| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Bacterial Skin and Skin Structure Infection |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 18.1 |
| 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 |
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| 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 of this study is to demonstrate that omadacycline 100 mg iv every 12 hours (q12h) for 2 doses, followed by 100 mg iv every 24 hours (q24h)/300 mg po q24h is non-inferior to linezolid 600 mg iv q12h/600 mg po q12h in the treatment of adults with ABSSSI known or suspected to be due to Gram-positive pathogens |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of omadacycline in the treatment of adult subjects with ABSSSI in the Safety population
• To evaluate the Clinical Response according to the identified causative pathogen
• To evaluate the pharmacokinetics (PK) of omadacycline in adult subjects with ABSSSI
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written and signed informed consent must be obtained before any assessment is performed.
2. Male or female, age 18 years or older.
3. Has a qualifying skin and skin structure infection
4.Has evidence of a systemic inflammatory response within the 24 hours prior to randomization as indicated by ONE of the following:
- Elevated white blood cell (WBC) count (≥ 10,000 cells/mm3) or leukopenia (≤ 4,000 cells/mm3)
- Elevated immature neutrophils (≥ 15% band forms, see % bands calculation in Appendix 1) regardless of total peripheral WBC count.
- Lymphatic involvement: lymphangitis or lymphadenopathy that is proximal to and in a location that suggests drainage from the qualifying infection
-Fever or hypothermia documented by the investigator (temperature > 38.0°C or < 36.0°C)
5. Females must have a negative urine pregnancy test at Screening, and agree to comply with using an acceptable method of birth control (eg, abstinence, oral contraceptive, intrauterine device [IUD], barrier contraception [condom], tubal ligation, hysterectomy, bilateral oophorectomy, postmenopausal or vasectomized partner) from Screening through Post Therapy Evaluation (PTE). Males must agree to use an acceptable method of birth control with female partner(s) and must not donate sperm from Screening through Post Therapy Evaluation (PTE)
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| E.4 | Principal exclusion criteria |
1-Has received 1 or more doses of a potentially effective systemic antibacterial treatment within the 72 hour period prior to first dose of study drug.
2. Has, for any reason, used a topical antibacterial agent(s) with specific antibacterial activity (eg, mupirocin, retapamulin, fusidic acid) continuously within the 72 hour period prior to first dose of study drug, if applied to the skin for ≥ 72 hours.
3. Infections where the outcome is strongly influenced by factors other than protocol-defined treatment and procedures, that require antibacterial treatment for greater than 14 days, are associated with chronic skin lesions that may obscure determination of response even after successful bacterial eradication has been achieved, or are suspected or known to be caused by a pathogen resistant to either study drug.
4. Has known or is clinically suspected for one or more of the following prior to randomization:
• Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 2 × Upper Limit of Normal (ULN),
• total bilirubin > 1.5 × ULN, or
• evidence of end-stage liver disease (eg, ascites, hepatic encephalopathy)
5. Has a known history of having experienced unstable cardiac disease (eg, unstable angina, myocardial infarction, acute congestive heart failure, unstable cardiac arrhythmia, etc.) within the 3 months prior to screening.
6. Requires any form of dialysis (eg, hemodialysis, peritoneal dialysis).
7. History or evidence of severe renal disease or has a calculated creatinine clearance (CrCl) of < 30 mL/min, using the Cockcroft-Gault equation.
8. Evidence of significant immunological disease
9. Requires acute pharmacologic intervention to stabilize blood pressure and/or adequate tissue perfusion, OR has evidence of septic shock.
10. Pregnant or nursing (breastfeeding) women.
11. Has a history of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other significant reaction) to any tetracycline (eg, minocycline, doxycycline or tigecycline) or to linezolid.
12. Has a history of pseudotumor cerebri, or prior (within 2 weeks prior to Screening) or planned concomitant use of isotretinoin.
13. Has a history of systemic lupus erythematosus or lupus-like syndrome.
14. Has current evidence of pancreatitis
15. Has received a monoamine oxidase inhibitor within 14 days prior to Screening (eg, phenelzine, isocarboxazid, selegiline, moclobemide; which are typically used to treat depression or Parkinson's Disease).
16. Use of other investigational drugs within 5 half-lives or within 30 days prior to Screening.
17. Has previously been treated with omadacycline or previously enrolled in this study.
18. Any planned medical intervention that might interfere with the ability to comply with the study requirements.
19. Has any concomitant condition that, in the opinion of the investigator, is likely to interfere with evaluation of the response of the infection under study, determination of adverse events, or completion of the expected course of treatment |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy outcome:
In order to satisfy different health authority requirements, the primary variables assessing efficacy will be tested with 2 response endpoints:
-Successful Early Clinical Response, defined as survival with a ≥ 20% reduction of lesion size compared to Screening measurements without receiving any rescue antibacterial therapy.
-Successful Investigator’s Assessment of Clinical Response at the Post Therapy Evaluation (PTE) visit defined as survival after completion of a study drug regimen, with resolution or improvement of signs and symptoms of infection to the extent that further antibacterial therapy is not necessary
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Successful Early Clinical Response is evaluated at 48-72 hours after the first dose of study drug.
-Successful Investigator’s Assessment of Clinical Response assessment at the Post Therapy Evaluation (PTE) visit.
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| E.5.2 | Secondary end point(s) |
1-The number and percentage of subjects classified as a Clinical Success, Clinical Failure and Indeterminate by the Investigator’s Assessment at PTE in the modified intent-to-treat population (mITT) and Clinical Evaluable (CE) populations for each treatment group.
2-The number and percentage of subjects in each treatment group in each response category for Early Clinical Response for the micro-mITT population.
3-The number and percentage of subjects who are classified as a Clinical Success and Clinical Failure by the investigator at the PTE visit in the Microbiologically Evaluable (ME) population.
4-The number and percentage of subjects with an Early Clinical Response of success and an Investigator’s Assessment of Clinical Response at PTE of Clinical Success by pathogen (including Gram-negative causative pathogens and Methicillin-Resistant Staphylococcus aureus (MRSA) will be provided in the micro-mITT and ME populations.
5-All-cause mortality (ACM) in the ITT population.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-At PTE
2-At 48-72h after first study dose
3-PTE
4-PTE
5- At 15 and 30 days after the first dose of study drug |
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| 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.8.2.4 | 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 | 40 |
| 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 |
| Croatia |
| Greece |
| Hungary |
| Israel |
| Latvia |
| Lithuania |
| Mexico |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Turkey |
| Ukraine |
| United States |
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| 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 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 18 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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