| 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 |
|
| 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 | 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 |
· To assess the overall safety and tolerability of oral nafithromycin;
· To assess the clinical response in the ITT population at Day 4; |
|
| E.2.2 | Secondary objectives of the trial |
· To assess the clinical response in the micro-ITT population at Day 4;
· To assess the clinical outcome in the ITT and CE populations at EOT and TOC;
· To assess early improvement in clinical symptoms and normalization of vital signs in the ITT population at Day 4;
· To assess clinical outcome in micro-ITT population at TOC;
· To assess by-subject and by-pathogen microbiological response in micro-ITT and ME populations at TOC;
· To assess readmission to the hospital (or admission to the hospital if not previously hospitalized) for any reason prior to FU |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 years of age
2. Willing to participate in the study and provide written informed consent before any protocol specific assessment is performed
3. Meet the following clinical criteria for CABP:
a. Have at least TWO of the following symptoms (new or worsening):
• Dyspnea (shortness of breath)
• Cough
• Production of purulent sputum
• Pleuritic chest pain
b. Have at least TWO of the following vital sign abnormalities:
• Fever or hypothermia documented by the Investigator (oral, rectal, or tympanic temperature > 38.0°C [100.4°F] or < 36.0°C [95.5°F])
• Hypotension, defined as systolic blood pressure < 90 mm Hg
• Tachycardia, defined as heart rate > 90 beats per minute
• Tachypnea, defined as respiratory rate > 20 breaths per minute
c. Have at least ONE of the following laboratory abnormalities:
• Hypoxemia defined as arterial oxygen saturation < 90% by pulse oximetry or PaO2 < 60 mm Hg by ABG
• Auscultatory findings on pulmonary examination consistent with bacterial pneumonia or pulmonary consolidation (e.g., rales, dullness on percussion, bronchial breath sounds, or egophony)
• Elevated total WBC count (> 10,000 cells/mm3) or leucopenia (WBC <4,000 cells/mm3)
• Elevated immature neutrophils (> 15% band forms), regardless of total peripheral WBC count
d. Radiographic evidence of CABP:
• Radiographically-confirmed pneumonia, i.e., new or progressive
pulmonary infiltrate(s) on CXR or CT scan consistent with acute bacterial pneumonia within 48 h prior to randomization
e. PORT score of 51 to 105 (PORT Risk Class of II, III or IV) (Appendix II)
4. All females must have a negative urine or serum pregnancy test (β-HCG) at Screening AND agree to the use of one of the following acceptable methods of contraception from Screening through TOC: surgical sterilization (defined as bilateral oophorectomy or bilateral salpingectomy, but excluding bilateral tubal occlusion), post-menopausal (defined by amenorrhea for at least 12 months
following cessation of all exogenous hormonal treatments), barrier contraception (e.g., condom, intrauterine device), levonorgestrel intrauterine system (e.g., Mirena®), regular medroxyprogesterone injections (e.g., Depo-Provera®), sexual intercourse with only vasectomised partners, or abstinence. Note that oral
contraceptives should not be used as the sole method of birth control because the effect of nafithromycin on the efficacy of oral contraceptives has not yet been established; subjects who take oral contraceptives must also use one of the acceptable forms of birth control (listed above) from Screening through TOC.
Males must agree to use an acceptable barrier method of birth control (i.e., condom) with female partner(s) and must not donate sperm from Screening through TOC.
5. Ability to ingest oral study drug (e.g., able to swallow large capsules intact, and no significant nausea, vomiting, diarrhea, or any other condition that might impair ingestion or absorption of oral study drug) |
|
| E.4 | Principal exclusion criteria |
1. Subjects with any of the following confirmed or suspected types of pneumonia:
• Aspiration pneumonia
• HABP, defined as pneumonia with onset of clinical signs and symptoms after at least 48 h hospitalization in an acute in-subject health care facility.
• HCAP, defined as pneumonia acquired in a long-term care or subacute healthcare facility or pneumonia with onset after recent hospital discharge (within 90 days of current admission and previously hospitalized for ≥ 48 h)
• VABP, defined as pneumonia with onset of clinical signs and symptoms after at least 48 h endotracheal intubation
• Pneumonia that may be caused by pathogen(s) resistant to either study drug (nafithromycin or moxifloxacin), including viral, mycobacterial, or fungal pneumonia
• Post-obstructive pneumonia
• Pneumonia associated with cystic fibrosis
2. Suspected or confirmed pleural empyema (a parapneumonic pleural effusion is not an exclusion criterion) or lung abscess
3. Suspected or confirmed non-infectious causes of pulmonary infiltrates
4. Receipt of 1 or more dose(s) of a potentially-effective systemic antibacterial treatment for treatment of the current CABP within 72 h prior to randomization with the exception of:
• Receipt of a single dose of a short-acting antibacterial agent within 72 h of randomization OR
• Failure (worsening of symptoms) of at least 48 h of treatment for the current episode of CABP with an antibacterial agent other than a ketolide or fluoroquinolone
5. Subjects requiring concomitant adjunctive or additional potentially effective systemic antibacterial treatment for management of CABP
6. Evidence of significant immunologic disease determined by any of the following:
• Current or anticipated neutropenia defined as < 500 neutrophils/mm3
• Known infection with HIV (prior to Screening) and a CD4 count that is unknown or documented to be < 200 cells/mm3 within the last year, or an AIDS-defining illness; note that neither HIV nor CD4 testing is required at Screening
• History of heart, lung, or kidney transplant
• The receipt of cancer chemotherapy, radiotherapy, or potent, noncorticosteroid immunosuppressant drugs (e.g., cyclosporine, azathioprine, tacrolimus, immune-modulating monoclonal antibody therapy) within the past 3 months, or the receipt of corticosteroids equivalent to or greater than 40 mg of prednisone per day for more than 14 days in the 30 days prior to randomization
7. Known or suspected primary or metastatic neoplastic lung disease, bronchiectasis, bronchial obstruction, chronic neurological disorder preventing clearance of pulmonary secretions, or severe COPD (severe COPD is defined as known [prior to Screening] FEV1/FVC < 0.70 and FEV1 < 50% normal); note that pulmonary function tests are not required at Screening
8. Compromised hepatic or renal function, including but not limited to: clinical evidence of end-stage liver disease (e.g., ascites, hepatic encephalopathy), screening serum total bilirubin > 2 times ULN (unless associated with an elevated indirect bilirubin typical of Gilbert syndrome), AST or ALT > 3 times ULN, serum creatinine > 2.0 mg/dl and/or BUN > 30 mg/dl. Other clinically-significant
abnormal laboratory findings should be discussed with the Medical Monitor prior to the subject's entry.
9. History of Clostridium difficile-associated disease within 6 months prior to enrolment
10. History of hypersensitivity, known contraindication (e.g. lactose intolerance,lactase deficiency and glucose-galactose malabsorption etc. ) or allergic reaction (e.g., anaphylaxis, urticaria, other significant reaction) to any ketolide,any
fluoroquinolone antibiotic medicinal products or any of their excipients.
11. Current second- or third- degree atrioventricular block or sick sinus syndrome, uncontrolled atrial fibrillation, severe or unstable angina, congestive heart failure, myocardial infarction within 3 months of the Screening visit, clinically significant ECG abnormalities including QTcF > 450 msec (males) or > 470 msec (females), or requirement for medications known to cause QT prolongation
12. Prior (within 14 days prior to randomization) or concomitant use of cytochrome P450 liver enzyme inducers (e.g., phenobarbital, carbamazepine, griseofulvin, sulfonylureas, phenytoin, or rifampin)
13. History of tendon rupture
14. Current peripheral neuropathy or myasthenia gravis
15. Known or suspected seizure disorder or other CNS disorders that may predispose the subject to seizures or lower the seizure threshold
16. Nursing mother or pregnant female
17. Subjects who received any experimental drug within 30 days prior to enrolment
18. Require admission to in intensive care unit for any reason, life expectancy of less than 2 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) |
· Clinical Response at Day 4 in the ITT population
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
· Clinical Response at Day 4, as described above, in the micro-ITT population
· Clinical Outcome at EOT (ITT and CE populations) and TOC (ITT, CE, and micro-ITT populations)
· Improvement in CABP Symptoms and Normalization in Vital Signs at Study Day 4 (ITT population)
· Hospitalization Prior to FU (ITT population): Hospital readmission for any reason between Day 1 and FU Visit, if previously hospitalized and discharged, or initial hospital admission for any reason between Day 2 and FU Visit, if not previously hospitalized on Day 1
Safety Endpoints:
Safety evaluation is based on TEAEs, clinical laboratory evaluation, vital signs, physical examination findings and electrocardiograms (ECGs) collected during the study. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Response at Day 4, Day 7 or within 2 days following Day 7 (EOT), Day 15 ±3 days (TOC)
Time points for PK sample collection will be:
· Pre-dose: pre-dose PK sample will be collected within 10 minutes before dosing.
· Post-dose at 2-4 h (Day 3) and 24-28 h (Day 4). Subjects who have been hospitalized are also required to have a post-dose PK sample at 6-10 h (Day 3).
FU is to be conducted on Day 31 ±3 days |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Georgia |
| Latvia |
| Romania |
| Russian Federation |
| Serbia |
| South Africa |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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