E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Community-Acquired Bacterial Pneumonia |
upala pluća stečena izvan bolnice |
|
E.1.1.1 | Medical condition in easily understood language |
Pneumonia acquired infectiously from normal contact. |
upala pluća dobivena preko uobičajenog društvenog kontakta |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010120 |
E.1.2 | Term | Community acquired pneumonia |
E.1.2 | System Organ Class | 100000004862 |
|
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 |
Primary objective: 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/300 mg po once every 24 hours (q24h) is non-inferior to moxifloxacin 400 mg iv/po q24h in the treatment of adults with CABP. |
Primarni cilj: 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 ili oralnim dozama moksifloksacina od po 400 mg svakih 24 sata u liječenju odraslih ispitanika oboljelih od bakterijske izvanbolničke upale pluća. |
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives: • To evaluate the safety of omadacycline in the treatment of adult subjects with CABP in the Safety population. • To evaluate the Clinical Response according to the identified causative pathogen. • To evaluate the pharmacokinetics (PK) of omadacycline in adult subject with CABP |
Sekundarni cilj:•Procijeniti sigurnost omadaciklina u liječenju odraslih ispitanika oboljelih od bakterijske izvanbolničke upale pluća 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.
|
|
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 protocol specific assessment is performed. 2. Male or female, age 18 years or older. 3. Has at least 3 of the following symptoms: • Cough • Production of purulent sputum • Dyspnea (shortness of breath) • Pleuritic chest pain 4. Has at least TWO of the following abnormal vital signs: • Fever or hypothermia documented by the investigator (po or rectal temperature > 38.0°C or < 36.0°C ) •Hypotension with systolic blood pressure (SBP) < 90 mm Hg •Heart rate > 90 beats per minute (bpm) •Respiratory rate (RR) > 20 breaths/minute 5. Has at least 1 clinical sign or laboratory finding associated with CABP: •Hypoxemia (partial pressure of arterial oxygen [PaO2] < 60 mm Hg by arterial blood gas [ABG] or oxygen saturation < 90% by pulse oximetry) •Physical examination findings of pulmonary consolidation (eg, dullness on percussion, bronchial breath sounds, or egophony) •An elevated total white blood cell (WBC) count (> 12,000 cells/mm3) or leucopenia (WBC < 4,000 cells/mm3) or elevated immature neutrophils (> 15% band forms, see % bands calculation in Appendix 4, regardless of total peripheral WBC count) 6. Radiographically-confirmed pneumonia, ie, new or progressive pulmonary infiltrate(s) on chest X-ray (CXR) or chest computed tomography (CT) scan consistent with acute bacterial pneumonia within 24 hours prior to the first dose of test article. 7. Has disease categorized as being PORT Risk Class II, III, or IV at Screening. 8. Is expected to require a minimum of at least 3 days of iv therapy for the initial treatment of CABP. 9. Females must have a negative urine pregnancy test at Screening and agree to comply with using an acceptable method of birth control as per your local requirements (eg, abstinence, po 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 acceptablemethod of birth control with female partner(s) and must not donate sperm from Screening through PTE. |
1.Potpisan informirani pristanak mora se pribaviti prije provođenja bilo kojeg postupka specifičnog za plan ispitivanja. 2.Bolesnici oba spola stariji od 18 godina. 3.Najmanje 3 od sljedećih simptoma: •kašalj; •proizvodnja gnojnog ispljuvka; •dispneja (plitko disanje) •pleuritična bol u prsima. 4.Najmanje dva od sljedećih abnormalnih vitalnih znakova: •vrućica ili pothlađenost koje je zabilježio ispitivač (oralna ili rektalna temperatura > 38,0 °C [100,4 °F] ili < 36,0 °C [95,5 °F]); •hipotenzija sa sistoličkim krvnim tlakom < 90 mmHg; •puls > 90 otkucaja u minuti; •brzina disanja > 20 udisaja u minuti. 5. Najmanje 1 klinički znak ili laboratorijski nalaz povezan s bakterijskom izvanbolničkom upalom pluća: •hipoksemija (parcijalni tlak kisika u arterijskoj krvi [PaO2] < 60 mmHg utvrđena plinskom analizom arterijske krvi ili zasićenje kisikom < 90 % utvrđeno pulsnom oksimetrijom); •nalaz konsolidacije pluća na fizikalnom pregledu (na primjer, perkutorna muklina, bronhijalno disanje, egofonija); •povišen ukupan broj bijelih krvnih zrnaca (> 12.000 stanica/mm3) ili leukopenija (< 4000 stanica/mm3) ili povišeni nezreli neutrofili (≥ 15 % štapićastih neutrofila [za izračun postotka štapićastih neutrofila pogledati prilog 4], bez obzira na ukupni broj perifernih bijelih krvnih zrnaca). 6.Radiološki potvrđena upala pluća, odnosno novi ili progresivni plućni infiltrati na rendgenskom snimku ili kompjutorskoj tomografiji pluća konzistentni s akutnom bakterijskom upalom pluća u 24 sata prije davanja prve doze ispitivanog lijeka. 7.Kategorizacija bolesti na probiru kao klasa II, III ili IV indeksa rizika PORT (vidjeti prilog 2). 8.Očekivanje da će za početno liječenje bakterijske izvanbolničke upale pluća biti potrebna najmanje 3 dana intravenskog liječenja. 9. Bolesnice moraju na probiru imati negativan urinski test na trudnoću te od probira do procjene nakon liječenja moraju pristati na korištenje prihvatljivog oblika kontracepcije prema lokalnim propisima (na primjer, apstinenciju, oralnu kontracepcije, unutarmaternični uložak, barijernu kontracepciju [kondom], podvezivanje jajovoda, odstranjivanje maternice, bilateralno odstranjivanje jajnika, stanje postmenopauze ili vazektomiju partnera). Bolesnici moraju pristati na korištenje prihvatljive metode kontracepcije sa ženskim partnericama te ne smiju donirati spermu od probira do procjene nakon liječenja. |
|
E.4 | Principal exclusion criteria |
1. Has received 1 or more dose(s) of a potentially effective systemic antibacterial treatment within the 72 hours prior to the first dose of study drug. 2. Is known or suspected to have CABP caused by a pathogen that may be resistant to either test article. 3. Suspected or confirmed empyema or lung abscess. 4. Subjects with known or suspected hospital-acquired pneumonia (HAP) or healthcare-associated pneumonia (HCAP). 5. Has known or is clinically suspected to have 1 or more of the following prior to randomization: • 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). 6. Has a known history of having experienced unstable cardiac disease within the 3 months prior to Screening. 7. Has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) > 450 msec (males) or > 470 msec (females), are known to have long QT syndrome, use drugs of potential proarrhythmic or QT prolonging effect, and/or present with tachyarrhythmia. 8. Requires any form of dialysis (eg, hemodialysis, peritoneal dialysis). 9. History or evidence of severe renal disease or has a calculated creatinine clearance (CrCl) of < 30 mL/minute, using the Cockcroft-Gault equation. 10. Evidence of significant immunological disease. 11. Requires acute pharmacologic intervention to stabilize blood pressure (BP) and/or adequate tissue perfusion, OR has evidence of septic shock. 12. Known or suspected primary or metastatic neoplastic lung disease, aspiration pneumonia, active tuberculosis, cystic fibrosis, bronchiectasis, bronchial obstruction (eg, post-obstructive pneumonia), chronic neurological disorder preventing clearance of pulmonary secretions, or severe chronic obstructive pulmonary disease (COPD). 13. Pregnant or nursing (breastfeeding) women. 14. Has a history of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other significant reaction) to any tetracycline (eg, minocycline, doxycycline or tigecycline) or to any fluoroquinolone antibiotic. 15. Has a history of pseudotumor cerebri, or prior (within 2 weeks prior to Screening) or planned concomitant use of isotretinoin. 16. Has a history of systemic lupus erythematosus or lupus-like syndrome. 17. Has current evidence of pancreatitis. 18. Has a history of a central nervous system disorder that may predispose to seizures or lower the seizure threshold. 19. Use of other investigational drugs within 5 half-lives or 30 days prior to Screening, whichever is longer. 20.Has previously been treated with omadacycline or previously enrolled in this study. 21.Any planned medical intervention that might interfere with the ability to comply with the study requirements 22. Has a life expectancy of less than or equal to 3 months or 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 AEs, 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.Bakterijska izvanbolnička upala pluća za koju je poznato ili se pretpostavlja da je izazvana patogenom koji bi mogao biti otporan na oba ispitivana lijeka 3.Pretpostavljeni ili potvrđeni empijem (parapneumonijski pleuralni izljev nije kriterij za neuključivanje) ili plućni apsces. 4.Bolesnici s poznatom ili pretpostavljenom bolničkom upalom pluća ili upalom pluća povezanom sa zdravstvenom njegom. 5.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 (na primjer, ascites ili jetrena encefalopatija). 6. Poznata povijest bolesti srčanih nestabilnosti (na primjer, nestabilna angina, infarkt miokarda, kongestivno zatajenje srca, srčana aritmija…) u 3 mjeseca prije probira. 7. QT-interval korigiran za srčani puls koristeći formulu Fridericia (QTcF) > 450 msec (muškarci) ili > 470 msec (žene), poznat sindrom dugog QT-intervala, korištenje lijekova s potencijalnim proaritmičkim učinkom ili učinkom produljenja QT-intervala i/ili postojanje tahiaritmije. 8. Potreba za bilo kojim oblikom dijalize (primjerice, hemodijaliza, peritonealna dijaliza). 9. Povijest ili dokaz ozbiljne bubrežne bolesti ili izračunat klirens kreatinina od < 30 ml/min, koristeći Cockroft-Gaultovu jednadžbu. 10. Dokaz značajne imunološke bolesti. 11. Potreba za akutnim farmakološkim zahvatom radi stabilizacije krvnog tlaka i/ili odgovarajuće perfuzije tkiva ili dokaz septičkog šoka. 12. Poznata ili pretpostavljena primarna ili metastatska neoplastična bolest pluća, aspiracijska upala pluća, aktivna tuberkuloza, cistična fibroza, bronhiektaza, opstrukcija bronhija (primjerice, postopstruktivna upala pluća, kronični neurološki poremećaj koji sprečava čišćenje plućnih sekreta ili ozbiljna kronična opstruktivna plućna bolest). 13.Trudnoća i dojenje. 14.Povijest preosjetljivosti ili alergijskih reakcija (na primjer, anafilaksa, urtikarija ili druga značajna reakcija) na bilo koji tetraciklin (primjerice, minociklin, doksiciklin ili tigeciklin) ili na bilo koji fluorokinolonski antibiotik. 15.Povijest moždanog pseudotumora ili prethodna (u 2 tjedna prije probira) ili planirana popratna primjena izotretinoina. 16.Povijest sistemskog lupus eritematodesa ili sindrom sličan lupusu. 17.Dokaz trenutnog pankreatitisa. 18.Povijest poremećaja središnjeg živčanog sustava koji bi bolesnika mogao predisponirati za napadaje ili sniziti prag za napadaje. 19.Primanje drugog ispitivanog lijeka u 5 poluživota lijeka ili u 30 dana prije probira. 20.Prethodno liječenje omadaciklinom ili prethodna uključenost u ovo ispitivanje. 21.Bilo koji planirani medicinski zahvat koji bi mogao utjecati na mogućnost praćenja zahtjeva iz ispitivanja. 22.Očekivanje trajanja života od najviše 3 mjeseca ili bilo koje popratno stanje koje bi prema mišljenju ispitivača vjerojatno utjecalo na procjenu odgovora ispitivane infekcije, utvrđivanje štetnih događaja ili završetak predviđenog tijeka liječenja
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy outcome: In order to satisfy different health authorities requirements the primary variables assessing efficacy will be tested with 2 response endpoints: - Successful Early Clinical Response will be determined programmatically and defined as survival with improvement in at least 2 of 4 subject symptoms (cough, sputum production, pleuritic chest pain, dyspnea), as assessed by the investigator, without deterioration in any of these 4 symptoms. - Successful Investigator’s Assessment of Clinical Response , defined as survival after completion of a study drug regimen, with resolution of signs and symptoms of the infection to the extent that further antibacterial therapy is not necessary. |
Primarne krajnje točke odgovora: 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 s poboljšanjem najmanje 2 od 4 simptoma koje ispitanik ima (kašalj, proizvodnja ispljuvka, pleuritična bol u prsima, dispneja) prema procjeni ispitivača i bez pogoršanja bilo kojeg od ta 4 simptoma; -uspješan klinički odgovor prema procjeni ispitivača na posjetu za procjenu nakon liječenja, definiran kao preživljavanje nakon završetka liječenja ispitivanim lijekom s rezolucijom znakova i simptoma infekcije u mjeri da daljnje antibakterijsko liječenje više nije potrebno.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Successful Early Clinical Response (72-120 hours after first dose). -Successful Investigator’s Assessment of Clinical Response at the PTE visit |
-uspješan rani klinički odgovor (72 do 120 sati nakon primanja prve doze ispitivanog lijeka) -uspješan klinički odgovor prema procjeni ispitivača na posjetu za procjenu nakon liječenja |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy variables will include: 1-The number and percentage of subjects classified as a Clinical Success, Clinical Failure and Indeterminate by the Investigator’s Assessment in the Intent-To-Treat (ITT) and Clinically Evaluable (CE) populations. 2-The number and percentage of subjects in each treatment group in each response category for Early Clinical Response will be presented for the Microbiological Intent-To-Treat (microITT) population. The number and percentage of subjects who are classified as a Clinical Success and Clinical Failure by the investigator at the PTE visit in ME population will be calculated. 3-The number and percentage of subjects with an Early Clinical Response of success and an Investigator’s Assessment of Clinical Response of Clinical Success by pathogen will be provided in the Microbiological Intent-To-Treat ( microITT) and Microbiologically Evaluable (ME) populations. 4-All cause mortality
|
Sekundarne krajnje točke ispitivanja: 1. Broj i postotak ispitanika klasificiranih kao klinički uspjeh, klinički neuspjeh i neodredivo prema procjeni ispitivača nakon liječenja u statističkim skupovima namjere liječenja i klinički procjenjivih. 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.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. 3. Broj i postotak ispitanika s uspješnim ranim kliničkim odgovorom i ispitivačeva procjena kliničkog odgovora za procjenu kliničkog uspjeha prema patogenu nakon liječenja u statističkim skupovima mikrobiološki modificirane namjere liječenja i mikrobiološki procjenjivih. 4. Smrtnost od svih uzroka
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-At Post Therapy Evaluation visit (PTE). 2-At PTE. 3- At PTE 4- At 15 and 30 days after the first dose of study drug
|
1-na posjetu za procjenu nakon liječenja 2-na posjetu za procjenu nakon liječenja 3-na posjetu za procjenu nakon liječenja 4-15 i 30 dana nakon uzimanja prve doze ispitivanog lijeka |
|
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 |
|
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 58 |
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 |
Belgium |
Brazil |
Bulgaria |
Croatia |
Czech Republic |
Georgia |
Germany |
Greece |
Hungary |
Israel |
Korea, Republic of |
Latvia |
Mexico |
Peru |
Philippines |
Poland |
Romania |
Russian Federation |
Slovakia |
South Africa |
Spain |
Taiwan |
Turkey |
Ukraine |
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 Patient Last Visit |
Posljednji ispitanik posljednji posjet |
|
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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |