| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Community-acquired bacterial pneumonia (CABP) is a commonly occurring serious infection that requires systemic antibiotic therapy and is associated with substantial morbidity, mortality, and considerable healthcare costs.It is the leading cause of death from infectious diseases |
|
| E.1.1.1 | Medical condition in easily understood language |
| Community-acquired bacterial pneumonia (CABP) is a commonly occurring serious infection that requires systemic antibiotic therapy |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004051 |
| E.1.2 | Term | Bacterial pneumonia, unspecified |
| 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 Objectives
• Demonstrate the non-inferiority (NI) of lefamulin versus comparator with respect to the Early Clinical Response (96 ± 24 hours after the first dose of study drug) in the Intent-to-Treat (ITT) Analysis Set (FDA endpoint).
• Demonstrate the NI of lefamulin versus comparator with respect to the Investigator’s Assessment of Clinical Response at Test of Cure (TOC) (i.e., 5-10 days after the last dose of study drug) in the modified-ITT (mITT) and Clinically Evaluable at TOC (CE-TOC) Analysis Sets (EMA endpoint). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
• Evaluate the Early Clinical Response in the Microbiological Intent-to-Treat (microITT) Analysis Set.
• Evaluate the Investigator’s Assessment of Clinical Response at TOC in the microITT and Microbiologically Evaluable at TOC (ME-TOC) Analysis Sets.
• Evaluate the By-Pathogen Microbiologic Response at TOC in the microITT and ME-TOC Analysis Sets.
• Evaluate the safety and tolerability of lefamulin versus comparator in the Safety Analysis Set.
• Evaluate 28 day all-cause mortality in the ITT Analysis Set. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Be male or female ≥ 18 years of age.
2. Provide written informed consent and be willing and able to adhere to the study-specified procedures and restrictions. NOTE: Consent may be provided by the subject’s legally authorized representative in accordance with local regulations.
3. Have an acute illness (≤ 7 days duration) with at least 3 of the following symptoms consistent with a lower respiratory tract infection (new or worsening):
• Dyspnea.
• New or increased cough.
• Purulent sputum production.
• Chest pain due to pneumonia.
4. Have at least 2 of the following vital sign abnormalities:
• Fever (body temperature > 38.0 °C (100.4 °F) measured orally or equivalent temperature from an alternate body site) or hypothermia (body temperature < 35.0 °C (95.0 °F) measured orally or equivalent temperature from an alternate body site).
• Hypotension (systolic blood pressure < 90 mmHg).
• Tachycardia (heart rate > 100 beats/min).
• Tachypnea (respiratory rate > 20 breaths/min).
5. Have at least 1 other clinical sign or laboratory finding of CABP:
• Hypoxemia (i.e., O2 saturation < 90 % on room air or while receiving supplemental oxygen at subject’s baseline requirement or PaO2 < 60 mmHg).
• Auscultatory and/or percussion findings consistent with pneumonia (e.g., crackles, egophony, dullness).
• White blood cell (WBC) count > 10 000 cells/mm3 or < 4 500 cells/mm3 or > 15 % immature neutrophils (bands) regardless of total WBC count.
6. Have radiographically-documented pneumonia within 48 hours before enrollment (i.e., infiltrates in a lobar or multilobar distribution or diffuse opacities on chest x-ray consistent with acute bacterial pneumonia). NOTE: if a chest computed tomography scan
has been performed within 48 hours of enrollment and demonstrates findings consistent with pneumonia, it can be used in place of a chest x-ray.
7. Have a Pneumonia Outcomes Research Team (PORT) Risk Class of II, III, or IV and be an appropriate candidate for oral antibiotic therapy as treatment for the current episode of CABP.
8. If female, meets the following criteria:
• Surgically sterile or ≥ 2 years postmenopausal, or if of childbearing potential (including being < 2 years postmenopausal), has a negative pregnancy test, and if participating in sexual activity that may lead to pregnancy, agrees to use an effective dual method of contraception (e.g., condom plus diaphragm, condom plus spermicide, intrauterine device plus spermicide) during the study and for ≥ 28 days after the last dose of study drug. If a male partner has been surgically sterile for ≥ 1 year, a single contraception method may be used. NOTE: The use of contraceptives containing progesterone is not permitted.
Agrees not to breastfeed during the study and through ≥ 28 days after the last dose of study drug.
9. If male, meets the following criteria:
• If not surgically sterile and if participating in sexual activity that may lead to pregnancy, agrees to use an effective dual method of contraception (e.g., condom plus diaphragm, condom plus spermicide, intrauterine device plus spermicide, oral contraceptive plus condom) during the study and through ≥ 28 days after the last dose of study drug. If surgically sterile for ≥ 1 year, a single contraception method may be used. |
|
| E.4 | Principal exclusion criteria |
1. Have received more than a single dose of a short-acting oral or IV antibacterial for CABP within 72 hours before randomization 2. Require concomitant systemic antibacterial therapy potentially effective against CABP pathogens
3. Have been hospitalized for 2 or more days within 90 days prior to the onset of symptoms or have resided in a nursing home or long-term healthcare facility within 30 days prior to the onset of symptoms.
4. Have confirmed or suspected CABP caused by a pathogen known to be resistant to any of
the study drugs (e.g., MRSA, Pseudomonas aeruginosa, any pathogen of the
Enterobacteriaceae Family) or attributable to etiologies other than community-acquired bacterial pathogens (e.g., ventilator-associated pneumonia, hospital-acquired bacterial pneumonia, bacterial aspiration pneumonia, Pneumocystis jiroveci pneumonia or other
fungal pneumonia, viral or mycobacterial infection of the lung).
5. Have a noninfectious cause of pulmonary infiltrates (e.g., pulmonary embolism, chemical pneumonitis from aspiration, hypersensitivity pneumonia, congestive heart failure, bronchial obstruction, lung cancer, cystic fibrosis).
6. Have confirmed or suspected pleural empyema (does not include sterile parapneumonic effusions).
7. Have or be at risk for major cardiac events or dysfunction including, but not limited to, the following:
• Known prolonged QT interval or family history of long QT syndrome
• Clinically significant hypokalemia which has not been treated prior to randomization
• Clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling pacemaker
• Complete left bundle branch block
• Receipt within 7 days before enrollment of Class IA or Class III anti-arrhythmic medication or, in the opinion of the Investigator, subject may require such medication during the study. (Class 1A: Quinidine, Procainamide, Disopyramide; Class III: Amiodarone, Dofetilide, Ibutilide, Sotalol)
• Receipt within 7 days before enrollment of medication that has the potential of prolonging the QT interval or, in the opinion of the Investigator, subject may require such medication during the study
8. Be receiving a strong p-glycoprotein inhibitor or a strong CYP3A inducer or inhibitor
9. Have a history of tendon disease/disorder, myasthenia gravis, or known or suspected central nervous system (CNS) disorders (severe cerebrovascular arteriosclerosis, epilepsy, or other risk factors that may predispose to seizures).
10. Have a history of any hypersensitivity or allergic reaction to any fluoroquinolone, or any drug in the pleuromutilin class (i.e., retapamulin).
11. Have severely impaired renal function, defined as estimated creatinine clearance (CrCl) ≤ 30 mL/min as calculated by the Cockcroft-Gault formula.
12. Have evidence of significant hepatic, hematologic, or immunologic disease including any of the following:
• Known acute hepatitis, including acute viral hepatitis.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level > 5 times the upper limit of normal (ULN),
• Total bilirubin > 3 times the ULN (unless known Gilbert’s disease).
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level > 3 times the upper limit of normal (ULN) and total bilirubin > 2 times the ULN.
• History of cirrhosis of the liver.
• Manifestation of end-stage liver disease, such as ascites or hepatic encephalopathy.
• Current or anticipated neutropenia (< 500 neutrophils/mm3).
• Thrombocytopenia (< 50 000 platelets/mm3).
• Known infection with human immunodeficiency virus and a CD4 count < 200/mm3.
13. Have known severe immunosuppression, including but not limited to receipt of corticosteroid therapy (≥20 mg of prednisone/day or equivalent for >4 weeks) within the previous 8 weeks; solid organ or bone marrow transplantation within the previous 12 months; or currently receiving cytotoxic chemotherapy.
14. Have a life expectancy of ≤ 3 months because of any disease other than the current episode of CABP (e.g., current or impending respiratory failure, acute heart failure, shock, acute coronary syndrome, unstable arrhythmia, hypertensive emergency, clinically relevant gastrointestinal bleeding, profound metabolic abnormality, or acute cerebrovascular event).
15. Have participated in any study involving administration of an investigational agent or device within 30 days or ≤ 5 terminal elimination half-lives of the previous investigational medicinal product, whichever is longer, before enrollment.
16. Have been previously treated with lefamulin or previously enrolled in this study.
17. Have any condition that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Demonstrate the non-inferiority (NI) of lefamulin versus comparator with respect to the Early Clinical Response (96 ± 24 hours after the first dose of study drug) in the Intent-to-Treat (ITT) Analysis Set (FDA endpoint).
• Demonstrate the NI of lefamulin versus comparator with respect to the Investigator’s Assessment of Clinical Response at Test of Cure (TOC) (i.e., 5-10 days after the last dose of study drug) in the modified-ITT (mITT) and Clinically Evaluable at TOC (CE-TOC) Analysis Sets (EMA endpoint). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The EMA supports assessment of clinical response by Investigators at a test of cure (TOC) visit, while the FDA adopted assessment of clinical signs and symptoms of CABP on Days 3 to 5 as the recommended primary endpoint.
FDA endpoint - 96 hours +/- 24 hours
EMA endpoint - 2 days after the last dose of study drug |
|
| E.5.2 | Secondary end point(s) |
Please use the following for secondary endpoints - the time of evaluation is in parentheses after the endpoint:
Secondary Objectives
- Evaluate the Early Clinical Response in the Microbiological Intent‑to‑Treat (microITT) Analysis Set. (96 ± 24 hours after the first dose of study drug)
- Evaluate the Investigator’s Assessment of Clinical Response at TOC in the microITT and Microbiologically Evaluable at TOC (ME-TOC) Analysis Sets. (5-10 days after the last dose of study drug)
- Evaluate the By-Pathogen Microbiologic Response at TOC in the microITT and ME-TOC Analysis Sets. (5-10 days after the last dose of study drug)
-Evaluate the safety and tolerability of lefamulin versus comparator in the Safety Analysis Set.
-Evaluate 28 day all-cause mortality in the ITT Analysis Set (Day 28)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Days 3 – 5, Day s 5 – 10 and Day 28 |
|
| 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 | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| This multicenter, multinational, randomized, double-blind, double-dummy, active-controlled efficacy |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| 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 |
| Brazil |
| Bulgaria |
| Chile |
| Georgia |
| Hungary |
| Korea, Republic of |
| Latvia |
| Mexico |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| South Africa |
| Spain |
| Taiwan |
| 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 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 | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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