| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Community Acquired Pneumonia |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010120 |
| E.1.2 | Term | Community acquired pneumonia |
|
| 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 compare the safety and efficacy of a 7-day course of therapy with cethromycin, dosed at 300mg QD to that of a 7-day course of therapy with clarithromycin (Klacid) dosed at 250mg BID, in subjects with community-acquired pneumonia. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Ambulatory male or female subjects 18 years of age or older.
2.A female must be non-lactating and at no risk for pregnancy for one of the following reasons:
•postmenopausal for at least 1 year, surgically sterile (hysterectomy) OR
•if of child bearing potential, the subject must have a negative human chorionic gonadotropin (HCG) pregnancy test and be utilizing a highly effective method of birth control throughout the course of the study. (A highly effective method of birth control is defined as one that results in a low failure rate when used consistently and correctly, such as implants, injectables, bilateral tubal ligation, combined oral contraceptives plus a barrier method, some intrauterine devices, sexual abstinence, or a vasectomized partner). If hormonal contraceptives are used, the specific contraceptive must have been used for at least 2 months prior to screening. If a subject is currently using an oral contraceptive the subject should also use a barrier method (e.g., condom or diaphragm) during the study and for 1 month after study completion.
•Subjects must not attempt to become pregnant during the study period.
(NOTE: All criteria are based on recommendations of the ICH Steering Committee dated July 16, 1997)
A male subject must be willing to utilize a highly effective method of birth control (i.e., condom, abstinence) and must make all efforts to avoid fathering children while participating in this study.
3.Ambulatory male or female subjects 18 years of age or older. Subject must have a chest X-ray consistent with a clinical diagnosis of bacterial pneumonia as interpreted by the radiologist. If a previous radiograph (within 48 hours before therapy) is available, the infiltrate must be a new one and there must have been no intercurrent procedures or antimicrobial treatment.
(NOTE: Subjects may be enrolled based upon investigator assessment of X-ray, but subsequent confirmation by a local board certified radiologist is required for assessment of evaluability. If the radiologist does NOT confirm CAP, the subject should not be automatically withdrawn from the study. Subjects should continue in the study based on the signs and symptoms of pneumonia as interpreted by the investigator. These subjects will be classified as indeterminate at Test-of-Cure Visit 4.)
4.Subject must be a suitable candidate for oral antibiotic therapy and must be able to swallow capsules intact.
5.The subject must present with a recent respiratory illness which, upon consideration of the signs and symptoms after physical examination, is consistent with the diagnosis of bacterial CAP. Subjects requiring immediate study drug therapy before culture results are known may be entered with a presumptive diagnosis based on a chest radiograph which demonstrates a new pulmonary infiltrate(s) and at least two of the following categories of signs and symptoms:
•cough;
•fever (oral temperature >38.0°C or >100.4°F or equivalent tympanic or rectal temperature);
•development of, or increase in, dyspnea or tachypnea (elevated respiratory rate ≥20/min);
•auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation (i.e., dullness on percussion, bronchial breath sounds [crackles, rhonchi, wheezes, or egophony]);
•an elevated total peripheral white blood cell count (WBC >10,000/mm3); or >15% immature neutrophils (bands), regardless of total peripheral WBC count; or leukopenia with WBC <4500/mm3 (based on local labs, if available)
6.Subjects are required to have specimens collected for microbiological documentation within 48 hours prior to enrollment. Specimens should include:
•Mucopurulent or purulent respiratory/sputum sample for testing via Gram stain, culture and susceptibility testing;
•Blood samples for culture of typical aerobic microorganisms (aerobic bottle only, X 2 samples) and serology for atypical pathogens (L. pneumophila, M. pneumoniae, and C. pneumoniae):
•Urine sample for antigen detection of L. pneumophila.
(NOTE: Subjects will be enrolled prior to Gram stain or microbiological results availability)
7.Written, voluntary informed consent must be obtained from the subject (or legal representative) prior to initiation of any study related procedures. |
|
| E.4 | Principal exclusion criteria |
1. Prior hospitalization within previous 4 weeks or residence at chronic care facility.
2. Evidence of active tuberculosis (or other mycobacterial infections), empyema, lung abscess, pulmonary embolism, pulmonary edema, cystic fibrosis, tumor (primary or metastatic) involving the lung, bronchial obstruction, history of post obstructive pneumonia (chronic obstructive pulmonary disease is not exclusionary), or known or suspected Pneumocystis carinii pneumonia.
3. Treatment with a long-acting injectable antimicrobial agent (e.g., penicillin G benzathine) within 4 weeks, treatment with ceftriaxone, azithromycin or dirithromycin antibiotics within 7 days, or subjects who have received more than 24 hours of treatment with other antibiotics within 7 days prior to study drug administration. Prior to enrollment, treatment with 1 dose of a short-acting antibiotic (e.g., amoxicillin, clarithromycin) is allowed if necessary.
4. Any infection which necessitates use of a concomitant antimicrobial agent, in addition to study drug.
5. History of hypersensitivity or allergic reactions to macrolide, ketolide, quinolone, azalide or streptogramin antimicrobials.
6. Treatment with an investigational drug within 4 weeks prior to study drug administration.
7. Females who are pregnant or lactating.
8. Subjects with known significant renal or hepatic impairment (or disease) based on historical medical data or known local laboratory chemistries prior to visit 1 enrollment:
•serum creatinine ≥2.0 mg/dl (172 mole/liter)
•SGOT (AST) >2X the upper limit of the reference range
•SGPT (ALT) >2 X the upper limit of the reference range
•total bilirubin ≥1.5 X the upper limit of the reference range
•GGT > 2X the upper limit of the reference range
9. Subjects with history of impaired renal function based on historical medical data or known local laboratory chemistries prior to visit 1 enrollment:
A creatinine clearance rate (CrCL) <50 mL/min. During the study, the CrCL will be calculated according to the following formulae:
MEN CrCL (mL/min) = (Body Weight (kg) x (140 - age in years))/( 72 x serum creatinine (mg/dL))
WOMEN CrCL (mL/min) = 0.85 x value calculated for men
10. Evidence of uncontrolled clinically significant cardiovascular, pulmonary, metabolic, gastrointestinal, neurological or endocrine disease, malignancy, or other abnormality.
11. Subjects who would require parenteral antimicrobial therapy for treatment of pneumonia should not be enrolled.
12. Any underlying condition or disease state that would interfere with the completion of the study procedures and evaluations or absorption of study drug.
13. Currently receiving or likely to require any of the following medications during the period between 2 weeks prior to Evaluation 1 and within 24 hours after last dose of study drug:
•astemizole (Hismanal®), or pimozide (Orap®).
14. Currently receiving or likely to require any of the following medications during the period between Evaluation 1 and within 24 hours after last dose of study drug:
•concomitant theophylline, or any theophylline analogue, unless adequately monitored (either clinically or by plasma levels) during the study. If plasma levels for theophylline will be monitored, sample will be collected in same tube as safety chemistry sample and measured and reported by the central laboratory.
•carbamazepine, dexamethasone, phenobarbital, phenytoin, St. John’s Wort, lamotrigine, troglitazone, warfarin and digitalis glycoside. Other barbiturates may be used with careful monitoring.
•concomitant midazolam, triazolam and alprazolam unless subject is carefully monitored.
•simvastatin, lovastatin and atorvastatin. (Note: Subjects currently taking statins may be enrolled provided that these medications are stopped at Evaluation 1 under the advisement of investigator and patient’s primary care physician. These medications may be restarted 32 hours after last dose of study drug.
15. Subject who is currently receiving or is likely to require any of the following medications during the period between Evaluation 1 and 4:
•other systemic antibiotic therapy
•rifampin or rifabutin
16. Immunocompromised subjects (e.g., neutropenic subjects with granulocytes ≤1000 mm3), subjects receiving immunosuppressive agents, or subjects with known HIV infection and history of AIDS defining condition or CD4+ T-lymphocyte count <200/mm3 (see Appendix G)
17. Subjects with known or suspected CNS disorder that may predispose subject to seizures or lower seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy).
18. Previous treatment in this study or another study for cethromycin.
19. Subjects with signs of septic shock (systemic inflammatory response syndrome) such as:
•Mental confusion
•Severe hypoxemia requiring supplemental oxygen and/or mechanical ventilation
•Severe hypotension requiring fluid resuscitation or pressors
•Any other condition requiring admission to Intensive Care Units |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for statistical analysis is the clinical cure rate at the Test-of-Cure visit. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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) | 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 | Yes |
| E.8.2.3 | Other | No |
| 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 | 45 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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