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1、Moxifloxacin for Isoniazid TrialTBTC 28November 7, 2005Version 2.0Evaluation of a Moxifloxacin-Based, Isoniazid-Sparing Regimen for Tuberculosis TreatmentTBTC Study 28Protocol chair: Richard E. Chaisson MD Johns Hopkins UniversityProtocol TeamSusan E. Dorman, M.D. Johns Hopkins University, Co-chairJ
2、ohn L. Johnson, M.D. Case Western Reserve University, Co-chairEric L. Nuermberger, M.D. Johns Hopkins UniversityJohn Bernardo, M.D. Boston University School of MedicineDick Menzies, M.D. McGill UniversityElizabeth Guy, M.D. Baylor College of MedicineNesri Padayatchi, M.D. Natal UniversityMaria Coraz
3、on Leus, R.N. University of Medicine and Dentistry of New JerseyGina Maltas, R.N. Johns Hopkins UniversityLorna Bozeman, MS CDCNong Shang, Ph.D. CDCPriya Guyadeen - WestatJacques H. Grosset, M.D. Johns Hopkins UniversityShurjeel Choudhri, MD Bayer PharmaceuticalsStefan Goldberg, MD CDC, project offi
4、cerTABLE OF CONTENTS1. PROTOCOL SYNOPSIS42. INTRODUCTION82.1. Background and Rationale82.2. Study Drugs193. METHODOLOGY283.1. Study Design 4-drug phase283.2. Continuation Phase Therapy293.3. Primary Objectives303.4. Secondary Objectives303.5. Study Endpoints303.6. Randomization313.7. Sample Size Cal
5、culation313.8. Patient Selection313.8.1. Inclusion Criteria323.8.2. Exclusion Criteria334. STUDY PLAN344.1. Study Procedures344.1.1. Screening Visit344.1.2. Randomization Visit344.1.3. Study visits intensive phase of therapy354.1.4. Study visits continuation phase of therapy354.1.5. Scheduled unblin
6、ding of study treatment regimens364.1.6. Compensation for study subjects.365. CLINICAL MANAGEMENT ISSUES365.1. Drug-Susceptibility Testing365.2. Management of patients with baseline drug-resistant isolates375.3. Study drug toxicity385.4. Adverse event reporting395.5. Management of adverse events395.
7、6. Criteria for discontinuation of study drugs405.7. Criteria for temporary discontinuation of study therapy415.8. Criteria for permanent discontinuation of study therapy415.9. Unscheduled unblinding of study assignment415.10. Concomitant medications during study phase425.11. HIV management435.12. M
8、anagement of patients with tuberculosis treatment failure.446. EVALUATION456.1. Data analysis457. ADMINISTRATIVE ISSUES467.1. Supply of study drugs467.2. Drug accountability and record keeping468. TBTC STUDY SITES469. HUMAN SUBJECTS PROTECTION479.1. Ethical issues in doing this trial in developing a
9、nd developed countries479.2. Ethical issues involving persons who are incarcerated479.3. Institutional review board involvement4810. REFERENCES4911. Appendix A Sample informed consent5812. Appendix B Karnofsky performance scale6513. Appendix C Clinically significant drug-drug interactions involving
10、rifamycins.6614. Appendix D Time events schedule6815. Appendix E National Cancer Institute Common Toxicity Criteria.701. PROTOCOL SYNOPSISThe primary objective of this Phase 2 clinical trial is to compare the safety and antimicrobial activity of a moxifloxacin-containing regimen (moxifloxacin, rifam
11、pin, pyrazinamide, ethambutol MRZE) in which moxifloxacin has been substituted for isoniazid, to the standard control regimen (isoniazid, rifampin, pyrazinamide, ethambutol HRZE) in the first two months of treatment of sputum smear-positive pulmonary tuberculosis. The assessment of antimicrobial act
12、ivity will be sputum culture-conversion. Higher rates of sputum culture conversion after 2 months of treatment with a moxifloxacin-containing regimen would support Phase 3 clinical trials of moxifloxacin in treatment regimens of less than the current 6 month standard regimens.The specific aims of th
13、is study are to:PrimaryTo compare the culture-conversion rates at the end of the intensive phase of therapy of the moxifloxacin regimen vs. that of the isoniazid regimenSecondaryTo compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimenTo determine the time t
14、o culture-conversion of the moxifloxacin regimen and the isoniazid regimen, using data from 2-, 4-, 6-, and 8-week cultures. To compare the proportion of patients with any Grade 3 or 4 adverse reactions To compare adverse events and 2-month culture conversion rate among HIV-infected patients vs. HIV
15、-uninfected patientsTo compare the rates of treatment failure of the moxifloxacin regimen to the isoniazid regimenTo determine whether there is delayed toxicity attributable to moxifloxacin (toxicity that becomes evident after the 2 months of moxifloxacin therapy)Rationale Current treatment of smear positive pulmonary tuberculosis requires a minimum of 6 months, a treatment duration that is challenging for patients and tuber
