Study Comparing the Safety and Efficacy of Cethromycin to Clarithromycin for the Treatment of Community-Acquired Pneumonia (CAP)
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Clarithromycin
|
Drug: Clarithromycin
Clarithromycin 250 mg twice per day (BID) for 7 days, administered orally
Other Names:
|
| Experimental: Cethromycin
|
Drug: Cethromycin
Cethromycin 300 mg once per day (QD) for 7 days, administered orally
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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).
Eligibility Criteria
Criteria
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)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | CANADA - Advanced Life Sciences | Woodridge | Illinois | United States | 60517 |
| 2 | SOUTH AFRICA - Advanced Life Sciences | Woodridge | Illinois | United States | 60517 |
| 3 | USA - Advanced Life Sciences | Woodridge | Illinois | United States | 60517 |
Sponsors and Collaborators
- Advanced Life Sciences, Inc.
Investigators
- Study Director: David A. Eiznhamer, PhD, Advanced Life Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CL05-001
Study Results
Participant Flow
| Recruitment Details | Subjects were recruited globally from January 2006 through October 2007. |
|---|---|
| Pre-assignment Detail | 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. |
| Arm/Group Title | Cethromycin | Clarithromycin |
|---|---|---|
| Arm/Group Description | 300 mg once per day (QD) for 7 days, administered orally | 250 mg twice per day (BID) for 7 days, administered orally |
| Period Title: Overall Study | ||
| STARTED | 291 | 291 |
| COMPLETED | 254 | 264 |
| NOT COMPLETED | 37 | 27 |
Baseline Characteristics
| Arm/Group Title | Cethromycin | Clarithromycin | Total |
|---|---|---|---|
| Arm/Group Description | 300 mg once per day (QD) for 7 days, administered orally | 250 mg twice per day (BID) for 7 days, administered orally | Total of all reporting groups |
| Overall Participants | 291 | 291 | 582 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
48.6
(14.5)
|
50.3
(16.3)
|
49.5
(15.4)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
140
48.1%
|
143
49.1%
|
283
48.6%
|
| Male |
151
51.9%
|
148
50.9%
|
299
51.4%
|
Outcome Measures
| Title | Clinical Cures in the Intent to Treat Population |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Cethromycin | Clarithromycin |
|---|---|---|
| Arm/Group Description | 300 mg once per day (QD) for 7 days, administered orally | 250 mg twice per day (BID) for 7 days, administered orally |
| Measure Participants | 261 | 254 |
| Clinical Cures |
217
74.6%
|
206
70.8%
|
| Clinical Failures |
14
4.8%
|
13
4.5%
|
| Indeterminates |
30
10.3%
|
35
12%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cethromycin, Clarithromycin |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | Delta will be determined by the highest clinical cure-rate between the Cethromycin treatment group and the Clarithromycin treatment group, as follows: Greater than or equal to 90%, delta = -10%; Greater than or equal to 80% and less than 90%, delta = -15%, Greater than or equal to 70% and less than 80%, -20%) | |
| Statistical Test of Hypothesis | p-Value | 0.5667 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 2.0 | |
| Confidence Interval |
(2-Sided) 95% -4.8 to 8.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Bacteriologic Cures in the Intent to Treat Population |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Cethromycin | Clarithromycin |
|---|---|---|
| Arm/Group Description | 300 mg once per day (QD) for 7 days, administered orally | 250 mg twice per day (BID) for 7 days, administered orally |
| Measure Participants | 81 | 85 |
| Bacteriologic Cures |
73
25.1%
|
73
25.1%
|
| Title | Clinical Cures in the Per Protocol Clinically Evaluable Population |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Cethromycin | Clarithromycin |
|---|---|---|
| Arm/Group Description | 300 mg once per day (QD) for 7 days, administered orally | 250 mg twice per day (BID) for 7 days, administered orally |
| Measure Participants | 218 | 208 |
| Clinical Cures |
205
70.4%
|
195
67%
|
| Clinical Failures |
13
4.5%
|
13
4.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Cethromycin, Clarithromycin |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | Delta will be determined by the highest clinical cure-rate between the Cethromycin treatment group and the Clarithromycin treatment group, as follows: Greater than or equal to 90%, delta = -10%; Greater than or equal to 80% and less than 90%, delta = -15%, Greater than or equal to 70% and less than 80%, -20%) | |
| Statistical Test of Hypothesis | p-Value | >0.9999 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 0.3 | |
| Confidence Interval |
() 95% -4.5 to 5.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Bacteriologic Cures in the Per Protocol Clinically Evaluable Population |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Cethromycin | Clarithromycin |
|---|---|---|
| Arm/Group Description | 300 mg once per day (QD) for 7 days, administered orally | 250 mg twice per day (BID) for 7 days, administered orally |
| Measure Participants | 73 | 69 |
| Bacteriologic Cures |
71
24.4%
|
67
23%
|
Adverse Events
| Time Frame | Reported adverse events were recorded for 30 days after the last dose of study drug for individual subjects. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | The safety population was defined as all randomized and dosed subjects with at least one follow up safety assessment. | |||
| Arm/Group Title | Cethromycin | Clarithromycin | ||
| Arm/Group Description | 300 mg once per day (QD) for 7 days, administered orally | 250 mg twice per day (BID) for 7 days, administered orally | ||
All Cause Mortality |
||||
| Cethromycin | Clarithromycin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Cethromycin | Clarithromycin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 13/288 (4.5%) | 9/291 (3.1%) | ||
| Cardiac disorders | ||||
| Acute myocardial infarction | 4/288 (1.4%) | 4 | 1/291 (0.3%) | 2 |
| Atrial Fibrillation | 1/288 (0.3%) | 1 | 0/291 (0%) | 0 |
| Cardiac failure congestive | 1/288 (0.3%) | 1 | 0/291 (0%) | 0 |
| Pericardial effusion | 1/288 (0.3%) | 1 | 0/291 (0%) | 0 |
| Angina pectoris | 0/288 (0%) | 0 | 1/291 (0.3%) | 1 |
| Infections and infestations | ||||
| Pneumonia | 4/288 (1.4%) | 4 | 2/291 (0.7%) | 2 |
| Empyema | 1/288 (0.3%) | 1 | 0/291 (0%) | 0 |
| Appendicitis | 0/288 (0%) | 0 | 1/291 (0.3%) | 1 |
| Lobar pneumonia | 0/288 (0%) | 0 | 1/291 (0.3%) | 1 |
| Injury, poisoning and procedural complications | ||||
| Ankle fracture | 1/288 (0.3%) | 1 | 0/291 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Lung adenocarcinoma | 1/288 (0.3%) | 1 | 1/291 (0.3%) | 1 |
| Metastatic neoplasm | 1/288 (0.3%) | 1 | 0/291 (0%) | 0 |
| Lung squamous cell carcinoma stage unspecified | 0/288 (0%) | 0 | 1/291 (0.3%) | 1 |
| Small cell lung cancer extensive stage | 0/288 (0%) | 0 | 1/291 (0.3%) | 1 |
| Renal and urinary disorders | ||||
| Renal failure acute | 1/288 (0.3%) | 1 | 0/291 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Chronic obstructive pulmonary disease | 1/288 (0.3%) | 1 | 1/291 (0.3%) | 1 |
| Pleural effusion | 1/288 (0.3%) | 1 | 0/291 (0%) | 0 |
| Pneumothorax | 0/288 (0%) | 0 | 1/291 (0.3%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Cethromycin | Clarithromycin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 55/288 (19.1%) | 37/291 (12.7%) | ||
| Gastrointestinal disorders | ||||
| Diarrhea | 13/288 (4.5%) | 13 | 12/291 (4.1%) | 13 |
| Nausea | 13/288 (4.5%) | 14 | 4/291 (1.4%) | 4 |
| Infections and infestations | ||||
| Urinary tract infection | 0/288 (0%) | 0 | 7/291 (2.4%) | 8 |
| Nervous system disorders | ||||
| Dysgeusia | 22/288 (7.6%) | 23 | 6/291 (2.1%) | 6 |
| Headache | 7/288 (2.4%) | 7 | 8/291 (2.7%) | 9 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | David Eiznhamer, PhD, Executive Vice President, Clinical Development |
|---|---|
| Organization | Advanced Life Sciences |
| Phone | 630-739-6744 |
| deiznhamer@advancedlifesciences.com |
- CL05-001