Clinical Trials List
Protocol NumberCE01-301
2014-02-01 - 2015-11-01
Phase III
Terminated1
Study ended1
A Randomized, Double-Blind, Multi-Center Study to Evaluate the Efficacy and Safety of Intravenous to Oral Solithromycin (CEM-101) Compared to Intravenous to Oral Moxifloxacin in the Treatment of Adult Patients with Community-Acquired Bacterial Pneumonia
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Trial Applicant
Syneos Health
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Sponsor
-
Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Hsin-I Shih 未分科
- Chien-Chung Lin Division of Thoracic Medicine
- 徐祥清 無
- Wen-Chien Ko Division of Infectious Disease
- 施新怡 無
- Seu-Chun Yang Division of Thoracic Medicine
- 鐘達榮 無
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Po-Chang Lin Division of Infectious Disease
- 林伯昌 Division of Infectious Disease
- 何承懋 Division of Infectious Disease
The Actual Total Number of Participants Enrolled
0 Study ended
Condition/Disease
Community-Acquired Bacterial Pneumonia
Objectives
Primary:
To determine noninferiority (NI) in early clinical response rate (defined as improvement at 72 [±12] 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.
Secondary:
To determine NI in early clinical response rate at 72 (±12) hours after the first dose of study drug of solithromycin compared to moxifloxacin in the weighted pooled microbiological ITT (mITT) population (randomized patients with an identified pathogen associated with CABP). For this analysis, data from this protocol will be pooled with data from CE01-300.
To determine NI in early clinical response rate of IV to oral solithromycin compared to IV to oral moxifloxacin in the mITT population.
To determine the overall clinical success rates of IV to oral solithromycin compared to IV to oral moxifloxacin at the Short-term Follow-Up Visit (SFU), 5-10 days after the last dose of study drug in the ITT and Clinically Evaluable (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.
To assess IV to oral solithromycin pharmacokinetics (PK) in adult patients with CABP.
Test Drug
Solithromycin (CEM-101)
Active Ingredient
Dosage Form
Dosage
200
Endpoints
Efficacy:
Clinical and microbiological assessments will be conducted as outlined in Table 1 Schedule of
Assessments and Procedures. An Early Clinical Response will be determined programmatically from symptom scores at 72 hours (±12 hours) following the first dose of study drug. Clinical Response will be evaluated at the End of Treatment (EOT) Visit (last dose of study drug) and the SFU Visit (5 to 10 days after the EOT Visit); An LFU visit for all-cause mortality (ACM) will be conducted 28 to 35 days after the first dose of study drug. If the patient cannot return for the LFU visit the study staff can obtain information
from the patient by telephone or other interactive technology.
Safety:
An independent Data Monitoring Committee (DMC) will assess the overall study status and safety of patients at intervals outlined in the charter and will make recommendations to Cempra on continuing or modifying the study based on these assessments. Women of childbearing potential will have a urine pregnancy test performed within 24 hours before receiving the first dose of study drug and a confirmatory serum pregnancy test done at the Central Laboratory at the Baseline and SFU visits. Adverse events (AEs) will be collected throughout the study. Findings from physical examinations, vital signs assessments, ECGs, and safety laboratory tests (hematology and chemistry) will be recorded at Baseline and throughout the study as described in Table 1 Schedule of Assessments and Procedures. All nonantibacterial concomitant medications taken 7 days prior to randomization through the SFU visit and
concomitant antibacterial medications taken 30 days prior to randomization through the LFU visit will be recorded in the electronic case report form (eCRF). Patients who discontinue early from study drug will have the EOT procedures performed and be followed through the LFU visit.
Exploratory Analysis: Health Outcomes Assessment:
To help determine the value of solithromycin in treating patients with CABP, comprehensive resource utilization data will be collected on the eCRFs for both study drugs, including length of hospital stay, days in the intensive care unit (ICU), emergency room, and step-down wards, and concomitant antibiotics during initial or subsequent hospitalization.
Microbial Diagnostics:
A significant effort must be made to obtain a respiratory sample for culture before the first dose of study drug (e.g. if the patient is not able to spontaneously produce a purulent expectorated sputum sample, consider sputum induction using nebulized non-bacteriostatic saline or an oral rinse with nonbacteriostatic saline followed by deep respirations, accompanied by gentle chest percussion).
Sputum Gram stain and culture will be performed at the local laboratory. The local laboratory will also prepare a duplicate sputum smear (unstained and heat-fixed) and send to the Central Laboratory, along with the interpreted Gram stained slide.
Blood cultures will be performed at the local laboratory.
Any pathogens isolated from the blood or sputum in the local microbiology laboratory will be subcultured, frozen and sent to the Central Laboratory, for confirmation of identification and antimicrobial susceptibility testing. S. pneumoniae isolates will be forwarded to a Specialty Microbiology Laboratory for serotyping.
Two sputum aliquot(s) will be frozen, sent to the Central Laboratory, and then forwarded to Specialty Microbiology Laboratories for L. pneumophila culture and antibiotic susceptibility testing and for polymerase chain reaction (PCR)-based multi-target respiratory pathogen detection.
Presumptive L. pneumophila isolates will be confirmed and serotyped by direct fluorescence antibody testing.
A urine sample will be collected at Baseline and sent to the Central Laboratory to test for the presence of S. pneumoniae and L. pneumophila antigen.
A serum sample for serology evaluations (for M. pneumoniae and L. pneumophila, and other possible pathogens) will be collected at Baseline and at the LFU visit and sent to the Central Laboratory.
A nasopharyngeal swab will be collected, frozen in a transport vial, sent to the Central Laboratory, and then forwarded to a Specialty Microbiology Laboratory for quantitative pneumococcal PCR assay, culture, and serotyping.
An oropharyngeal swab will be collected, frozen in a transport vial, sent to the Central Laboratory, and then forwarded to a Specialty Microbiology Laboratory for M. pneumoniae culture, antibiotic susceptibility testing, and PCR detection.
Clinical and microbiological assessments will be conducted as outlined in Table 1 Schedule of
Assessments and Procedures. An Early Clinical Response will be determined programmatically from symptom scores at 72 hours (±12 hours) following the first dose of study drug. Clinical Response will be evaluated at the End of Treatment (EOT) Visit (last dose of study drug) and the SFU Visit (5 to 10 days after the EOT Visit); An LFU visit for all-cause mortality (ACM) will be conducted 28 to 35 days after the first dose of study drug. If the patient cannot return for the LFU visit the study staff can obtain information
from the patient by telephone or other interactive technology.
Safety:
An independent Data Monitoring Committee (DMC) will assess the overall study status and safety of patients at intervals outlined in the charter and will make recommendations to Cempra on continuing or modifying the study based on these assessments. Women of childbearing potential will have a urine pregnancy test performed within 24 hours before receiving the first dose of study drug and a confirmatory serum pregnancy test done at the Central Laboratory at the Baseline and SFU visits. Adverse events (AEs) will be collected throughout the study. Findings from physical examinations, vital signs assessments, ECGs, and safety laboratory tests (hematology and chemistry) will be recorded at Baseline and throughout the study as described in Table 1 Schedule of Assessments and Procedures. All nonantibacterial concomitant medications taken 7 days prior to randomization through the SFU visit and
concomitant antibacterial medications taken 30 days prior to randomization through the LFU visit will be recorded in the electronic case report form (eCRF). Patients who discontinue early from study drug will have the EOT procedures performed and be followed through the LFU visit.
Exploratory Analysis: Health Outcomes Assessment:
To help determine the value of solithromycin in treating patients with CABP, comprehensive resource utilization data will be collected on the eCRFs for both study drugs, including length of hospital stay, days in the intensive care unit (ICU), emergency room, and step-down wards, and concomitant antibiotics during initial or subsequent hospitalization.
Microbial Diagnostics:
A significant effort must be made to obtain a respiratory sample for culture before the first dose of study drug (e.g. if the patient is not able to spontaneously produce a purulent expectorated sputum sample, consider sputum induction using nebulized non-bacteriostatic saline or an oral rinse with nonbacteriostatic saline followed by deep respirations, accompanied by gentle chest percussion).
Sputum Gram stain and culture will be performed at the local laboratory. The local laboratory will also prepare a duplicate sputum smear (unstained and heat-fixed) and send to the Central Laboratory, along with the interpreted Gram stained slide.
Blood cultures will be performed at the local laboratory.
Any pathogens isolated from the blood or sputum in the local microbiology laboratory will be subcultured, frozen and sent to the Central Laboratory, for confirmation of identification and antimicrobial susceptibility testing. S. pneumoniae isolates will be forwarded to a Specialty Microbiology Laboratory for serotyping.
Two sputum aliquot(s) will be frozen, sent to the Central Laboratory, and then forwarded to Specialty Microbiology Laboratories for L. pneumophila culture and antibiotic susceptibility testing and for polymerase chain reaction (PCR)-based multi-target respiratory pathogen detection.
Presumptive L. pneumophila isolates will be confirmed and serotyped by direct fluorescence antibody testing.
A urine sample will be collected at Baseline and sent to the Central Laboratory to test for the presence of S. pneumoniae and L. pneumophila antigen.
A serum sample for serology evaluations (for M. pneumoniae and L. pneumophila, and other possible pathogens) will be collected at Baseline and at the LFU visit and sent to the Central Laboratory.
A nasopharyngeal swab will be collected, frozen in a transport vial, sent to the Central Laboratory, and then forwarded to a Specialty Microbiology Laboratory for quantitative pneumococcal PCR assay, culture, and serotyping.
An oropharyngeal swab will be collected, frozen in a transport vial, sent to the Central Laboratory, and then forwarded to a Specialty Microbiology Laboratory for M. pneumoniae culture, antibiotic susceptibility testing, and PCR detection.
Inclution 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 >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 <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.
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 >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 <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.
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. Presence of known:
a. Viral or 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 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 450 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 solithromycincould 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 or investigational devices used 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).
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. Presence of known:
a. Viral or 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 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 450 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 solithromycincould 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 or investigational devices used 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).
The Estimated Number of Participants
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Taiwan
32 participants
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Global
860 participants
