or induration extending at least 5 cm in the shortest distance from the peripheral margin of the abscess and with a minimum total lesion surface area of 75 cm2
• 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 regional or 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 (101.3°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 incision surgical site infection 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 (spontaneous or therapeutic) with surrounding erythema, edema, and/or induration extending at least 5 cm in the shortest distance from the peripheral margin of the wound and with a minimum total lesion surface area of 75 cm2
At least 1 of the following regional or 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 (101.3°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 (spontaneous or therapeutic) with surrounding erythema, edema, and/or induration extending at least 5 cm in the shortest distance from the peripheral margin of the wound and with a minimum total lesion surface area of 75 cm2
At least 1 of the following regional or 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 (101.3°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
4. Suspected or documented gram-positive infection from baseline Gram stain or culture. The microbiological 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. Specimens for culture are required for abscesses and wounds at Screening; cellulitis specimens are to be collected according to standard practice at the site
5. Able to give informed consent and willing to comply with all required study procedures
|
|
| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria are not eligible to participate in this study:
1. Uncomplicated skin and skin structure infections 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. However, arthropod (eg, insects, spiders, ‘bugs’) bites are allowed; these are not considered animal bites in this study
• Infections at vascular catheter sites or involving thrombophlebitis
• Incision surgical site infection 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; chronic open wounds to be grafted or covered)
Follows dirty surgery (purulent inflammation [eg, abscess]; preoperative perforation of respiratory, gastrointestinal, biliary, or genitourinary tract)
Extends into the fascia 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 the first infusion 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 the first infusion of study drug
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. Chronic (daily for the previous 30 days) use of antipyretic medication (eg, acetaminophen, paracetamol, nonsteroidal anti-inflammatory drugs). Low-dose aspirin (≤ 200 mg per day) for cardiovascular prophylaxis is allowed
11. Receiving treatment for active tuberculosis
12. Last known CD4 count < 200 cells/mm3 in patients with AIDS
13. Current or anticipated neutropenia with absolute neutrophil count (ANC) < 1000 cells/mm3
14. 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
15. ALT or AST ≥ 8 x upper limit of normal OR severe hepatic disease with Child Pugh score >9 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
To calculate the Child-Pugh score, see Section 6.1
16. 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
17. Triptan treatment for migraine headaches within 3 years
18. ECG finding of corrected QT interval > 500 msec using Bazett’s correction method (QTcB) or Fridericia’s correction method (QTcF)
19. to 29. Not listed due to charakter limitations |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy outcome is the early clinical response rate at 48-72 hours after the first infusion of study drug in the ITT analysis set. Early clinical response (responder [≥20% reduction from baseline in the area of erythema, edema, and/or induration from baseline of the primary ABSSSI lesion] and nonresponder) will be determined programmatically from lesion area measurements data recorded on the electronic case report form (e-CRF). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary outcome measures are the following:
• Clinical response at the EOT Visit in the ITT and CE-EOT analysis sets
• Investigator’s assessment of clinical success at the PTE Visit in the ITT and CE-PTE analysis sets. Patients assessed as a clinical failure at the EOT Visit are considered a clinical failure at the PTE Visit
• Investigator’s assessment of clinical response at the 48-72 Hour and Day 7 Visits
• Change from baseline in the pain scores at each time point
Additional Efficacy Outcomes
• Change from baseline in lesion size, assessment of local signs and symptoms, and regional or systemic signs (lymphadenopathy, temperature, percentage immature neutrophils, WBC count)
• Per-patient favorable (eradication or presumed eradication) microbiological response at the PTE Visit in the microbiological ITT (MITT) and microbiologically evaluable (ME) analysis set. Per-patient microbiological response is based on per-pathogen outcomes
• Per-pathogen microbiological response at the PTE Visit in the MITT and ME analysis sets
• Investigator’s assessment of clinical success at the PTE Visit in the MITT and ME analysis sets
• Per-pathogen Investigator’s assessment of clinical success at the PTE Visit in the MITT and ME analysis sets
Safety Outcomes
Safety will be assessed through summaries of AEs, laboratory evaluations (hematology and chemistry), vital signs, ECGs, physical examinations.
Pharmacokinetic Analysis
The objectives of the population PK analysis are:
• To characterize the PK profile of TR-700 in patients, including estimation of typical PK
parameters and interindividual and residual variability
• To estimate the effects of individual-specific covariate factors of TR-700 PK in this population
• To provide individual metrics of TR-700 exposure for modeling probabilities of clinical success, microbiological response, or safety outcomes
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 48-72 Hour Visit; Day 7 Visit; EOT Visit (Day 11); PTE Visit |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Linezoid tablets and Linezoid IV |
|
| 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 | 35 |
| 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 |
| Australia |
| Brazil |
| Germany |
| Greece |
| New Zealand |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Thailand |
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
