| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Bacterial Skin and Skin Structure Infection |
| Akutna bakterijska infekcija kože i kožnih struktura |
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| E.1.1.1 | Medical condition in easily understood language |
| Skin infections |
| Infekcija kože |
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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 | 18.0 |
| 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 |
| Primarni cilj ovog ispitivanja je dokazati da dvije intravenske doze od po 100 mg omadaciklina svakih 12 sati (q12h) i jedna intravenska doza od 100 mg svakih 24 sata (q24h) ili oralna doza od 300 mg svakih 24 sata nije inferiorna intravenskim dozama linezolida od po 600 mg svakih 12 sati ili oralnim dozama od po 600 mg svakih 12 sati u liječenju odraslih ispitanika oboljelih od akutne bakterijske infekcije kože i kožnih struktura za koju je poznato ili se sumnja da je izazvana gram-pozitivnim patogenima. |
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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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•Procijeniti sigurnost omadaciklina u liječenju odraslih ispitanika oboljelih od akutne bakterijske infekcije kože i kožnih struktura iz sigurnosne populacije.
•Procijeniti klinički odgovor prema identificiranom uzročnom patogenu.
•Procijeniti farmakokinetiku omadaciklina u odraslih ispitanika oboljelih od akutne bakterijske infekcije kože i kožnih struktura
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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) 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 (oral or rectal temperature > 38.0°C or < 36.0°C
5. Females of child-bearing potential who are less than 2 years post-menopausal must have a negative pregnancy test (beta-human Chorionic Gonadotropin [β-hCG]) at Screening, and agree to comply with using a highly effective form of birth control (eg, abstinence, oral contraceptive, intrauterine device [IUD], barrier contraception [condom], tubal ligation, hysterectomy, bilateral oophorectomy, or vasectomized partner) from Screening through Post Therapy Evaluation (PTE). Males must use a highly effective method of birth control with female partner(s) and must not donate sperm from Screening through Post Therapy Evaluation (PTE)
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1.Potpisan informirani pristanak mora se pribaviti prije provođenja bilo kojeg postupka.
2.Bolesnici oba spola stariji od 18 godina.
3.Infekcija kože i kožnih struktura koja bolesnika kvalificira za ispitivanje.
4.Dokaz sistemskog upalnog odgovora u 24 sata prije randomizacije, na što ukazuje jedno od sljedećeg:
•povišen broj bijelih krvnih zrnaca (≥ 10.000 stanica/mm3) ili leukopenija (≤ 4000 stanica/mm3);
•povišen broj nezrelih neutrofila (≥ 15 % štapićastog oblika) bez obzira na ukupni broj perifernih bijelih krvnih zrnaca;
•uključenje limfe: limfangitis ili limfadenopatija u blizini i na mjestu koje ukazuje na drenažu iz kvalificirane infekcije;
•vrućica ili pothlađenost koje je zabilježio ispitivač (oralna ili rektalna temperatura > 38,0 °C [100,4 °F] ili < 36,0 °C
[95,5 °F]).
5.Bolesnice moraju na probiru imati negativan urinski test na trudnoću te od probira do procjene nakon liječenja moraju pristati na korištenje visokoučinkovitog oblika kontracepcije (na primjer, apstinenciju, oralnu kontracepcije, unutarmaternični uložak, barijernu kontracepciju [kondom], podvezivanje jajovoda, odstranjivanje maternice, bilateralno odstranjivanje jajnika ili vazektomiju partnera). Bolesnici moraju pristati na korištenje visokoučinkovite metode kontracepcije sa ženskim partnericama te ne smiju donirati spermu od probira do procjene nakon liječenja.
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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, congestive heart failure, 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 is known to have 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 |
1.Primanje 1 ili više doza potencijalno učinkovitog sistemskog antibakterijskog lijeka u razdoblju od 72 sata prije primanja prve doze ispitivanog lijeka.
2.Kontinuirano korištenje, iz bilo koje razloga, antibakterijskog agensa za površinsku primjenu sa specifičnom antibakterijskom aktivnošću (na primjer, mupirocin, retapamulin, fusidična kiselina) u razdoblju od 72 sata prije prve doze ispitivanog lijeka, ako je primjenjivan na koži ≥ 72 sata.
3.Infekcije na čiji ishod snažno utječu čimbenici izvan u planu ispitivanja definiranih liječenja i postupaka, a koji zahtijevaju antibakterijsko liječenje dulje od 14 dana, infekcije koje su povezane s kroničnim lezijama kože koje bi mogle omesti utvrđivanje odgovora čak i nakon što je ostvarena uspješna eradikacija bakterija ili infekcije za koje se zna ili se sumnja da su uzrokovane patogenom otpornim na oba ispitivana lijeka,
4.Poznato ili klinički pretpostavljeno jedno ili više od sljedećeg prije randomizacije:
•alanin aminotransferaza (ALT) ili aspartat aminotransferaza (AST) ≥ 2 x gornja granica normale;
•ukupni bilirubin ≥ 1,5 x gornja granica normale;
•dokaz zadnje faze bolesti jetre.
5.Poznata povijest bolesti srčanih nestabilnosti u 3 mjeseca prije probira.
6.Potreba za bilo kojim oblikom dijalize (primjerice, hemodijaliza, peritonealna dijaliza).
7.Povijest ili dokaz ozbiljne bubrežne bolesti ili poznat klirens kreatinina od < 30 ml/min, koristeći Cockroft-Gaultovu jednadžbu (vidi Prilog 1).
8.Dokaz značajne imunološke bolesti utvrđene bilo čime od sljedećeg:
•tekućom ili očekivanom neutropenijom definiranom kao < 500 neutrofila/mm3;
•zaraza HIV-om i broj CD4 limfocita < 200 stanica/mm3 ili druga bolest koja definira AIDS;
•liječenje raka kemoterapijom, zračenjem ili jakim nekortikosteroidnim imunosupresivima u prošla 3 mjeseca ili primanje kortikosteroida u količini ekvivalentnoj ili većoj od 40 g prednizona na dan ili u trajanju duljem od 14 dana u prethodnih 30 dana.
9.Potreba za akutnim farmakološkim zahvatom radi stabilizacije krvnog tlaka i/ili odgovarajuće perfuzije tkiva ili dokaz septičkog šoka definiran svim sljedećim:
•vrućica ili pothlađenost koje je zabilježio ispitivač (oralna ili rektalna temperatura > 38,0 C [100,4 F] ili < 36,0 C[95,5 F];
•puls > 90 otkucaja u minuti;
•brzina disanja > 20 udisaja u minuti;
•broj bijelih krvnih zrnaca > 12.000 stanica/mm3 ili < 4000 stanica/mm3 ili ≥ 10 % nezrelih (štapićastih) neutrofila bez obzira na ukupni broj perifernih bijelih krvnih zrnaca;
•hipotenzija sa sistoličkim krvnim tlakom < 90 mmHg unatoč intravenskoj nadoknadi tekućine od 20-30 cc/kg tijekom razdoblja od 30 minuta;
•perfuzijske abnormalnosti koje mogu uključivati, ali se ne ograničavaju samo na laktacidozu (koncentracija laktata u krvi ≥ 4 mmol/l), oliguriju ili akutnu promjenu mentalnog stanja.
10.Trudnoća i dojenje.
11.Povijest preosjetljivosti ili alergijskih reakcija (na primjer, anafilaksa, urtikarija ili druga značajna reakcija) na bilo koji tetraciklin ili na linezolid.
12.Povijest moždanog pseudotumora ili prethodna (u 2 tjedna prije probira) ili planirana popratna primjena izotretinoina.
13.Povijest sistemskog lupus eritematodesa ili sindrom sličan lupusu.
14.Dokaz trenutnog pankreatitisa.
15.Primanje inhibitora monoamin oksidaze u 14 dana prije probira.
16.Primanje drugog ispitivanog lijeka u 5 poluživota lijeka ili u 30 dana prije probira.
17.Prethodno liječenje omadaciklinom ili prethodna uključenost u ovo ispitivanje.
18.Bilo koji planirani medicinski zahvat koji bi mogao utjecati na mogućnost praćenja zahtjeva iz ispitivanja.
19.Bilo koje popratno stanje koje bi prema mišljenju ispitivača vjerojatno utjecalo na procjenu odgovora ispitivane infekcije, utvrđivanje štetnih događaja ili završetak predviđenog tijeka liječenja. |
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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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•Radi zadovoljavanja zahtjeva različitih zdravstvenih regulatornih tijela, primarne varijable za utvrđivanje učinkovitosti testirat će se prema 2 krajnje točke odgovora:
-uspješan rani klinički odgovor definiran kao preživljavanje sa smanjenjem veličine lezije ≥ 20 % u usporedbi s mjerenjima na probiru i bez primanja bilo kojeg antibakterijskog liječenja za spašavanje;
-uspješan klinički odgovor prema procjeni ispitivača na posjetu za procjenu nakon liječenja, definiran kao preživljavanje nakon završetka liječenja ispitivanim lijekom s rezolucijom ili ublažavanjem znakova i simptoma infekcije u mjeri da daljnje antibakterijsko liječenje više nije potrebno.
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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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-uspješan rani klinički odgovor evaluiran 48 do 72 sata nakon primanja prve doze ispitivanog lijeka
-uspješan klinički odgovor prema procjeni ispitivača na posjetu za procjenu nakon liječenja |
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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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1. Broj i postotak ispitanika klasificiranih kao klinički uspjeh, klinički neuspjeh i neodredivo prema procjeni ispitivača na posjetu za procjenu nakon liječenja u statističkim skupovima modificirane namjere liječenja i klinički procjenjivih za svaku skupinu liječenja.
2.Broj i postotak ispitanika u svakoj skupini liječenja i u svakoj kategoriji odgovora za rani klinički odgovor u statističkom skupu mikrobiološki modificirane namjere liječenja.
3. Broj i postotak ispitanika klasificiranih kao klinički uspjeh i klinički neuspjeh prema procjeni ispitivača na posjetu za procjenu nakon liječenja u statističkom skupu mikrobiološki procjenjivih.
4. Broj i postotak ispitanika s uspješnim ranim kliničkim odgovorom i ispitivačeva procjena kliničkog odgovora na posjetu za procjenu kliničkog uspjeha prema patogenu nakon liječenja (uključujući Gram-negativne uzročne patogene i zlatni stafilokok otporan na penicilin) u statističkim skupovima mikrobiološki modificirane namjere liječenja i mikrobiološki procjenjivih.
5. Smrtnost od svih uzroka u statističkom skupu namjere liječenja.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-At PTE
2-At 48-72h first study dose
3-PTE
4-PTE
5- At 15 and 30 days after the first dose of study drug
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1-na posjetu za procjenu nakon liječenja
2-48 do 72 sata nakon primanja prve doze ispitivanog lijeka
3-posjet za procjenu nakon liječenja
4-posjet za procjenu nakon liječenja
5- 15 do 30 dana nakon primanja prve doze ispitivanog lijeka |
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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 |
| Germany |
| 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
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| Last patient last visit (LPLV) |
| Posljednji ispitanik posljednja posjeta |
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| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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