| 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 | 18.0 |
| 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 determine noninferiority (NI) in early clinical response rate (defined as improvement at 72 [-12/+36] hours after the first dose of study drug), in at least 2 of the following 4 cardinal symptoms: cough, shortness of breath, chest pain, and sputum production (without worsening of any), of intravenous (IV) to oral solithromycin compared to IV to oral moxifloxacin in adult patients with community-acquired bacterial pneumonia (CABP) in the Intent to Treat (ITT) population. |
|
| E.2.2 | Secondary objectives of the trial |
To determine NI in early clinical response rate
- at 72 (-12/+36) hours after the first dose of study drug of solithromycin compared to moxifloxacin in the mITT population
- of IV to oral solithromycin compared to IV to oral moxifloxacin in the mITT population
- in at least 2 of the following 4 cardinal symptoms: cough, shortness of breath, chest pain, and sputum production (without worsening of any), and improvement in vital signs of IV to oral solithromycin compared to IV to oral moxifloxacin in adult patients with CABP in the ITT population.
- To determine the overall clinical success rates of IV to oral solithromycin compared to IV to oral moxifloxacin at the SFU, 5-10 days after the last dose of study drug in the ITT and CE-SFU populations
- To assess the safety and tolerability of IV to oral solithromycin compared to IV to oral moxifloxacin in adult patients with CABP.
- IV to oral solithromycin pharmacokinetics (PK) in adult patients with CABP. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
|
| E.3 | Principal inclusion criteria |
1. Male and female patients ≥18 years of age.
2. An acute onset of at least 3 of the following signs and symptoms (new or worsening):
a. Cough
b. Production of purulent sputum
c. Shortness of breath (dyspnea)
d. Chest pain due to pneumonia
3. At least 1 of the following:
a. Fever: (defined as body temperature >38°C [100.4°F] measured orally, >38.5°C [101.3°F] measured tympanically or by temporal artery thermometry, >37.5°C [99.5°F] by axillary measurement, or >39°C [102.2°F] measured rectally) b. Hypothermia: (defined as body temperature <35°C [95.0°F] measured orally, <35.5°C [95.9°F] measured tympanically or by temporal artery thermometry, <34.5°C [94.1°F] by axillary measurement, or <36°C [96.8°F] measured rectally)
c. Presence of pulmonary rales and/or evidence of pulmonary consolidation (dullness on percussion, bronchial breath sounds, or egophony)
4. The patient will have received no systemic antibiotics other than a single dose of a short-acting antibiotic (penicillins, cephalosporins [not ceftriaxone], tetracyclines, or trimethoprimsulfamethoxazole) in the 7 days prior to enrollment.
5. PORT Risk Class II, III or IV (pneumonia severity scores of 51 to 130, inclusive).
6. In the opinion of the Investigator, intravenous therapy is both warranted and feasible.
7. Presence of lobar, multilobar, or patchy parenchymal infiltrate(s) consistent with acute bacterial pneumonia on a pulmonary imaging study (e.g. chest radiograph [CXR] [posteroanterior and lateral preferred; single view acceptable if conclusive] or computed tomography [CT] of thorax) within 48 hours before the first dose of study drug. The Investigator may interpret the imaging study to qualify a patient for enrollment; however, the imaging study must also be interpreted by a local radiologist.
8. Females of non-childbearing potential: surgically sterile (e.g. tubal ligation) or at least 2 years postmenopausal
9. Females of childbearing potential (including females less than 2 years post-menopausal) must have a negative pregnancy test at enrollment and must agree to use highly effective methods of birth control (i.e. diaphragm plus spermicide or male condom plus spermicide, oral contraceptive in combination with a second method, contraceptive implant, injectable contraceptive, indwelling intrauterine device, sexual abstinence, or a vasectomized partner) while participating in the study and for 30 days after the last dose of study drug.
10. Males must agree to use a double barrier method of contraception (condom plus spermicide or diaphragm plus spermicide) while participating in the study and for 30 days after the last dose of study drug, or the male patient or his female partner must be surgically sterile (e.g. vasectomy, tubal ligation) or the female partner must be post-menopausal.
11. The patient has voluntarily signed and dated the Investigational Review Board/Independent Ethics Committee (IRB/IEC) approved ICF prior to any study-specific screening procedures.
12. The patient must be able to attend all study visits and comply with all study procedures. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria:
1. Ventilator-associated pneumonia.
2. Known anatomical or pathological bronchial obstruction or a history of bronchiectasis or documented severe COPD defined as forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) <70% and FEV1 <50% predicted. Note: Patients with less severe COPD are not excluded. Patients with COPD without a documented FEV1/FVC or FEV1 may be enrolled if in the Investigator’s opinion the COPD is not severe.
3. Current diagnosis of :
a. Fungal pneumonia
b. Pneumocystis jiroveci pneumonia
c. Aspiration pneumonia
d. Other non-infectious causes of pulmonary infiltrates (e.g. pulmonary embolism, hypersensitivity pneumonia, congestive heart failure)
e. Primary or metastatic lung cancer
f. Cystic fibrosis
g. Active or suspected tuberculosis
h. Empyema (not including sterile parapneumonic effusions).
4. Presence of pneumonia known to be caused by a pathogen resistant to moxifloxacin or solithromycin.
5. Hospitalization within 90 days or residence in a long-term care (skilled nursing) facility within 30 days prior to the onset of symptoms (i.e. healthcare-associated pneumonia).
6. Any condition that could affect drug absorption, e.g. status post gastrectomy.
7. History of post-antibiotic colitis within the last 3 months.
8. Mean QTcF (QT interval corrected with the Fridericia formula) greater than 460 msec on screening summary (or triplicate) electrocardiogram (ECG).
9. Concomitant use of drugs known to prolong the QT interval, including class Ia (quinidine, procainamide) or Class III (amiodarone, sotalol) antiarrhythmics.
10. Concomitant use of drugs, foods, or herbal products known to be moderate to potent inhibitors of CYP3A4 isozymes: oral antifungal agents (e.g. ketoconazole, itraconazole, posaconazole, fluconazole and voriconazole); human immunodeficiency virus (HIV) protease inhibitors (e.g. ritonavir and saquinavir), hepatitis C virus (HCV) protease inhibitors (e.g. boceprevir and telaprevir), nefazodone, fluvoxamine, conivaptan, diltiazem, verapamil, aprepitant, ticlopidine, crizotinib, imatinib; grapefruit or grapefruit juice.
11. Any use within the prior 7 days of drugs or herbal products known to be moderate to potent inducers of CYP3A4 isozymes: St. John’s Wort, rifampin, rifabutin, anti-convulsants (e.g. phenobarbital, carbamazepine, phenytoin, rufinamide), modafinil, armodafinil, etraverine, efavirenz, bosentan.
12. Required current use of drugs with narrow therapeutic indices that are principally metabolized by CYP3A4 or transported by P-glycoprotein (P-gp), for which a drug interaction with solithromycin could result in higher and possibly unsafe exposures to these drugs: e.g. the P-gp substrates digoxin or colchicine and the CYP3A4 substrates alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, midazolam, pimozide, quinidine, sirolimus, tacrolimus, everolimus, and terfenadine.
13. Receiving or anticipated to receive a daily dose of ≥20 mg of systemic prednisone or equivalent within the period starting 14 days prior to enrollment. Note: Patients are allowed to receive an acute, short course of methylprednisolone or prednisone (or equivalent) for management of an acute exacerbation of COPD or reactive airway disease in asthmatics.
14. Cytotoxic chemotherapy or radiation therapy within the previous 3 months.
15. Known history of significant and ongoing renal, hepatic, or hematologic impairment. Current treatment for HCV infection.
16. Any of the following laboratory parameters:
a. Creatinine clearance (CrCl) <30 mL/min calculated by the Cockcroft-Gault formula
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3× the upper limit of normal (ULN)
c. Total bilirubin >2×ULN
d. Platelet count <50,000 cells/mm3
17. Known HIV infection.
18. Known history of myasthenia gravis.
19. Women who are pregnant or nursing.
20. Previously randomized in this protocol.
21. Any investigational drugs taken within 4 weeks before administration of the first dose of study drug.
22. Concomitant conditions requiring additional antibacterial therapy that is potentially effective for the current CABP.
23. History of intolerance or hypersensitivity to fluoroquinolone or macrolide antibiotics.
24. History of tendinopathy with fluoroquinolone use.
25. Clinical presentation with pneumonia that would require mechanical ventilation.
26. Any concomitant condition that, in the opinion of the Investigator, would preclude evaluation of a
response or make it unlikely that the contemplated course of therapy and follow-up could be completed (e.g. life expectancy <30 days). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy: The primary efficacy outcome is the early clinical response rate at 72 hours (±12 hours) following the first dose of study drug in the ITT population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy: Early Clinical Response - 72 hours (± 12 hours) following the first dose of study drug.
Safety: at all visits |
|
| E.5.2 | Secondary end point(s) |
Efficacy: the number and percentage of patients categorized as response, non-response and indeterminate
for the primary efficacy outcome of early clinical response.
The number and percentage of patients categorized as response, non-response and indeterminate for the primary efficacy outcome of early clinical response will also be presented for the mITT population and a two-sided unadjusted 95% CI for the difference in response rate will be calculated using a continuity corrected Z-test. However, the formal test of NI will be conducted in the weighted pooled population from this
study and the second NI study in CABP.
The number and percentage of patients in each treatment group with an Investigator Assessment of clinical success, clinical failure and indeterminate at SFU will be reported in the ITT and CE-SFU populations. Two-sided unadjusted 95% CIs will be calculated for the difference in clinical success rates. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- EOT - Day 7 (+2 days)
- SFU - 5 to 10 days after last dose of study drug (Day 12-17) |
|
| 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 | Yes |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 111 |
| 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 |
| Bulgaria |
| Chile |
| Colombia |
| Georgia |
| Germany |
| Guatemala |
| Hungary |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Malaysia |
| Netherlands |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Taiwan |
| Ukraine |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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