| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Community-Acquired Bacterial Pneumonia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pneumonia acquired infectiously from normal contact. |
|
| 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 | 18.1 |
| 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. |
|
| 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 |
|
| 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 (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 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 |
|
| 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) < 30 mL/minute, using the Cockcroft-Gault
equation.
10. Evidence of significant immunologic 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.
|
|
| 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. |
|
| 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 |
|
| 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
|
|
| 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
|
|
| 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 | 3 |
| 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 | 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 |
| Chile |
| 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
|
|
| 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 |
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