Pneumonia
Conditions
Keywords
Pneumonia, Respiratory, Infection, Infectious, Advanced, Life, Sciences, Lung, Pulmonary, Cethromycin, Restanza, Clarithromycin, Biaxin
Brief summary
The purpose of this study is to compare the efficacy of cethromycin to clarithromycin for the treatment of mild to moderate community-acquired pneumonia (CAP).
Detailed description
Lower respiratory tract infections remain one of the leading causes of death worldwide. Increasing rates of antibiotic resistance and newer, more pervasive pneumonia-causative pathogens contribute to this statistic. Currently available macrolide antibiotics for the treatment of community-acquired pneumonia are slowly losing effectiveness, resulting in the need to develop newer drugs to fight resistant infections. In this study, we compare the safety and efficacy of a common macrolide, clarithromycin, to a new ketolide, cethromycin.
Interventions
DRUGCethromycin
Cethromycin 300 mg once per day (QD) for 7 days, administered orally
DRUGClarithromycin
Clarithromycin 250 mg twice per day (BID) for 7 days, administered orally
Sponsors
Advanced Life Sciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ambulatory male or female, 18 years of age or older * If female, non-lactating and at no risk or pregnancy (post-menopausal or must use adequate birth control) * Positive Chest X-ray consistent with diagnosis of bacterial pneumonia * Must be a suitable candidate for oral antibiotic therapy and must be able to swallow capsules intact * Recent history of respiratory illness consistent with the clinical signs and symptoms of bacterial CAP * Must be able to produce sputum
Exclusion criteria
* Prior hospitalization within previous 4 weeks * Residence at a chronic care facility * Active tuberculosis (or other mycobacterial infection, empyema, lung abscess, pulmonary embolism, pulmonary edema, cystic fibrosis, tumor (primary or metastatic) involving the lung, bronchial obstruction, a history of post-obstructive pneumonia (chronic obstructive pulmonary disease \[COPD\] is not exclusionary), known or suspected Pneumocystis carinii pneumonia * Treatment with long-acting antimicrobial agents within the last 4 weeks, treatment with ceftriaxone, azithromycin or dirithromycin antibiotic within the last 7 days, or subjects who have received more than 24 hours of treatment with other antibiotics within 7 days prior to study drug administration * Any infection which requires the use of a concomitant antimicrobial agent * History of hypersensitivity or allergic reactions to macrolide, ketolide, quinolone, azalide or streptogramin antimicrobials * Treatment with another investigational drug within the last 4 weeks * Females who are pregnant or lactating * Subjects with known significant renal or hepatic impairment or disease * Subjects with a history of impaired renal function * Evidence of uncontrolled clinically significant cardiovascular, pulmonary, metabolic, gastrointestinal, neurological or endocrine disease, malignancy, or other abnormality (other than the disease being studied) * Subjects who would require parenteral antimicrobial therapy for the treatment of pneumonia * Any underlying disease or condition that would interfere with the completion of the study procedures and evaluations or absorption of the study drug * Currently receiving or are likely to require any of the following medications during the period between 2 weeks prior to Evaluation 1 and within 24 hours after the last dose of study drug: astemizol (Hismanal®) or pimozide (Orap®) * Currently receiving or are likely to require any of the following during the period from Evaluation 1 and within 24 hours after the last dose of study drug: theophylline or theophylline analogues (unless adequately monitored), carbamazepine, dexamethasone, phenobarbital, phenytoin, St. John's Wort, lamotrigine, troglitazone, warfarin and digitalis glycoside. Other barbiturates may be used with careful monitoring * Subjects who are currently receiving or who are likely to require any of the following medications during the period between Evaluation 1 and 4: other systemic antibiotic therapy, rifampin or rifabutin * Immunocompromised subjects, subjects receiving immunosuppressive agents, subjects with known human immunodeficiency virus (HIV) infections and history of acquired immune deficiency syndrome (AIDS) defining conditions or CD4+ T-lymphocyte count \<200. * Subject with known or suspected central nervous system (CNS) disorder that predisposes them to seizures/lower seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) * Previous treatment with cethromycin * Subjects with signs of septic shock (e.g., mental confusion, severe hypoxemia, severe hypotension, any other condition requiring intensive care unit \[ICU\] admission)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cures in the Intent to Treat Population | Test of Cure Visit, defined as 14-22 days after the first dose of study drug. | Investigators evaluated subjects for a clinical response of cure, failure, or indeterminate. Cure: Improvement or return to preinfection state or lack of progression of all pulmonary infiltrates, and resolution of all signs/symptoms present at enrollment. Failure: Persistence or worsening of signs/symptoms, the need for additional antibiotic, new pulmonary infection, progression of the chest radiograph, or death due to pneumonia. Indeterminate: Evaluation was not possible (lost to follow up, adverse event, major protocol violation). Indeterminates default to failure for analysis. |
| Clinical Cures in the Per Protocol Clinically Evaluable Population | Test of Cure Visit, defined as 14-22 days after the first dose of study drug | Investigators evaluated subjects for a clinical response of cure, failure, or indeterminate. Cure: Improvement or return to preinfection state or lack of progression of all pulmonary infiltrates, and resolution of all signs/symptoms present at enrollment. Failure: Persistence or worsening of signs/symptoms, the need for additional antibiotic, new pulmonary infection, progression of the chest radiograph, or death due to pneumonia. Indeterminate: Evaluation was not possible (lost to follow up, adverse event, major protocol violation). Indeterminates default to failure for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bacteriologic Cures in the Intent to Treat Population | Test of Cure Visit, defined as 14-22 days after the first dose of study drug. | All bacteriologically evaluable subjects (ie., the subject had at least one, protocol-defined evaluable pathogen) who demonstrated eradication of all evaluable pathogens (S. pneumoniae, S. aureus, H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, L. pneumophila). |
| Bacteriologic Cures in the Per Protocol Clinically Evaluable Population | Test of Cure Visit, defined as 14-22 days after the first dose of study drug. | All bacteriologically evaluable subjects (ie., the subject had at least one, protocol-defined evaluable pathogen) who demonstrated eradication of all evaluable pathogens (S. pneumoniae, S. aureus, H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, L. pneumophila). |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited globally from January 2006 through October 2007.
Pre-assignment details
In each treatment arm, one subject was enrolled and randomized to a blinded treatment but discontinued from study prior to administration of the first dose of drug. Thus, while official enrollment totalled 584 subjects, only 582 were randomized and dosed with blinded study drug.
Participants by arm
| Arm | Count |
|---|---|
| Cethromycin 300 mg once per day (QD) for 7 days, administered orally | 291 |
| Clarithromycin 250 mg twice per day (BID) for 7 days, administered orally | 291 |
| Total | 582 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 9 |
| Overall Study | Lack of Efficacy | 8 | 4 |
| Overall Study | Lost to Follow-up | 7 | 4 |
| Overall Study | Other | 7 | 7 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Cethromycin | Clarithromycin | Total |
|---|---|---|---|
| Age Continuous | 48.6 years STANDARD_DEVIATION 14.5 | 50.3 years STANDARD_DEVIATION 16.3 | 49.5 years STANDARD_DEVIATION 15.4 |
| Sex: Female, Male Female | 140 Participants | 143 Participants | 283 Participants |
| Sex: Female, Male Male | 151 Participants | 148 Participants | 299 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 55 / 288 | 37 / 291 |
| serious Total, serious adverse events | 13 / 288 | 9 / 291 |
Outcome results
Primary
Clinical Cures in the Intent to Treat Population
Investigators evaluated subjects for a clinical response of cure, failure, or indeterminate. Cure: Improvement or return to preinfection state or lack of progression of all pulmonary infiltrates, and resolution of all signs/symptoms present at enrollment. Failure: Persistence or worsening of signs/symptoms, the need for additional antibiotic, new pulmonary infection, progression of the chest radiograph, or death due to pneumonia. Indeterminate: Evaluation was not possible (lost to follow up, adverse event, major protocol violation). Indeterminates default to failure for analysis.
Time frame: Test of Cure Visit, defined as 14-22 days after the first dose of study drug.
Population: The Intent to Treat Population is defined as all subjects with a confirmed diagnosis of community acquired pneumonia who took at least one dose of study medication. Subjects without a radiologist-confirmed chest X-ray for pneumonia were not included in the efficacy populations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cethromycin | Clinical Cures in the Intent to Treat Population | Clinical Failures | 14 Participants |
| Cethromycin | Clinical Cures in the Intent to Treat Population | Indeterminates | 30 Participants |
| Cethromycin | Clinical Cures in the Intent to Treat Population | Clinical Cures | 217 Participants |
| Clarithromycin | Clinical Cures in the Intent to Treat Population | Clinical Failures | 13 Participants |
| Clarithromycin | Clinical Cures in the Intent to Treat Population | Clinical Cures | 206 Participants |
| Clarithromycin | Clinical Cures in the Intent to Treat Population | Indeterminates | 35 Participants |
Comparison: The rate of clinical cure in each treatment group was calculated (number of cures/number of patient eligible for analysis). Non-inferiority will be demonstrated when the lower limit of the two-sided 95% confidence interval for the difference in the clinical cure rate at the Test-of-Cure visit between treatment groups (Cethromycin -Clarithromycin) is greater than delta, and includes zero, for both Per-Protocol (PP) and Intent-to-Treat (ITT) analyses.p-value: 0.566795% CI: [-4.8, 8.9]Fisher Exact
Primary
Clinical Cures in the Per Protocol Clinically Evaluable Population
Investigators evaluated subjects for a clinical response of cure, failure, or indeterminate. Cure: Improvement or return to preinfection state or lack of progression of all pulmonary infiltrates, and resolution of all signs/symptoms present at enrollment. Failure: Persistence or worsening of signs/symptoms, the need for additional antibiotic, new pulmonary infection, progression of the chest radiograph, or death due to pneumonia. Indeterminate: Evaluation was not possible (lost to follow up, adverse event, major protocol violation). Indeterminates default to failure for analysis.
Time frame: Test of Cure Visit, defined as 14-22 days after the first dose of study drug
Population: The Per Protocol Clinically Evaluable Population included all ITT subjects who took the protocol-defined minimum therapy duration, were dosed with no other antimicrobials (unless allowed by protocol), and had no other major protocol violations
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cethromycin | Clinical Cures in the Per Protocol Clinically Evaluable Population | Clinical Cures | 205 Participants |
| Cethromycin | Clinical Cures in the Per Protocol Clinically Evaluable Population | Clinical Failures | 13 Participants |
| Clarithromycin | Clinical Cures in the Per Protocol Clinically Evaluable Population | Clinical Failures | 13 Participants |
| Clarithromycin | Clinical Cures in the Per Protocol Clinically Evaluable Population | Clinical Cures | 195 Participants |
Comparison: The rate of clinical cure in each treatment group was calculated (number of cures/number of patient eligible for analysis). Non-inferiority will be demonstrated when the lower limit of the two-sided 95% confidence interval for the difference in the clinical cure rate at the Test-of-Cure visit between treatment groups (Cethromycin -Clarithromycin) is greater than delta, and includes zero, for both Per-Protocol (PP) and Intent-to-Treat (ITT) analyses.p-value: >0.999995% CI: [-4.5, 5.1]Fisher Exact
Secondary
Bacteriologic Cures in the Intent to Treat Population
All bacteriologically evaluable subjects (ie., the subject had at least one, protocol-defined evaluable pathogen) who demonstrated eradication of all evaluable pathogens (S. pneumoniae, S. aureus, H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, L. pneumophila).
Time frame: Test of Cure Visit, defined as 14-22 days after the first dose of study drug.
Population: Includes all Intent to Treat subjects that were bacteriologically evaluable (ie., subjects with at least 1 evaluable pathogen) who showed eradication of all evaluable pathogens.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cethromycin | Bacteriologic Cures in the Intent to Treat Population | Bacteriologic Cures | 73 Participants |
| Clarithromycin | Bacteriologic Cures in the Intent to Treat Population | Bacteriologic Cures | 73 Participants |
Secondary
Bacteriologic Cures in the Per Protocol Clinically Evaluable Population
All bacteriologically evaluable subjects (ie., the subject had at least one, protocol-defined evaluable pathogen) who demonstrated eradication of all evaluable pathogens (S. pneumoniae, S. aureus, H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, L. pneumophila).
Time frame: Test of Cure Visit, defined as 14-22 days after the first dose of study drug.
Population: Includes all Per Protocol Clinically Evaluable subjects that were bacteriologically evaluable (ie., subjects with at least 1 evaluable pathogen) who showed eradication of all evaluable pathogens.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cethromycin | Bacteriologic Cures in the Per Protocol Clinically Evaluable Population | Bacteriologic Cures | 71 Participants |
| Clarithromycin | Bacteriologic Cures in the Per Protocol Clinically Evaluable Population | Bacteriologic Cures | 67 Participants |