Prospective, Randomized, Blinded Phase II Pharmacokinetic/Pharmacodynamic Study of the Efficacy and Tolerability of Levofloxacin in Combination With Optimized Background Regimen for the Treatment of MDR-TB
Phase: PHASE2
Conditions: Tuberculosis, Multidrug-Resistant
Sponsor: Boston University

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Prospective, Randomized, Blinded Phase 2 
Pharmacokinetic/Pharmacodynamic Study of the Efficacy and 
Tolerability of Levofloxacin in Combination with Optimized 
Background Regimen (OBR) for the treatment of MDR-TB 
Acronym: “Opti-Q Study” 
NCT01918397 
DMID Funding Mechanism:  U01 
Pharmaceutical Support Provided by: MacLeods Pharmaceuticals, Mumbai, 
India 
Other Identifying Numbers: CDC TBTC Study 32 
IND Sponsor: MacLeods Pharmaceuticals, Mumbai, India 
(IND#115872) 
Principal Investigator: C. Robert Horsburgh, Jr, MD,                  
Boston University, Boston MA 
Telephone:   617-414-1282 
    Email:   rhorsbu@bu.edu 
DMID Representative: Francisco Leyva, MD, PhD, ScM 
Version Number:  4.0 
Date: 07 April 2017 
 
 
 
Statistical Analysis Plan see pages 52-59 
 

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STATEMENT OF COMPLIANCE 
This study will be carried out in accordance with Good Clinical Practice (GCP) as required by: 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• 
ICH E6; 62 Federal Register 25691 (1997)  
• 
NIH Clinical Terms of Award 
 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable US federal regulations and ICH guidelines. 
 
Site Investigator:* 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
* The protocol should be signed by the local investigator who is responsible for the study implementation 
at his/her specific site; i.e., if Investigational New Drug study, the individual who signs the Form FDA 
1572. 

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TABLE OF CONTENTS 
Page 
Statement of Compliance 
ii 
Signature Page 
iii 
Table of Contents 
iv 
List of Abbreviations 
vii 
Protocol Summary 
ix 
1 
Key Roles 
1 
2 
Background Information and Scientific Rationale 
6 
2.1 
Background Information .......................................................................................... 6 
2.1.1. MDR-TB Epidemiology .................................................................................. 6 
2.1.2. State of MDR-TB treatment ........................................................................... 6 
2.1.3. Efficacy of Fluoroquinolones for TB treatment ............................................... 6 
2.1.4. Other new drugs for treatment of MDR-TB .................................................... 8 
2.1.5. Why levofloxacin will be the drug of choice for treatment of MDR-TB ............ 8 
2.1.6. Currently used levofloxacin doses are suboptimal ......................................... 8 
2.1.7. Emergence of fluoroquinolone resistance ..................................................... 9 
2.1.8. Pharmacokinetic and pharmacodynamic parameters of levofloxacin ........... 10 
2.1.9. Assessing Response to MDR-TB treatment ................................................ 10 
2.1.10. Alternative Study Designs ......................................................................... 11 
2.2 
Scientific Rationale ............................................................................................... 11 
2.3 
Potential Risks and Benefits ................................................................................. 13 
2.3.1 
Potential Risks .......................................................................................... 13 
2.3.2 
Known Potential Benefits........................................................................... 18 
3 
Objectives 
20 
3.1 
Study Objectives ................................................................................................... 20 
3.2 
Study Outcome Measures .................................................................................... 20 
3.2.1 
Primary Outcome Measures ...................................................................... 20 
3.2.2 
Secondary Outcome Measures ................................................................. 21 
4 
Study Design 
22 
4.1 
Study Population ................................................................................................... 22 
4.2 
Treatment delivery and duration ........................................................................... 22 
4.3 
Assessment of study objectives and measurement of endpoints .......................... 23 
4.4 
Optimized Background Regimen (OBR)................................................................ 23 
5 
Study Enrollment and Withdrawal 
24 
5.1 
Randomization Inclusion Criteria .......................................................................... 24 
5.2 
Randomization Exclusion Criteria ......................................................................... 25 
5.3 
Treatment Assignment Procedures ....................................................................... 25 
5.3.1 
Randomization Procedures ....................................................................... 25 
5.3.2 
Masking Procedures .................................................................................. 25 
5.3.3 
Reasons for Withdrawal of Study Drug ...................................................... 26 

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5.3.4 
Handling of Patients whose Study Drug is Withdrawn ............................... 26 
5.3.5 
Termination of Study ................................................................................. 27 
6 
Study Intervention/Investigational Product 
28 
6.1 
Study Product Description .................................................................................... 28 
6.1.1 
Acquisition ................................................................................................. 29 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 29 
6.1.3 
Product Storage and Stability .................................................................... 29 
6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................. 29 
6.3 
Modification of Study Intervention/Investigational Product for a Participant ........... 30 
6.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) ... 31 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ................................................................................................................. 31 
6.6 
Concomitant Medications/Treatments ................................................................... 31 
6.7 
OBR (Companion Drugs) ...................................................................................... 31 
7 
Study Schedule 
33 
7.1 
Screening / Consenting Visit ................................................................................. 33 
7.2 
Randomization/Baseline ....................................................................................... 33 
7.3 
Follow-up .............................................................................................................. 34 
7.4 
Final Study Visit .................................................................................................... 39 
7.5 
Early Termination Visit .......................................................................................... 39 
7.6 
Unscheduled Visit ................................................................................................. 39 
8 
Study Procedures/Evaluations 
40 
8.1 
Clinical Evaluations ............................................................................................... 40 
8.2 
Laboratory Evaluations ......................................................................................... 40 
8.2.1 
Clinical Laboratory Evaluations ................................................................. 40 
8.2.2 
Special Assays or Procedures ................................................................... 42 
8.2.3 
Specimen Preparation, Handling, and Shipping ........................................ 43 
9 
Assessment of Safety 
44 
9.1 
Specification of Safety Parameters ....................................................................... 44 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ........................................................................................................... 44 
9.2.1 
Adverse Events ......................................................................................... 44 
9.2.2 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings ........................................................ 47 
9.3 
Reporting Procedures ........................................................................................... 47 
9.3.1 
Serious Adverse Events ............................................................................ 48 
9.3.2 
Regulatory Reporting for Studies Not Conducted Under 
DMID-Sponsored IND ............................................................................... 48 
9.3.3 
Reporting of Pregnancy ............................................................................. 49 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events ........................ 49 
9.5 
Guidance for Temporary Discontinuation of Study Drug ....................................... 49 

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9.6 
Safety Oversight ................................................................................................... 49 
9.6.1 
Data and Safety Monitoring Board (DSMB) ............................................... 49 
9.6.2 
Independent Safety Monitor (ISM) ............................................................. 49 
9.6.3 
Halting Rules ............................................................................................. 50 
10 
Clinical Monitoring 
51 
10.1 
Site Monitoring Plan .............................................................................................. 51 
11 
Statistical Considerations 
52 
11.1 
Study Hypotheses ................................................................................................. 52 
11.2 
Sample Size Considerations ................................................................................. 52 
11.3 
Planned Interim Analyses (if applicable) ............................................................... 56 
11.4 
Final Analysis Plan ............................................................................................... 56 
12 
Source Documents and Access to Source Data/Documents 
60 
13 
Quality Control and Quality Assurance 
61 
14 
Ethics/Protection of Human Subjects 
62 
14.1 
Ethical Standard ................................................................................................... 62 
14.2 
Institutional Review Board .................................................................................... 62 
14.3 
Informed Consent Process ................................................................................... 62 
14.4 
Informed Consent/Assent Process (in Case of a Minor) ........................................ 63 
14.5 Exclusion of Women, Minorities, and Children (Special Populations)........................ 63 
14.6 Subject Confidentiality .............................................................................................. 64 
14.7 Study Discontinuation ............................................................................................... 64 
14.8 
Future Use of Stored Specimens .......................................................................... 64 
15 
Data Handling and Record Keeping 
65 
15.1 Data Management Responsibilities .......................................................................... 65 
15.2 Data Capture Methods ............................................................................................. 66 
15.3 Types of Data ........................................................................................................... 66 
15.4 Timing/Reports ......................................................................................................... 66 
15.5 Study Records Retention .......................................................................................... 66 
15.6 Protocol Deviations ................................................................................................... 66 
16 
Publication Policy 
68 
17 
Literature References 
69 
APPENDIX A: SCHEDULE OF EVENTS* 
74 
APPENDIX B: KARNOFSKY SCALE 
75 
APPENDIX C: TOXICITY MANAGEMENT ALGORITHM 
77 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Aminotransferase 
ANC 
Absolute neutrophil count 
AUC 
Area Under the Curve (24 hours) 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CPX 
Ciprofloxacin 
CRF 
DCC 
Case Report Form 
Data Coordinating Center 
DMID 
 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
DOT 
Directly Observed Therapy 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EBA 
Early Bactericidal Activity 
FDA 
Food and Drug Administration 
FQ 
Fluoroquinolone 
FTP 
File Transfer Protocol 
GFX 
Gatifloxacin 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention To Treat 
LFX 
Levofloxacin 
MDR-TB 
Multidrug-resistant tuberculosis 
MIC 
Minimum Inhibitory Concentration 
MFX 
Moxifloxacin 
MOP 
Manual of Procedures 
MPC 
Mutant Prevention Concentration 
N 
Number (typically refers to subjects) 
NIH 
National Institutes of Health 
OAT 
Organic Ion Transport 
OBR 
Optimized Background Regimen 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OCT 
Organic Cation Transport 
OFX 
Ofloxacin 

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OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PZA 
Pyrazinamide 
SAE 
Serious Adverse Event/ Serious Adverse Experience 
SD 
Standard Deviation 
SOPSSCC 
Standard Operating Procedure Serial Sputum Colony Counts 
TB 
Tuberculosis 
TTD 
Time to Detection 
US 
United States 
WHO 
World Health Organization 
XDR-TB 
Extensively Drug Resistant Tuberculosis 
 
 
 

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PROTOCOL SUMMARY 
Title: 
Prospective, Randomized, Blinded Phase II 
Pharmacokinetic/Pharmacodynamic Study of the Efficacy and 
Tolerability of Levofloxacin in Combination with Optimized 
Background Regimen for the Treatment of MDR-TB 
Phase: 
II 
Population: 
The proposed study will randomize adults with pulmonary 
MDR-TB with sputum that is isoniazid and rifampin resistant by 
MTBDRplus and fluoroquinolone susceptible by MTBDRsl at 
sites in Peru and South Africa. 
Number of Sites: 
Three 
Study Duration: 
Four years.  
Subject Participation 
Duration: 
Randomized patients will have directly observed therapy 
(DOT) every day for 24 weeks (168 doses). Final study visit 
will occur at 28 weeks. 
Description of Agent or 
Intervention: 
Randomize patients with MDR-TB to 11, 14, 17 or 20 mg/Kg 
daily of levofloxacin in combination with optimized background 
regimen (OBR). OBR in this protocol is defined as an 
optimized regimen to accompany, but not including, a 
quinolone. 
Objectives: 
 
Primary: 
1. Determine the levofloxacin AUC/MIC that provides the 
shortest time to sputum culture conversion on solid 
medium. 
2. Determine the highest levofloxacin AUC that is both 
safe and associated with fewer than 25% of patients 
discontinuing or reducing their dose of levofloxacin. 
3. Develop a dosing algorithm to achieve the AUC 
associated with maximal efficacy and acceptable safety 
and tolerability. 
Secondary: 
1. Determine the levofloxacin AUC/MIC that provides the 
shortest time to sputum culture conversion in liquid 
medium. 

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2. Determine if baseline PZA susceptibility is associated 
with shorter time to sputum culture conversion after 
controlling for levofloxacin AUC 
3. Describe the differences in safety and efficacy between 
assigned study dose groups. 
Description of Study 
Design: 
 
• 
Subjects: Adult patients with pulmonary TB, whose 
sputum contains isoniazid and rifampin resistant, 
ofloxacin susceptible M. tuberculosis, HIV positive (with 
or without antiretroviral therapy) or negative (but not 
unknown), weight >40kg, age > 18 years, Karnofsky 
score of > 60 
• 
260 patients screened and 120 or more randomized to 
reach target for evaluation for the primary endpoint (62 
for efficacy and 80 for tolerability)  
• 
Information to collect at screening: duration of TB, 
known duration of MDR-TB, number and duration of 
previous episodes of TB treatment, extent of disease 
(radiographic), height, weight, age, sex, HIV status, 
CD4 count if HIV-infected, co-morbid conditions, prior 
drug susceptibility results, BUN, creatinine, ALT, 
bilirubin, concurrent medications.  
• 
Randomized 1:1:1:1 to treatment with levofloxacin , 4 
doses (all plus OBR):  
Dose 1 - 11 mg/kg (<60 kg= 750 mg [3x 250 mg 
tablets]; 60+ kg= 750 mg [3x 250 mg tablets]) 
Dose 2 - 14 mg/kg (<60 kg= 750 mg [3x 250 mg 
tablets]; 60+ kg= 1000 mg [4x 250 mg tablets]) 
Dose 3 - 17 mg/kg (<60 kg= 1000 mg [4x 250 mg 
tablets]; 60+ kg= 1250 mg [5x 250 mg tablets])  
Dose 4 - 20 mg/kg (<60 kg= 1250 mg [5 250 mg 
tablets]; 60+ kg= 1500 mg [6x 250 mg tablets]) 
• 
Blinded, controlled (all subjects take 6 tablets; single 
daily dose) 
• 
All doses directly administered and observed 
(levofloxacin and companion drugs) 
• 
Bi-weekly sputum cultures on 7H11 and in MGIT for 12 
weeks, then every 4 weeks up to 24 weeks of 
treatment  
• 
Intensive PK (6 samples), conducted during a 24 hour 
period between day 14 through day 28 
• 
Primary exposure variable for efficacy: AUC/MIC 
• 
Primary exposure variable for tolerability: AUC 
• 
Primary exposure for toxicity: Number of Grade 3,4,or 5 
AEs 

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• 
Primary exposure variable for development of 
algorithm: Dose of levofloxacin 
Estimated Time to 
Complete randomization: 
24 months from start of randomization 

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Schematic of Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screen subjects, ensure eligibility and obtain informed consent. 
Randomization (1:1:1:1)
Supervised spot sputum collection; Assess for safety and tolerability; serum and urine biomarker 
Assessment of Final Study Outcome 
Measures 
LEVOFLOXACIN  
11 mg/kg  
+ OBR 
LEVOFLOXACIN  
14 mg/kg  
+ OBR 
LEVOFLOXACIN  
17 mg/kg  
+ OBR 
LEVOFLOXACIN  
20 mg/kg  
+ OBR 
Day 0 
Study phase 
Early morning sputum collection; Assess for safety and tolerability 
Assess for safety and tolerability 
Assess for safety and tolerability 
Early morning Sputum collection; Assess for safety and tolerability; serum and urine biomarker 
Early morning sputum collection; Assess for safety and tolerability 
Assess for safety and tolerability 
Assess for safety and tolerability 
Early morning sputum collection; PK*; Assess for safety and tolerability 
Assess for safety and tolerability 
Early morning Sputum collection; Assess for safety and tolerability 
Early morning Sputum collection; Assess for safety and tolerability 
Early morning Sputum collection; Assess for safety and tolerability 
* PK once between days 14 and 28
Day 7 
Day 14 
Day 21 
Day 28  
Day 35 
Day 42 
Day 49 
Day 56  
Day 84  
Day 112  
Day 140  
Day 168  

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1 
KEY ROLES 
 
Individuals: 
 
 
Principal Investigator: 
 
C. Robert Horsburgh, Jr., MD, MUS 
Department of Epidemiology 
Boston University School of Public Health 
715 Albany Street, T3E 
Boston MA USA 02118 
Email: rhorsbu@bu.edu 
 
Co-Investigators: 
 
Andreas Diacon, MD 
Task Applied Science 
Brooklyn Chest Hospital 
Cape Town, South Africa 
E-mail: ahd@sun.ac.za 
 
Nancy Dianis, MS 
Westat, Inc. 
1600 Research Boulevard 
Rockville, MD 20850 
Tel: 301.738.8379 
Email: nancydianis@westat.com 
 
Kathleen Eisenach, PhD 
University of Arkansas for Medical Sciences 
4301 W. Markham, Slot 845 
Biomedical Research Center II, Rm 607-2 
Little Rock, AR 72205 
Tele (501) 526-6966 
FAX  (501) 526-6886 
E-mail: EisenachKathleenD@uams.edu 
 
Eduardo Gotuzzo, MD 
Universidad Peruana Cayetano Heredia  
Lima, Peru 
E-mail: eduardo.gotuzzo@upch.pe 
 
Leonid Lecca, MD 
SociosEnSalud Sucursal Peru/ Partners In Health 
Avenida Merino, Reyna 575, Carabayllo, Lima 6, Peru 
Llecca_SES@pih.org 

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Neel R Gandhi, MD 
Centers for Disease Control and Prevention 
Division of TB Elimination 
1600 Clifton Road, MS E-10 
Atlanta, GA 30333 
E-mail: neel.r.gandhi@emory.edu 
 
Beverly Metchock, PhD 
Centers for Disease Control and Prevention 
Division of TB Elimination 
1600 Clifton Road, MS F-08 
E-mail: bem1@cdc.gov 
 
Carole Mitnick, DSc 
Harvard Medical School 
641 Huntington Avenue, Boston, MA 02115 
+1-617-432-6018 
+1-617-432-2565 
carole_mitnick@hms.harvard.edu 
 
Charles Peloquin, Pharm. D 
University of Florida 
1600 SW Archer Road, Rm P4-33 
Gainesville, FL 32610 
Tel.: 352.273.6266 
Email: peloquin@cop.ufl.edu 
 
Patrick Phillips, PhD 
MRC Clinical Trials Unit 
125 Kingsway 
London WC2B 6NH 
Tel: +44.0.20.7670.4637 
Email: Patrick.phillips@ucl.ac.uk 
 
 
 
Institutions: 
Clinical sites: 
1. Task Biosciences at Brooklyn Chest Hospital, Cape 
Town, South Africa 
2. Socios en Salud, Lima, Peru 
3.Universidad Peruana Cayetano Heredia , Lima, Peru 
 
 

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Central Microbiology Laboratory:  
Mycobacteriology Reference Laboratory 
Centers for Disease Control and Prevention 
1600 Clifton Road, Atlanta GA USA 
30333 
 
Central Clinical Pharmacology Laboratory: 
University of Florida, College of Pharmacy, 1600 
SW Archer Rd. Room P4-33, Gainesville, FL USA 
32610-0486 
Tel: 352-273-6266 
Fax: 352-273-6804 
 
Data Coordinating Center: 
 
Westat, Inc. 
1600 Research Boulevard 
Rockville, MD USA 20850-3129 
 
 
Industry Collaborator:  
 
Macleods Pharmaceuticals, Ltd, 3rd floor, Atlanta Arcade, 
Church Road, Near Leela Hotel, Andheri-Kurla Road, 
Andheri (E), Mumbai – 400 059, India 
 
 
DMID Representative:  
 
Francisco J. Leyva MD, PhD, ScM 
Medical Officer 
Tuberculosis, Leprosy and other Mycobacterial Diseases 
Section 
Respiratory Diseases Branch - DMID 
NIAID - NIH - HHS 
5601 Fishers Ln., Room 8E27 
Rockville MD 20852-9825 
Phone: 240-627-3347 
Fax: 240-627-3138 
 
Mohamed (Mo) Elsafy, MD 
DMID Medical Monitor 
Tel:  301-451-3026   
Cell: 301-204-3735  
Email: mo.elsafy@nih.gov 

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Tena Knudsen, RN 
DMID Clinical Project Manager 
Tel: 240-627-3290  
Fax: 301-496-8030  
Email: knudsent@mail.nih.gov 
 
Institutional Review 
Boards 
 
Institution Name: 
Boston University 
Address: 
 
560 Harrison Ave, Suite 300, Boston, MA 02118, USA 
FWA Number:  
00005790 
Name of site PI: 
Charles Robert (Bob) Horsburgh, MD 
Note:  
 
IRB approval will be obtained at this site 
 
Institution Name: 
University of Florida 
Address: 
 
PO Box 100173, Gainesville, FL 32610, USA 
FWA Number:  
00005790 
Name of site PI: 
Charles Peloquin, PharmD 
Note:  
 
Site is “not engaged” 
 
 
Institution Name: 
Harvard University 
Address: 
 
90 Smith St, 3rd Fl Rm 336, Boston, MA 02120, USA 
FWA Number:  
FWA00007071 
Name of site PI: 
Carole Mitnick, ScD 
Note:  
 
Site is “not engaged” 
 
Institution Name: 
University of Arkansas 
Address: 
 
4301 W. Markham St., Slot 636, Little Rock, AR 72205 
FWA Number:  
00001119 
Name of site PI: 
Kathleen Eisenach, PhD 
Note:  
 
Site is “not engaged” 
 
Institution Name: 
University of California, San Francisco 
Address: 
 
3333 California Street, Suite 16, San Francisco, CA 94143, USA 
FWA Number:  
00000068 
Name of site PI: 
Payam Nahid, MD 
Note:  
 
Site is “not engaged” 
 
 
Institution Name: 
Westat, Inc. 

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Address: 
 
1600 Research Boulevard, Rockville, MD 20850-3129 
FWA Number:  
00005551 
Name of site PI: 
Nancy Dianis, RN 
Note:  
 
Site is “not engaged” 
 
Institution Name: 
University College of London / MRC Clinical Trials 
Address: 
 
University College London, Gower Street, London WC1E 6BT, UK 
FWA Number:  
00003159 
Name of site PI: 
Patrick Phillips, PhD 
Note:  
 
Site is “not engaged” 
 
 
Institution Name: 
Centers for Disease Control and Prevention 
Address: 
 
1600 Clifton Rd, NE MS E-10, Atlanta, GA 30333, USA 
FWA Number:  
00001413 
Name of site PI: 
Neel R Gandhi, MD 
Note:  
 
Site is “not engaged” 
 
Institution Name: 
University of Stellenbosch Human Research Ethics Committee 
Address: 
 
PO Box 19063 Tygerberg, 7505, Cape Town, South Africa 
FWA Number:  
00005239/00005240 
Name of site PI: 
Andreas Diacon, MD 
Note:  
 
IRB approval will be obtained at this site 
 
Institution Name: 
ERB Universidad Peruana Cayetano Heredia 
Address: 
 
Av. Honorio Delgado 430, Urb. Ingeniería, S.M.P. Lima, Peru. 
FWA Number:  
00000525 
Name of site PI: 
Eduardo Gotuzzo, MD 
Note:  
 
IRB approval will be obtained at this site 
 
Institution Name: 
Comite Instrucional de Etica en Investigacion del Hospital Nacional 
Hipolito Unanue 
Address: 
 
Av. Cesar Vallejo 1390, El Agustino, Lima, Peru 
FWA Number:  
00015265 
Name of site PI: 
Leonid Lecca, MD 
Note:  
 
IRB approval will be obtained at this site 
See Section 14.2 for definition of “engaged” and “not engaged” 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
2.1.1. MDR-TB Epidemiology 
Approximately 5% of the 9 million new tuberculosis (TB) cases globally each year are caused by 
organisms that are resistant to isoniazid and rifampin, the two most important first-line anti-TB 
drugs, resulting in multidrug-resistant (MDR) TB.1MDR-TB is not distributed equally around the 
globe; rather it occurs in areas defined by WHO as “hot spots”.  South Africa is estimated to 
have 10,000 new cases of MDR-TB each year, while Peru has 2,300.1 
 
The situation is even worse when additional drug resistance is present, such as is seen in 
patients with M. tuberculosis isolates also resistant to fluoroquinolones and second-line 
injectable agents, known as XDR-TB. XDR-TB is estimated to occur in 5% of persons with 
MDR-TB and has been detected in 58 countries.1 Among patients with XDR-TB, only 44% have 
satisfactory outcomes, and 21% die..2  Patients with XDR-TB and HIV infection have even 
worse outcomes.3 In light of the potential severe implications of the existence and spread of 
MDR- and XDR-TB, particularly in high HIV-prevalence settings, improved outcomes among 
patients with MDR- are essential. 
 
2.1.2. State of MDR-TB treatment 
A recent review summarized the results of observational studies of MDR-TB and found that 
success is less common as a final treatment outcome than in the treatment of drug-susceptible 
TB, which results in 85-95% successful outcomes.4 Statistically significant risk factors in 
multivariate analysis, in addition to fluoroquinolone use, include HIV infection,5-6the number of 
drugs to which the patient’s pretreatment isolate is resistant,7-9quinolone resistance,10-11male 
sex,12previous treatment for MDR-TB8, 11younger age,13low BMI,11, 14cavitation8, 15and poor 
adherence to the regimen.15 
 
 
Despite the use of specialized regimens for treatment, MDR-TB cure rates are substantially 
lower than those expected when treating drug-susceptible TB. Prior to the advent of the FQs, 
MDR-TB treatment was characterized by a cure rate of only 56%, with 37% five year mortality.16 
Including an FQ in the regimen has led to improved overall cure rates to 61%-75% and ~20% 
mortality.4, 10-11, 13-14 Although there have been no controlled clinical trials of FQ use in treatment 
of MDR-TB, a number of observational studies have linked FQ use with good treatment 
outcomes.15, 17-21 Thus, FQ are an essential part of MDR-TB treatment regimens. 
 
2.1.3. Efficacy of Fluoroquinolones for TB treatment 
Fluoroquinolones target the DNA gyrase of bacteria, including that of Mycobacterium 
tuberculosis. The in vivo activity of the fluoroquinolones is concentration-dependent. Early 
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and were essential to good outcomes in several observational studies of the treatment of MDR-
TB.15, 19-25 Newer members of the fluoroquinolone class, levofloxacin (LFX), moxifloxacin (MFX) 
and gatifloxacin (GFX), have demonstrably increased anti-tuberculosis activity in vitro compared 
to ciprofloxacin (CPX) and ofloxacin (OFX). Improved pharmacokinetics and pharmacodynamics 
have also been observed with the later-generation fluoroquinolones (Table 1).26 
 
Table 1. Comparative PK/PD of fluoroquinolones after single oral dose in humans 
Drug 
Pharmacokinetics 
Pharmacodynamics 
Dose 
(mg) 
Cmax 
(µg/ml) 
AUC 
(µg-h/ml) 
MIC90 
(µg/ml) 
CMax/MIC90 
AUC/MIC90 
 
Ciprofloxacin 
500 
2.4 
11.6 
1.0 
2.4 
11.6 
Ofloxacin 
400 
3 
24 
2.0 
1.5 
12 
Levofloxacin 
500 
6.2 
45 
1.0 
6.2 
45 
Moxifloxacin 
400 
4.3 
39 
0.5 
8.6 
78 
 
Murine models of TB show clearly increasing anti-TB activity with increasing doses of ofloxacin, 
sparfloxacin and levofloxacin to doses greater than those usually employed.27-28 In humans, 
early studies of ciprofloxacin 500 mg daily and ofloxacin 400 mg daily for treatment of drug-
susceptible TB indicated that these agents were well tolerated but did not improve upon 
standard treatment.15, 29 Subsequent reports demonstrated that increasing the dose led to more 
robust responses.21 When levofloxacin (which is twice as potent as ofloxacin on a per-gram 
basis) became available, it was used at a dose of 750 mg daily30 and resulted in improved 
outcomes.31 In patients with MDR-TB, it has been observed that patients with isolates with in 
vitro ofloxacin resistance may still respond to regimens containing FQs that achieve increased 
serum concentrations.32A recent meta-analysis of 13 observational studies of XDR-TB treatment 
found that studies in which a higher proportion of patients received a later generation FQ 
(levofloxacin, moxifloxacin or non-marketed sparfloxacin) reported a higher proportion of 
favorable outcomes, suggesting that the pharmacodynamic advantage of more potent FQs can 
overcome resistance to ofloxacin.2 This phenomenon may be explained by the results of MIC 
testing of TB isolates showing that many isolates resistant to ofloxacin have MICs just above the 
clinical cutoff, indicating that increased FQ dosing might render them susceptible.33-34 
 
Fluoroquinolones are the most active class of antimycobacterial agents currently available for 
use in patients with MDR-TB. Although there have been no controlled clinical trials of quinolone 
use in treatment of MDR-TB, a number of observational studies have linked fluoroquinolone use 
with good treatment outcomes.15, 17-21 Prior to the advent of the quinolones, MDR-TB treatment 
was characterized by a cure rate of only 56%, with 37% five year mortality.16 Including a 
quinolone in the regimen has led to improved overall cure rates to 61%-75% and ~20% 
mortality. In the absence of prospective clinical trials to determine the optimal dose of FQ for 
treatment of TB, doses which had been optimized for treatment of serious bacterial infections 
were simply carried over to TB treatment. Rapid emergence of resistance to FQ in patients 
being treated for MDR-TB suggests that these doses are suboptimal, and may even promote 

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acquisition of antimycobacterial resistance, particularly when combined with suboptimal 
companion drugs.21, 35 
 
2.1.4. Other new drugs for treatment of MDR-TB 
 
Substantial improvement in treatment outcomes for patients with MDR-TB will require both 
optimization of fluoroquinolone dosing and addition to the regimen of new antimycobacterial 
agents that are more efficacious than current second-line anti-TB agents. Two promising 
compounds, bedaquiline and delamanid, have recently completed Phase 2 clinical trials in 
patients with MDR-TB. Bedaquiline, when added to an optimized background regimen (OBR) in 
a study of 159 patients, resulted in more rapid sputum culture conversion in liquid media than 
OBR plus placebo (12 weeks versus 18 weeks) and a higher proportion of cures at 24 
months.36-37 A phase 2 study of delamanid using a similar design was recently reported.37a. 
While new FQ agents are being developed for use and anti-TB agents (TBK-613, KRQ-10018), 
none is yet in stage 1 trials.38-39 
 
2.1.5. Why levofloxacin will be the drug of choice for treatment of MDR-TB 
Ciprofloxacin is clearly inferior to the later generation FQ, and most experts recommend against 
its use for treatment of TB.40Ofloxacin is the same active moiety as levofloxacin but also 
contains 50% of the inactive isomer, so that 800 mg of ofloxacin is equivalent to 400 mg of 
levofloxacin. Thus, levofloxacin is preferable to ofloxacin for treatment of TB. Gatifloxacin and 
sparfloxacin have been taken off the market because of toxicities (dysglycemia and 
hypersensitivity, respectively). Therefore either levofloxacin or moxifloxacin will be the optimal 
FQ for TB treatment. 
 
Moxifloxacin is relatively well tolerated at 400 mg daily, but in vitro studies have 
suggested that this dose is sub-optimal.31 However, there are few data on tolerability of higher 
doses, because the 400 mg dose is associated with substantial QT interval prolongation.41 
Despite the fact that higher doses of moxifloxacin might be more efficacious, no reports of 
tolerability of higher doses have been published, and the sponsor will not support clinical studies 
using higher doses. Levofloxacin has no QT interval prolongation at doses up to 20 mg/kg 
daily.42 Unfortunately, both TMC-207 and OPC-67683 have the potential to cause QT-
prolongation. For this reason, the current clinical studies of TMC-207 and OPC-67683 both 
require that moxifloxacin not be used in combination with the investigational product. Therefore, 
it is likely that, when these drugs are licensed for use in treating MDR-TB, as anticipated, the 
label will state that moxifloxacin should not be used concurrently. Therefore, levofloxacin will be 
the FQ of choice for treatment of MDR-TB for at least the next decade  
 
2.1.6. Currently used levofloxacin doses are suboptimal 
Evidence that levofloxacin, and more generally other late-generation fluoroquinolones, dose and 
activity against M. tuberculosis could be increased without sacrificing tolerance is emerging.43 
Accumulated safety and tolerability data permit recommended LFX doses as high as 1000 

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mg.44-45 A recent early bactericidal activity (EBA) study demonstrated that levofloxacin 1000 mg 
per day in adults has activity against M. tuberculosis equivalent to currently employed dosage of 
400 mg QD of moxifloxacin.46 Furthermore, this dose achieves comparable AUC/MIC and 
Cmax/MIC values to those achieved by GFX and MFX, each at 400 mg/day. In animal studies, 
increasing doses to the equivalent of 20 mg/kg resulted in greater decreases in M. tuberculosis 
colony counts. 
 
The current study proposes to study levofloxacin at 4 doses (11 mg/kg, 14 mg/kg, 17 mg/kg and 
20 mg/kg; these are roughly equivalent to 750 mg, 1000 mg, 1250 mg and 1500 mg per day for 
a 70-kg person. These doses will be given in combination with an optimized background 
regimen (OBR), for efficacy and tolerability in treatment of patients with MDR-TB. Patients will 
be followed intensively for the first six months of treatment, with the primary endpoint being time 
to culture conversion; subjects who have not experienced culture conversion at 6 months will be 
classified as being at increased risk for a poor treatment outcome. This efficacy endpoint will be 
combined with intensive pharmacokinetic sampling so that the optimal target AUC/MIC ratio for 
levofloxacin can be established. Based on murine studies, the target AUC/MIC will be 100.47 
 
Levofloxacin at a dose of 11 mg/kg is well tolerated by patients with TB.15, 30, 48 Levofloxacin at 
14 mg/kg/day has recently been adopted by some TB programs, and also appears to be well-
tolerated.44-45 Levofloxacin has been used for treatment of TB meningitis at doses of 20 
mg/kg/day in 15 adults with TB meningitis for 60 days.49No side effects attributable to the 
levofloxacin were seen.50 This dose was also studied in children with recurrent or persistent 
otitis media; 786 children ages <1 to 5 years received levofloxacin 20 mg/kg day for an average 
of 10.2 days.51 There were no significant differences in adverse effects between levofloxacin 
and the comparator regimen, amoxicillin/clavulanate 90 mg/kg/day. In a larger study of 2523 
children treated with levofloxacin 20 mg/kg/day, a small but significant increase in 
musculoskeletal disorders, largely arthralgias, was seen in patients receiving this dose of 
levofloxacin (2.1% vs. 0.9% of subjects).52 It is possible that children excrete levofloxacin more 
rapidly than adults, so that the levofloxacin AUC achieved in patients in the proposed study 
could be higher than those well-tolerated in children. However, we believe that the frequency of 
intolerance to the highest study dose (20 mg/kg) among patients with MDR-TB will be low. 
 
2.1.7. Emergence of fluoroquinolone resistance 
Rates of quinolone resistance seen in M. tuberculosis isolates are increasing.53 In some cases, 
drug resistance to FQ among TB patients is associated with use of FQ for treatment of 
community acquired pneumonia.54-55 More worrisome has been the recent report of emergence 
of resistance to FQ in patients receiving FQ for treatment of MDR-TB; a rate of 20% acquisition 
of FQ resistance per year has been reported.35 In another study, 6 % of patients developed both 
FQ resistance and resistance to a second-line injectable agent.56 Such FQ resistance is usually 
attributable to with mutations in gyrA and gyrB.57-58  Disease in patients whose M. tuberculosis 
develops FQ resistance while on treatment for MDR-TB are called “Pre-XDR-TB” and have a 
high risk of progressing to XDR-TB. Studies with other fluoroquinolones have demonstrated that 

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higher AUC must be achieved to prevent emergence of resistance than to kill M. tuberculosis.57, 
59Thus, there may be additional benefit to increasing the AUC achieved with levofloxacin over 
and above that needed to maximize killing of M. tuberculosis. 
 
2.1.8. Pharmacokinetic and pharmacodynamic parameters of levofloxacin 
The PK/PD concentration of parameter that corresponds to maximal bactericidal (or sterilizing 
activity) for fluoroquinolones in the treatment of TB has not been identified.   
Evidence from other serious bacterial infections suggests that this would be AUC/MIC ratio.60 
This parameter is the best predictor in the mouse model of tuberculosis for the activity of 
fluoroquinolones; this model suggests that better responses will be seen when the AUC/MIC 
ratio is > 100.47 The relationship between antimycobacterial activity and AUC/MIC in patients 
with MDR-TB will be evaluated in the current proposal. 
2.1.9. Assessing Response to MDR-TB treatment 
Interim indicators of treatment response have been infrequently reported for MDR-TB. Time to 
culture conversion, however, has been associated with final outcomes of MDR-TB treatment.61 
Even for drug-susceptible TB, the only partially validated surrogate endpoint for cure is 
dichotomous evaluation of sputum culture conversion at a fixed point in time.62 This endpoint is 
commonly assessed as the proportion culture negative rate at 2 months of regimen. This 
endpoint however, has serious limitations including limited specificity and sensitivity. Moreover, 
it requires sample sizes of 100-250 per arm for Phase 2b trials. This makes Phase 2b one of the 
key bottlenecks in TB drug development. Recently, an elegant analysis demonstrated the 
increased precision provided by measuring culture conversion as a continuous endpoint and 
calculating the outcome as time to culture conversion with survival analysis. Validation of such a 
continuous marker of a binary endpoint could lead to reduced sample sizes in future MDR-TB 
trials.63-64 Consequently, the present study will also assess rate of change in time to positivity in 
liquid medium as a surrogate marker of culture conversion in the first 6 months. 
 
 
Serial Sputum Colony Counts (SSCC) have also been carefully studied as a surrogate endpoint 
for clinical trials of tuberculosis treatment. Plots of these counts over time show a biphasic 
decline in SSCC that varies by study arm. This work has confirmed that the decline has two 
phases, an early “fast” phase and a prolonged “slow” phase. Non-linear mixed effects 
regression analysis has demonstrated that the rate of decline of the slow phase predicts 
sterilizing activity of antituberculosis regimens.64-65 Use of SSCC as an endpoint in clinical trials 
is hampered by the expense and intensity of labor required for accurate assessment of this 
endpoint. Since sputum colony counts are highly correlated with Time-To-Detection (TTD) of M. 
tuberculosis from sputum in liquid medium,66-68Weiner et al. analyzed the results of TTD as a 
predictor of treatment failure and found that risk factors commonly associated with treatment 
failure were more strongly associated with TTD than with culture conversion at 2 
months.63Hessling, et al also found that baseline TTD predicted both 2-month culture 

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conversion and relapse in drug-susceptible TB.69 The present study will explore the relationship 
between TTD and outcomes in MDR-TB.  
 
2.1.10. Alternative Study Designs 
Studies of increasing drug dose to evaluate safety of higher doses are often performed in a 
stepwise fashion, such that one dose is studied and evaluated in a single group of patients 
before making a decision to enroll patients in the next-highest dose (a “dose-escalation study”).  
We have decided not to follow such a strategy for the following reasons: 
1. We believe that doses of 20 mg/kg/day have already been demonstrated to be well-
tolerated in man (see section 2.1.6) so that patients are not at risk for excessive 
occurrence of adverse events up to this dose. 
2. The extremely poor clinical response to MDR-TB treatment and the high associated 
mortality with regimens containing lower doses of levofloxacin, combined with animal 
and in vitro data strongly suggesting that increased doses of levofloxacin could be more 
efficacious justifies the small potential for increased occurrence of adverse effects with 
doses up to 20 mg/kg/day. 
3. The need to follow study subjects in each dose group for 6 months would mean that a 
study of 25 subjects at each of four doses would require 14 months per group (6 months 
to enroll 25 subjects+ 6 months to follow the last enrolled subject+2 months laboratory 
follow-up+2 months to decide on the next dose and begin enrollment), lengthening the 
study to at least 64 months. 
4. Sequential evaluation of each dose would preclude randomization to dose. Without 
randomization to dose, each dose group would need to be substantially larger to achieve 
equivalent precision in the estimates of efficacy, tolerability and safety. We estimate that 
such a design would require approximately 50 subjects per group rather than 25.This 
would increase the number of study subjects exposed to higher doses and greatly 
increase the cost and duration of the study. 
Therefore, we conclude that the minimal expectation of increased adverse events with doses up 
to 20 mg/kg is outweighed by the potential benefit of fewer exposed patients, shorter time to 
study results, decreased cost and the need for better treatment options for these patients. 
 
2.2 
Scientific Rationale 
 
Optimization of levofloxacin dose is important for two reasons.  First, it is the least toxic of 
current “third-generation” fluoroquinolones; moxifloxacin, which is still under patent protection, is 
associated with substantial QT prolongation, while gatifloxacin induces disglycemia, may lead to 
diabetes, and has been removed from the market. New fluoroquinolones are still in preclinical 
development, and will not come to market for at least 8-10 years. Thus, levofloxacin is likely to 
be the most widely used fluoroquinolone for treatment of TB, especially MDR-TB, for the 
foreseeable future.  
 

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Second, optimization of levofloxacin dose minimizes the likelihood that FQ resistance will 
emerge during MDR-TB treatment. Hollow fiber studies of both ciprofloxacin and moxifloxacin 
have demonstrated that the target AUC for prevention of the emergence of resistance (Mutant 
Prevention Concentration, or MPC) in M. tuberculosis is substantially higher than that for 
bactericidal effect, and that unless this concentration is exceeded, resistant mutants are 
selected and replace the susceptible population.57, 70When used against gram-negative bacteria 
in an animal model, suboptimal concentrations of FQ not only lead to the emergence of FQ-
resistant bacteria, but they also promote emergence of resistance to other antibiotics, through 
SOD-mediated mutagenesis.71 Thus, dosing strategies that result in high AUC/MIC ratios could 
be important in prevention of the emergence of resistance to FQ, and to other agents in M. 
tuberculosis.  
 
By identifying target AUC and AUC/MIC ratios, and by increasing our understanding of their 
relationship to levofloxacin dose, this study will allow physicians to treat MDR-TB patients with 
the highest doses of levofloxacin that are associated with acceptable tolerability. However, Most 
patients with MDR-TB receive treatment in geographic areas where monitoring of serum drug 
concentrations and subsequent adjustment of doses is impractical. Therefore we propose 
development of an algorithm that will predict the mg/Kg dose most likely to achieve the AUC 
and AUC/MIC ratios. This is complicated by the fact that the levofloxacin AUC distribution in 
patients with TB can be very broad; more than 100-fold differences in AUC have been seen with 
the same dose in two separate studies 72-73  Therefore, optimizing levofloxacin dosing for TB 
treatment will both require a better understanding of the factors underlying this variability and a 
strategy for optimizing dosing despite this variability.  
 
We hypothesize that the proposed examination of clinical predictors of AUC will provide result in 
easily implemented identification of patients whose AUC can be expected to be at the high and 
low ends of the distribution, allowing construction of an algorithm that will generate treatment 
guidelines to prevent under- or over-dosing such patients. Thus, physicians without access to 
levofloxacin concentrations will be able to make a reasonable estimate of the highest dose that 
the patient is likely to tolerate, thus achieving the greatest efficacy.  
 
This study will also provide firm evidence for the efficacy of the highest tolerated dose of 
levofloxacin, up to 20mg/Kg.  Currently, moxifloxacin is being used by some programs as an 
alternative to levofloxacin for treatment of MDR-TB. There is much enthusiasm for moxifloxacin, 
despite the lack of evidence that it is superior to levofloxacin; in fact, a recent EBA study 
demonstrated that levofloxacin 14 mg/Kg per day has activity against M. tuberculosis that is 
similar to that of moxifloxacin at the standard dose (400 mg per day).46 Moreover, levofloxacin 
will soon be off patent worldwide, while moxifloxacin will remain on patent for 5 more years. 
Therefore it is important to define the most effective dose of levofloxacin for TB treatment that is 
both safe and well-tolerated.  

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2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
2.3.1.1 WARNINGS AND PRECAUTIONS  
 
 
2.3.1.1.1 Tendinopathy and Tendon Rupture  
Fluoroquinolones, including levofloxacin, are associated with an increased risk of tendinitis and 
tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, 
and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in 
the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also 
been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture 
is further increased in older patients usually over 60 years of age, in those taking corticosteroid 
drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and 
corticosteroid use, that may independently increase the risk of tendon rupture include strenuous 
physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. 
Tendinitis and tendon rupture have been reported in patients taking fluoroquinolones who do not 
have the above risk factors. Tendon rupture can occur during or after completion of therapy; 
cases occurring up to several months after completion of therapy have been reported. 
Levofloxacin should be discontinued if the patient experiences pain, swelling, inflammation or 
rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon 
rupture, and to contact their healthcare provider regarding changing to a non-quinolone 
antimicrobial drug.  
 
 
2.3.1.1.2 Hypersensitivity Reactions  
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been 
reported in patients receiving therapy with fluoroquinolones, including levofloxacin. These 
reactions often occur following the first dose. Some reactions have been accompanied by 
cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, 
angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction 
(including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, 
urticaria, itching, and other serious skin reactions. Levofloxacin should be discontinued 
immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious 
acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative 
measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, 
and airway management, as clinically indicated.  
 
 
2.3.1.1.3 Other Serious and Sometimes Fatal Reactions  
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to 
uncertain etiology, have been reported rarely in patients receiving therapy with fluoroquinolones, 
including levofloxacin. These events may be severe and generally occur following the 

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administration of multiple doses. Clinical manifestations may include one or more of the 
following:  
• 
fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-
Johnson Syndrome);  
• 
vasculitis; arthralgia; myalgia; serum sickness;  
• 
allergic pneumonitis;  
• 
interstitial nephritis; acute renal insufficiency or failure;  
• 
hepatitis; jaundice; acute hepatic necrosis or failure;  
• 
anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic 
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other 
hematologic abnormalities.  
 
The drug should be discontinued immediately at the first appearance of skin rash, jaundice, or 
any other sign of hypersensitivity and supportive measures instituted. 
 
 
2.3.1.1.4 Hepatotoxicity  
Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have 
been received for patients treated with levofloxacin. No evidence of serious drug-associated 
hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity 
generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. 
Most cases of severe hepatotoxicity were not associated with hypersensitivity. The majority of 
fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not 
associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient 
develops signs and symptoms of hepatitis.  
 
 
2.3.1.1.5 Central Nervous System Effects  
Convulsions and toxic psychoses have been reported in patients receiving fluoroquinolones, 
including levofloxacin. Fluoroquinolones may also cause increased intracranial pressure and 
central nervous system stimulation which may lead to tremors, restlessness, anxiety, 
lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, 
rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these 
reactions occur in patients receiving levofloxacin, the drug should be discontinued and 
appropriate measures instituted. As with other fluoroquinolones, levofloxacin should be used 
with caution in patients with a known or suspected central nervous system (CNS) disorder that 
may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral 
arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to 
seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction.).  
 
 
2.3.1.1.6 Clostridium difficile-Associated Diarrhea  
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all 
antibacterial agents, including levofloxacin, and may range in severity from mild diarrhea to fatal 

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colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to 
overgrowth of C. difficile.  
 
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin 
producing strains of C. difficile because increased morbidity and mortality, as these infections 
can be refractory to antimicrobial therapy and may require colectomy. CDAD must be 
considered in all patients who present with diarrhea following antibiotic use. Careful medical 
history is necessary since CDAD has been reported to occur over two months after the 
administration of antibacterial agents.  
 
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may 
need to be discontinued. Appropriate fluid and electrolyte management, protein 
supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted 
as clinically indicated. 
 
 
2.3.1.1.7 Peripheral Neuropathy  
Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large 
axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been 
reported in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be 
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, 
numbness, and/or weakness or other alterations of sensation including light touch, pain, 
temperature, position sense, and vibratory sensation in order to prevent the development of an 
irreversible condition.  
 
 
2.3.1.1.8 Prolongation of the QT Interval  
Some fluoroquinolones, including levofloxacin, have been associated with prolongation of the 
QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade 
de pointes have been spontaneously reported during post-marketing surveillance in patients 
receiving fluoroquinolones, including levofloxacin. Levofloxacin should be avoided in patients 
with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients 
receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic 
agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval.  
 
 
2.3.1.1.9 Musculoskeletal Disorders in Pediatric Patients and Arthropathic 
Effects in Animals  
Levofloxacin is indicated in pediatric patients (≥6 months of age) only for the prevention of 
inhalational anthrax (post-exposure). An increased incidence of musculoskeletal disorders 
(arthralgia, arthritis, tendonopathy, and gait abnormality) compared to controls has been 
observed in pediatric patients receiving levofloxacin.  
In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in 
increased osteochondrosis. Histopathological examination of the weight-bearing joints of 
immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other 

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quinolones also produce similar erosions in the weight-bearing joints and other signs of 
arthropathy in immature animals of various species.  
 
 
2.3.1.1.10 Blood Glucose Disturbances  
As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper- 
and hypoglycemia, have been reported with levofloxacin, usually in diabetic patients receiving 
concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these 
patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction 
occurs in a patient being treated with levofloxacin, levofloxacin should be discontinued and 
appropriate therapy should be initiated immediately.  
 
 
2.3.1.1.11 Photosensitivity/Phototoxicity 
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as 
exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) 
involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the 
forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or 
UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. 
Drug therapy should be discontinued if photosensitivity/phototoxicity occurs.  
 
 
2.3.1.1.12 Development of Drug Resistant Bacteria  
Prescribing levofloxacin in the absence of a proven or strongly suspected bacterial infection or a 
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the 
development of drug-resistant bacteria.  
 
2.3.1.2 ADVERSE REACTIONS  
 
 
2.3.1.2.1 Serious and Otherwise Important Adverse Reactions  
The following serious and otherwise important adverse drug reactions are discussed in greater 
detail in other sections of labeling:  
• 
Tendon Effects 
• 
Hypersensitivity Reactions 
• 
Hepatotoxicity 
• 
Central Nervous System Effects 
• 
Clostridium difficile-Associated Diarrhea 
• 
Peripheral Neuropathy 
• 
Prolongation of the QT Interval 
• 
Musculoskeletal Disorders in Pediatric Patients 
• 
Blood Glucose Disturbances 
• 
Photosensitivity/Phototoxicity 
• 
Development of Drug Resistant Bacteria 
 

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Hypotension has been associated with rapid or bolus intravenous infusion of levofloxacin. 
Levofloxacin should be infused slowly over 60 to 90 minutes, depending on dosage.  
Crystalluria and cylindruria have been reported with quinolones, including levofloxacin. 
Therefore, adequate hydration of patients receiving levofloxacin should be maintained to 
prevent the formation of highly concentrated urine.  
 
 
2.3.1.2.2 Clinical Trial Experience  
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 
of another drug and may not reflect the rates observed in practice.  
The data described below reflect exposure to levofloxacin in 7537 patients in 29 pooled Phase 3 
clinical trials. The population studied had a mean age of 50 years (approximately 74% of the 
population was < 65 years of age), 50% were male, 71% were Caucasian, and 19% were Black. 
Patients were treated with levofloxacin for a wide variety of infectious diseases. Patients 
received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice 
daily. Treatment duration was usually 3-14 days, and the mean number of days on therapy was 
10 days.  
 
The overall incidence, type and distribution of adverse reactions was similar in patients 
receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or 
twice daily. Discontinuation of levofloxacin due to adverse drug reactions occurred in 4.3% of 
patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of 
patients treated with the 750 mg dose. The most common adverse drug reactions leading to 
discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea 
(0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse 
drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), 
primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%).  
 
Adverse reactions occurring in ≥1% of levofloxacin-treated patients are shown in Table 2. The 
most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, insomnia, 
constipation, and dizziness.  
 
Table 2: Common (≥1%) Adverse Reactions Reported in Clinical Trials with levofloxacin 
System/Organ Class  
Adverse Reaction  
% (N=7537)  
Infections and 
Infestations  
moniliasis 
1  
Psychiatric Disorders  
Insomnia 
4  
Nervous System 
Disorders  
Headache, dizziness 
6, 3  
Respiratory, Thoracic 
and Mediastinal 
Disorders  
Dyspnea 
1  

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Gastrointestinal 
Disorders  
Nausea, diarrhea, constipation, abdominal 
pain, vomiting, dyspepsia  
7, 5, 3, 2, 2, 2  
Skin and Subcutaneous 
Tissue Disorders  
Rash[see Warnings and Precautions (5.2)] 
Pruritus  
2 1  
Reproductive System 
and Breast Disorders  
Vaginitis 
1b  
General Disorders and 
Administration Site 
Conditions  
Edema, injection site reaction, chest pain  
1 11 
 
 
 2.3.1.3 Alternative data gathering procedures 
In studies to determine the optimal dose of a new drug, dose-escalation is usually employed.  In 
such a design, one assures that one dose is safe and well tolerated before increasing the dose 
in search of greater efficacy.  However, levofloxacin is not a new drug and its safety and toxicity 
profile is well known. There is ample evidence that it is well tolerated by patients with TB for 
prolonged periods of time at doses of 11mg/kg and 14 mg/kg. In addition, there are a number of 
studies indicating that it is well tolerated at doses up to of 20 mg/kg, the highest dose proposed 
for this study (see section 2.1.6).  The alternative to the proposed study design would be to first 
examine the safety and tolerability of 17 mg/kg and then proceed to adding the 20 mg/kg group.  
This would require a substantial alteration in the present study design, as the analysis relies on 
randomization to the four dose arms, and sequential addition of dose arms would preclude such 
randomization.   
 
We believe that the likelihood of toxicity with the 17 mg/kg dose is so low that study of this dose 
alone is not necessary. Therefore, our design is, in effect, a dose escalation design that begins 
with the escalation from 14mg/kg to 20 mg/kg. Moreover, we have built in an unbIinded 
evaluation of the safety of the 20 mg/kg dose by the DSMB As noted in Section 9.6, “the DSMB 
will review safety and tolerability of the all doses three months after 40 patients have been 
randomized and again three months after 60 patients have been randomized. If more than 50% 
of patients in any dose arm have permanently discontinued treatment for any reason before 
completing 24 weeks of treatment, the DSMB will recommend that randomization to that arm be 
terminated. 
 
2.3.2 Known Potential Benefits 
Levofloxacin is known to have benefit for treatment of TB in persons with disease caused by 
susceptible isolates. Therefore, participation in this study will ensure that patients are being 
treated with an agent that is effective against the causal organism of their disease.  In addition, 
patients in this study will have additional anti-tuberculosis agents selected to have activity 
against their organism, resulting in use of an optimized regimen. Thus patients may have more 
rapid treatment response, accelerated conversion, enabling them to return to work more quickly 
and pose less risk to their households and communities. In addition, study participation is likely 

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to gain them quicker access to drug susceptibility testing and subsequent modification of 
treatment regimens and more careful follow-up than would be received by patients receiving 
standard TB care. 

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3 
OBJECTIVES 
3.1 
Study Objectives 
 
Primary Objectives 
 
1. Determine the levofloxacin AUC/MIC that provides the shortest time to sputum 
culture conversion on solid medium. 
2. Determine the highest levofloxacin AUC that is both safe and associated with fewer 
than 25% of patients discontinuing or reducing their dose of levofloxacin. 
3. Develop a dosing algorithm to achieve the AUC associated with maximal efficacy 
and acceptable safety and tolerability. 
 
Secondary Objectives 
1. Determine the levofloxacin AUC/MIC that provides the shortest time to sputum 
culture conversion in liquid medium. 
2. Determine if baseline PZA susceptibility is associated with shorter time to sputum 
culture conversion after controlling for levofloxacin AUC 
3. Describe the relationship between assigned study dose (in mg/kg/day and time to 
sputum culture conversion, safety and ability to complete 24 months of assigned 
study dose. 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
Endpoint for Primary Objective 1. Efficacy – The primary efficacy endpoint is the time 
to sputum culture conversion from positive to negative for M. tuberculosis growth on 
solid medium. This is defined as the time from initiation of study treatment to the first of 
two successive negative cultures one study visit apart that are not followed by a culture-
positive specimen within 28 weeks of treatment initiation. To ensure that each subject 
will be evaluable for the primary endpoint, bi-weekly sputum cultures will be collected for 
12 weeks, then every 4 weeks through 24 weeks of treatment.  If the week 20 culture is 
positive (and the week 24 culture is pending or negative) the patient should provide a 
week 28 specimen for culture to allow the assessment of conversion at week 24.  
Subjects who are unable to produce specimens for sputum culture despite repeated 
attempts will be considered to have had a negative culture on that date.  Sputum 
cultures that are overgrown by bacteria and/or yeast despite additional laboratory 
measures to recover mycobacteria (e.g., re-decontamination of the specimen or pellet) 
will be deemed un-evaluable. 
 

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Endpoint for Primary Objective 2a. Safety – The primary safety endpoint will be the 
number of grade 3 or greater adverse events (AEs) occurring up to and including the 
time on study drug plus four weeks post study drug completion.  
 
Endpoint for Primary Objective 2b. Tolerability – The primary endpoint for the 
analysis of tolerability will be the ability to complete 24 weeks of treatment with the 
assigned levofloxacin dose (in mg/kg at randomization).  Subjects who continue the 
assigned study dose but change to twice-daily administration of the same total daily 
dose prior to completion of 24 weeks of therapy will be considered to be on the assigned 
dose and will not have met a study endpoint; subjects who change their assigned dose 
to levofloxacin at a reduced daily dose prior to protocol-defined completion of 24 weeks 
of therapy will be considered to have met the study endpoint of failing to complete the 
assigned levofloxacin dose. Completion of 24 weeks of levofloxacin treatment is defined 
as the receipt of 168 daily doses of assigned study drug dose within 200 days of 
initiation of study regimen.   
 
Endpoint for Primary Objective 3. Dosing algorithm – The primary outcome for this 
objective is the development of a dosing algorithm that identifies the levofloxacin dose 
(in mg/Kg) for a given patient that can be expected to achieve the AUC associated with 
maximal efficacy and acceptable safety and tolerability.  
3.2.2 Secondary Outcome Measures 
Endpoint for Secondary Objective 1. Efficacy of levofloxacin – The endpoint is the 
time to sputum culture conversion from positive to negative for M. tuberculosis growth on 
liquid medium. 
 
Endpoint for Secondary Objective 2. Efficacy of PZA.  – The endpoint for this 
analysis is time to sputum culture conversion in solid and liquid medium (2 analyses), 
after controlling for levofloxacin AUC/MIC. 
 
Endpoint for Secondary Objective 3. Relationship between dose and efficacy and 
toxicity. - The endpoint is the time to sputum culture conversion from positive to 
negative for M. tuberculosis growth (in both solid and liquid medium). The endpoint for 
the analysis of tolerability will be the ability to complete 24 weeks of treatment with the 
assigned levofloxacin dose. The primary safety endpoint will be the number of grade 3, 4 
and 5 adverse events (AEs), occurring up to and including the time on study drug plus 
four weeks post study drug completion. 
 
 
 

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4 
STUDY DESIGN 
In this Phase 2 study, we propose to determine the levofloxacin dose that achieves the greatest 
reduction in mycobacterial burden with acceptable tolerability by randomizing 120 patients with 
MDR-TB to the mg/kg equivalent of 750, 1000, 1250 and 1500 mg daily (in combination with 
Optimized Background Regimen, OBR) and observing the effect of the drug concentrations 
achieved on time to sputum culture conversion over the 6-month period. A second outcome of 
interest will be the ability to complete 6 months of treatment with the assigned levofloxacin dose. 
In addition, because there is substantial variability in levofloxacin drug concentration achieved 
within a given dose category, we will construct and algorithm to allow clinicians to select the 
levofloxacin dose most likely result in achieving the optimal levofloxacin AUC while minimizing 
toxicity. 
 
4.1 
Study Population 
 
The study will randomize 120 adults with pulmonary MDR-TB, sputum that is isoniazid and 
rifampin resistant by MTBDRplus and fluoroquinolone susceptible by MTBDRsl, HIV positive or 
negative (but not unknown), and with a weight at or greater than 40kg, at sites in Peru and 
South Africa. Randomization is expected to occur over a 24-month period, with 6 months of 
follow-up for each study subject. This will be a blinded, controlled trial, but there is no placebo 
arm. See sections 5.1 and 5.2 for complete inclusion and exclusion criteria. 
 
Patients will be randomized to one of four levofloxacin dose categories (see section 6.2 for 
details). The study will be blinded, but not placebo-controlled; all subjects will receive the same 
number of pills, with varying proportions of active drug and placebo.  All patients will receive at 
least 11 mg/kg daily of levofloxacin, the current WHO recommended dose.  
 
4.2 
Treatment delivery and duration 
 
After randomization, subjects will have daily administration of study drug and companion drugs 
initiated by DOT. Study drug and companion drugs (OBR) will be given by DOT 7 days a week.  
However, DOT may be supervised by non-study staff or a trained family member. The duration 
of the study regimen, while defined as “24 weeks”, will be determined by the number of doses 
ingested, not by calendar time.  Patients will have completed Study regimen when they have 
ingested 168 directly-observed, daily doses.  To be eligible for inclusion in the per-protocol 
analysis of culture conversion, study regimen must have been completed within no less than 
168 calendar days and no more than 200 calendar days. 
 

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4.3 
Assessment of study objectives and measurement of endpoints 
 
• 
Each subject will have intensive PK analysis performed over a 24-hour period between 
day 14 and day 28 of treatment. 
• 
All baseline M. tuberculosis isolates will have MIC for levofloxacin and PZA susceptibility 
testing performed at the CDC Mycobacteriology laboratory. 
• 
All subjects will have follow-up sputum cultures performed at pre-specified intervals (see 
appendix A) at the local mycobacteriology laboratory on 7H11S solid medium and in 
MGIT 960 liquid medium. Subjects who are unable to produce sputum after induction will 
be classified as “Sputum culture-negative”. 
 
4.4 
Optimized Background Regimen (OBR) 
 
For this study “OBR” will mean optimized regimen, not including a quinolone. OBR will be 
selected at the discretion of the study investigator to conform with standards of care and local 
site guidelines (Table 3).  In general, the OBR regimen should include at least 3 drugs (other 
than levofloxacin) to which the patient’s isolate is not expected to be resistant, with one of these 
being an injectable agent, at the usual recommended doses.74 If sensitivity cannot be confirmed, 
and/or there has been prior exposure to drugs included in the regimen, more than 3 drugs 
should be added (in addition to levofloxacin) to ensure that the regimen contains at least 4 likely 
effective drugs.74 
 
Table 3. Customary MDR-TB OBR regimen, by site (in addition to fluoroquinolone) 
 
Site 
Injectable 
Drug 2 
Drug 3 
Drug 4 
Drug 5 
Lima 
Kanamycin 
PZA 
Ethambutol 
Ethionamide 
Cycloserine 
Cape Town 
Kanamycin 
PZA 
Ethionamide 
Terizidone 
 
 
OBR may be changed by the provider at any time during the study for one of the following 
reasons:  
1) in vitro susceptibility test results become available which indicate resistance to one or 
more of the drugs in the OBR regimen;  
2) the patient develops toxicity to one or more of the drugs in the OBR regimen 
necessitating discontinuation of the drug.       
 
Change of OBR will not be considered a study endpoint. However, patients who change 
levofloxacin dose because of inability to tolerate the assigned daily levofloxacin/placebo dose 
will be considered to have met a study endpoint.  

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Study entry is open to males and females, age 18 years or older, of any ethnic background, who 
meets study eligibility criteria.  Historically, approximately 60% of patients with tuberculosis at 
clinical sites are males. The recent multi-center TMC-207 trial reported their subjects were 
predominantly male (74%) and HIV-negative (87%), with a median age of 33 years (range, 18 to 
57). We would expect similar distributions in the study population of MDR-TB patients, either 
newly diagnosed or previously treated. The gender, ethnicity, and socioeconomic background of 
study subjects are expected to mirror that of the populations served by the study sites, and that 
of the population most affected by multidrug-resistant tuberculosis.   This study will include HIV 
infected MDR-TB patients, with no restriction on CD4 count concentration, and uninfected 
individuals with MDR-TB.  
 
The study will randomize 120 participants, or more, if needed to achieve the target for 
evaluation of the primary endpoint (62 for efficacy and 80 for tolerability) after late exclusions 
and loss to follow-up. Approximately half will be randomized in South Africa and half in Lima, 
Peru; no site-specific ceiling is established. 
5.1 
Randomization Inclusion Criteria 
1. Patients with pulmonary TB 
2. Sputum that is isoniazid and rifampin resistant by MTBDRplus and fluoroquinolone 
susceptible by MTBDRsl 
3. HIV seropositive or seronegative but not unknown HIV serostatus. If the last 
documented negative HIV test was more than 3 months prior to randomization the 
current serostatus must be assessed. 
4. Age ≥ 18 years. 
5. Weight > 40 Kg 
6. Karnofsky score of > 60 (see Appendix B) at screening and randomization 
7. Willingness by the patient to attend scheduled follow-up visits and undergo study 
assessments. 
8. Women with child-bearing potential must agree to practice an adequate birth control1 or 
to abstain from heterosexual intercourse during study regimen.  
9. Laboratory parameters (performed within 14 days prior to randomization): 
• 
Estimated Serum creatinine clearance should be >50, using nomogram78 
• 
Hemoglobin concentration ≥ 9.0 g/dL 
• 
Platelet count of ≥ 80,000/mm3 
• 
Absolute neutrophil count (ANC) > 1000/ mm3 
 
1 The only birth control methods that work well enough to be safe while you are on this study are oral contraceptives 
(the pill), intrauterine devices (IUDs), contraceptive implants under the skin, contraceptive rings or patches or 
injections, diaphragms with spermicide and condoms with foam. You should not participate in this study if you are a 
woman who has sex with men and cannot use one of these birth control methods. 

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• 
Negative pregnancy test (for women of childbearing potential) during 
randomization/baseline 
• 
CD4 count if HIV infected (within 6 months) 
• 
Serum ALT and total bilirubin <3 times upper limit of normal 
10. Able to provide informed consent  
5.2 
Randomization Exclusion Criteria 
1. Currently breast-feeding or pregnant. 
2. Known allergy or intolerance to or toxicity from fluoroquinolones or other medications 
utilized in this study. 
3. In the judgment of the physician the patient is not expected to survive for 6 months 
4. Anticipated surgical intervention for the treatment of pulmonary tuberculosis 
5. Participation in another investigational drug trial within the past 30 days 
6. Concurrent use of known QT-prolonging drugs: a list of such medications can be found 
at http://www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm 
7. Poorly controlled diabetes, defined as HgB A1c >9% 
8. Known glucose-6-phosphate dehydrogenase (G6PD) deficiency 
9. Use of quinolone for 7 days within past 30 days 
10. QTc interval (Fridericia corrected) greater than 450 msec for men and women at 
screening and randomization 
5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
Eligible patients giving consent to be randomized in the trial will be randomized to one of the 
four treatment arms in the ratio 1:1:1:1. Randomization will be done using pre-prepared lists 
using blocks of varying sizes with separate lists prepared for each site. Since the sample size is 
small, randomization will only be stratified by site and, in South Africa, by HIV status. The 
randomization list will be prepared by a statistician independent to the study. 
5.3.2 Masking Procedures 
Generalized unblinding of treatment allocation for all patients will not occur until all randomized 
have finished study therapy (minimum 168 doses) plus four weeks of post-last dose of study 
therapy follow-up.  There is a potential situation that may lead to earlier unblinding of treatment 
on a patient by patient basis, when, in the opinion of the study investigator, and the concurrence 
with the protocol team, the definitive attribution of the adverse event to the study drug will 
benefit the management of the patient’s disease.  Investigators must petition the study protocol 
team, which will review and endorse or decline to endorse the request.  All unscheduled early 
unblinding episodes will be reported to the DSMB at the same time as the reporting of the 
related adverse event.    

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5.3.3 Reasons for Withdrawal of Study Drug 
Discontinuation of study drug is strongly advised for patients who experience a grade 3 adverse 
event or higher that is Definitely or Probably related to study drug (see section 9.2.1 for 
definitions). Given the severity and relatively poor prognosis of the treatment of MDR TB in the 
absence of a fluoroquinolone, patients, with the advice of their clinicians, may wish to continue 
treatment with open label levofloxacin 750 mg daily or other fluoroquinolone while being closely 
monitored.   
 
Discontinuation of Study Drug is also strongly advised if the patient develops: 
• 
ventricular arrhythmia 
• 
prolongation of the heart rate-corrected QT interval (QTc by Fridericia method) 
where the QTc is above 500 ms (for either males or females) 
• 
severe neuropsychiatric effect (e.g., psychosis, convulsions, syncope) that is not 
believed to be caused by other TB drugs (e.g. cycloserine, terizidone) 
• 
Clostridium difficille colitis 
• 
significant joint pain or tendon rupture    
• 
pregnancy once treatment started 
• 
symptomatic hypoglycemia 
• 
patient’s initial isolate is determined by phenotypic resistance testing to be 
susceptible to isoniazid or rifampin or resistant to ofloxacin 
Given the severity and relatively poor prognosis of the treatment of MDR TB in the absence of a 
fluoroquinolone, patients, with the advice of their clinicians and depending on the circumstance, 
may wish to continue treatment with levofloxacin 750 mg/day or other fluoroquinolone while 
being closely monitored.   
5.3.4 Handling of Patients whose Study Drug is Withdrawn 
Patients who permanently discontinue study treatment prior to completion of the study, if 
possible, will be followed for 6 months of MDR treatment or 4 weeks past discontinuation of 
study drug depending on which option proves to be longer.  Patients may be taken off study 
drug but continue to receive follow-up in the following circumstances: 
• 
Drug-related toxicity (see section 6.3 Modification of Study Intervention/Investigational 
Product for a Participant ) 
• 
Requirement for prohibited concomitant medications 
• 
Any reason deemed necessary by the investigator or treating physician 
• 
If the patients requests to stop study treatment, but does not withdraw consent for follow-
up 
 
Patients who withdraw consent for further participation, including follow-up, prior to completion 
of the study will not undergo any further study procedures or data collection. Data collected prior 
to withdrawal will be analyzed with complete data sets as is appropriate (e.g., time to sputum 
negativity for a patient who withdraws after becoming AFB negative).   

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5.3.5 Termination of Study 
The study may be terminated by DMID, the PI, one of the IRBs, the US FDA or another 
regulatory agency. Termination could occur after the development of unacceptable toxicities or 
as a recommended outcome of a DSMB review. 

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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
 
LEVOFLOXACIN is a quinolone antibiotic used to treat lung, sinus, skin, and urinary tract 
infections caused by bacteria.  Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is 
the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-
(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-
1,4benzoxazine-6-carboxylic acid hemihydrate. 
 
 
 
Pharmacokinetic and pharmacodynamic parameters of levofloxacin 
The PK/PD parameter that corresponds to maximal bactericidal (or sterilizing activity) for 
fluoroquinolones in the treatment of TB has not been identified. Evidence from other serious 
bacterial infections has suggested that the AUC/MIC ratio correlates with bactericidal efficacy.60 
This parameter is the best predictor in the mouse model of tuberculosis for the activity of 
fluoroquinolones.47 The relationship between antimycobacterial activity and AUC/MIC in patients 
with MDR-TB will be evaluated in the current proposal. If such an association is confirmed, it is 
likely to be generalizable to all drugs of the FQ class.  
 
Tolerability of levofloxacin 
Levofloxacin up to 750mg per day is well tolerated.15, 30, 48 Levofloxacin use at 1000 mg per day 
has recently been adopted by some TB programs, but there are few data on the efficacy and 
tolerability of this dose. Levofloxacin has been used in small numbers of patients with TB at 
doses up to 20 mg/kg without notable serious adverse events.50, 75 
 
Levofloxacin Drug-Drug Interactions 
LEVOFLOXACIN Tablets should be administered at least three hours before or three hours 
after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as 
iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets or the 
pediatric powder for oral solution.  The potential for pharmacokinetic drug interactions between 
LEVOFLOXACIN and antacids warfarin, theophylline, cyclosporine, digoxin, probenecid, and 
cimetidine has been evaluated and dose adjustment is not required for concomitant use. 
 

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Quinolone absorption and excretion 
Levofloxacin is absorbed from the intestine and excreted from the kidney. Dose adjustment is 
required for patients with significant renal insufficiency. If patient creatinine clearance falls below 
50 ml/min, dose adjustment will be performed by unblinded pharmacist. 
6.1.1 Acquisition 
Levofloxacin and matching placebo – which consist of the excipient contained in the levofloxacin 
tablets with no active drug - will be obtained from MacLeods Pharmaceuticals, Ltd., Mumbai 
India.   
 
Study sites will supply all other antituberculosis drugs, either directly or indirectly through the 
National TB Programme.  Such drugs will be purchased from distributors/manufacturers 
distributing products which are approved by a stringent regulatory authority or which are pre-
qualified by WHO Program on Essential Drugs.  Inventory of other antituberculosis drugs will be 
monitored by individual sites, but will not be monitored by the study. 
 
The investigator, or his/her designee, will acknowledge receipt of and keep an inventory of 
levofloxacin/placebo.  Study staff has the responsibility to assure that study drugs are dispensed 
to patients in compliance with the protocol.  
6.1.2 Formulation, Packaging, and Labeling 
Levofloxacin will be formulated as 250 mg tablets and packaged and labeled in a way that is 
consistent with FDA guidelines (package insert for Macleods levofloxacin has been developed 
as part of Macleods approval of its levofloxacin product by FDA). 
6.1.3 Product Storage and Stability 
Levofloxacin should be stored in tightly closed containers, in a dry place, away from excessive 
heat (>40 degrees centigrade). 
6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational Product 
 
Administration of levofloxacin/placebo and other anti-tuberculosis drugs in the patient’s 
treatment regimen will be directly observed seven days a week. However, DOT may be 
supervised by trained, non-study personnel 3 of the 7 days per week. Each dose should be 
recorded in the DOT log. 
 
Levofloxacin dosing will be weight based at the time of randomization, with two dosing bands as 
described in Table 4. To retain blinding, all participants will receive 6 tablets. The exact number 
of tablets containing active agent and the exact number containing placebo are shown in Table 
4. 
 

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Table 4. Dosing of LFX by treatment arm and weight at randomization 
 
*For subjects in the 11 mg/kg group who are 48-59 kg, a dose of 2 tablets (500 mg) would result 
in these subjects receiving less than the standard-of care levofloxacin dose of 11 mg/kg/day; 
therefore all subjects assigned to the 11 mg/kg group will receive 3 tablets (750 mg). 
 
Levofloxacin will be administered in conjunction with the optimized background regimen. The 
optimized background regimen will be composed by study and collaborating physicians, using 
drugs procured through the program’s routine procurement mechanism. Regimens will contain 
levofloxacin plus at least 3 additional drugs which have documented or expected activity against 
the patient’s M. tuberculosis isolate.  If sensitivity cannot be confirmed, and/or there has been 
prior exposure to drugs included in the regimen, more than 3 drugs should be added (in addition 
to levofloxacin) to ensure that the regimen contains at least 4 likely effective drugs.74 
 
Treatment with the OBR plus LFX 750 mg will continue after completion of the study period 
according to local protocol and the discretion of local physicians. 
6.3 
Modification of Study Intervention/Investigational Product for a Participant 
 
Subject-initiated, provider-initiated and protocol-mandated interruptions include both inadvertent 
and deliberate interruptions of study drug dose.  For the study’s primary endpoint, 200 days (7 
days a week) are allowed for completion of at least 168 doses of study medication. Guidelines 
for clinical evaluation of adverse events and attribution/non-attribution of these events to specific 
drugs are given in Appendix C. If a non-severe adverse reaction attributable to levofloxacin is 
suspected, clinicians may elect to give the study drug in two divided doses instead of once daily; 
if the adverse reaction persists, management should proceed as outlined in the algorithm. If 
twice daily dosing is requested, the unblinded study pharmacist will prepare the study drug as 
requested (please refer to MOP for additional details). 
 
For any SAE that is related to the study agent (Definitely, Probably, Possibly; see section 9.2.1), 
the subject will be strongly advised to discontinue the study levofloxacin regimen. 
Weight 
Band 
11 mg/kg 
14 mg/kg 
17 mg/kg 
20 mg/kg 
L=250 mg 
LFX 
P=250 mg 
placebo 
# LFX & 
placebo 
Total 
LFX 
(mg) 
# LFX & 
placebo 
Total 
LFX(m
g) 
# LFX & 
placebo 
Total 
LFX 
(mg) 
# LFX 
& 
placebo 
Total 
LFX 
(mg) 
<60 kg 
3L*+3P 
750 
3L+3P 
750 
4L+2P 
1000 
5L+1P 
1250 
>=60 kg 
3L+3P 
750 
4L+2P 
1000 
5L+1P 
1250 
6L+0P 
1500 

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6.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) 
 
The investigator will acknowledge receipt of and keep an inventory of study drug, companion 
drugs, and matching placebos. Study staff has the responsibility to assure that study drugs are 
dispensed to patients in compliance with the protocol. Details are available in the MOP and in 
the Pharmacy Plan.  
 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational Product 
 
Administration of all doses of study and companion drugs will be supervised by study staff and 
recorded in a log book (see Sections 6.2 and 8.1). Delivery of study medications may occur in 
health center, hospital, or a place convenient to the subject (home, place of work). The decision 
will be made jointly between subjects and treatment supervisors.  
6.6 
Concomitant Medications/Treatments 
 
Concomitant medications, including start dates, stop dates, and dose changes, will be recorded 
in the medical chart and CRF at each study visit.  Study personnel will not be providing direct 
care for HIV infection in study patients.  HIV care will be provided to patient by their primary care 
clinicians according to provincial and national guidelines.  In recognition that HIV care can 
profoundly influence outcomes for persons infected with both HIV and TB, HIV infected patients 
will additionally be questioned at each study visit regarding their use of anti-retroviral agents and 
medicines to treat and prevent opportunistic infections. 
 
Use of known QT-prolonging drugs is prohibited: albuterol, alfuzosin, amantadine, amiodarone, 
amitryptyline, amphetamine, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, 
chloroquine, clomipramine, dolasetron, metaproterenol, phentermine, and 
phenylpropanolamine. 
6.7 
OBR (Companion Drugs) 
 
Optimized Background Regimen companion medications include three or more of the standard 
drugs used for antituberculous chemotherapy for documented drug-resistant tuberculosis. The 
doses taken will be reported in a DOT log at each visit. According to the 2008 WHO guidelines 
for the programmatic management of drug-resistant tuberculosis, the standard drugs are:74 
 
 
 
 

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Table 5. Drugs for use in treating MDR-TB 
 
Group 
Description 
Drug 
1 
First-line oral 
antituberculosis drugs 
Ethambutol 
Pyrazinamide 
2 
Injectable 
antituberculosis drugs 
Kanamycin 
Amikacin 
Capreomycin 
4 
Oral bacteriostatic 
second-line 
antituberculosis drugs 
Ethionamide 
Protionamide 
Cycloserine 
Terizidone 
p-aminosalicylic acid 
 
As the OBR may include other second-line drugs, the expected adverse reactions and toxicities 
from these drugs are described below: 
• 
Cycloserine 
o Psychosis 
o Convulsions 
o Depression 
o Headaches 
o Rash 
o Drug interactions 
• 
Ethionamide 
o Gastrointestinal upset 
o Hepatotoxicity 
o Hypersensitivity 
o Metallic taste 
o Bloating 
• 
P-Aminosalicylic acid 
o Gastrointestinal upset 
o Hepatotoxicity 
o Hypersensitivity 
o Sodium load 
• 
Capreomycin 
o Toxicity: Auditory, vestibular, renal 
• 
Kanamycin and amikacin 
o Toxicity: Auditory, vestibular, renal 
• 
Streptomycin 
Toxicity: Auditory, vestibular, renal 
 

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7 
STUDY SCHEDULE 
7.1 
Screening / Consenting Visit 
 
Subjects with a prior diagnosis of pulmonary tuberculosis at the site of initial diagnosis or TB 
Clinic will be asked to review and sign the consent form. Subjects will then be screened for 
eligibility. The following will be performed: 
• 
participants will be asked questions related to demographics, current and past medical 
history, comorbidities, HIV status, medications they are taking, alcohol, and TB risk 
factors, past treatment for TB and prior susceptibilities.  
• 
a sputum sample (expectorated) will be obtained for smear and culture at the local site 
microbiology laboratory. Sputum will be tested for Isoniazid, rifampin, and ofloxacin 
susceptibility by MTBDRPlus and MTBDR-sl. 
• 
participants will have height and weight measured 
• 
blood will be drawn for a CBC with differential and platelet count, serum or plasma 
creatinine, ALT, total bilirubin, and blood HgBA1c. 
• 
an HIV test, using any testing method approved by the U.S. Food and Drug 
Administration (or, for non U.S. study sites, approved by local authorities), will be 
obtained at this visit. unless the patient is known to have HIV infection (documented by a 
positive ELISA and Western Blot or an HIV-RNA concentration greater than 5000 
copies/mL) or has written documentation of a negative HIV test within the past 3 months.   
• 
a urine or serum pregnancy test (if patient is a woman of child-bearing potential) 
• 
Review of concomitant medications. 
• 
Review of previous TB treatment to assess whether subject meets study eligibility 
criteria.Targeted symptom assessment 
• 
EKG 
• 
Karnofsky score 
• 
Physcial examination 
• 
A posteroanterior chest radiograph will also be taken, unless a posteroanterior chest 
radiograph done within the previous 14 days is available for review.  The chest 
radiograph must be read prior to study randomization.  
• 
HIV-infected; most recent CD4 count (blood test for CD4 count if result of test done in 
previous 6 months is not available) 
7.2 
Randomization/Baseline 
 
Subjects: Patients with pulmonary TB, in whom a rapid test detects rifampin resistance and FQ 
susceptibility, HIV positive or negative (but not unknown), and weight >40kg will be invited to 
participate. Written informed consent, using IRB-approved consent forms, will be obtained by 

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trained study personnel prior to performing any study-specific procedures.  The informed 
consent process is described in detail in Section 14.3. 
 
The following will be performed: 
• 
participants will be asked questions related to interval since screening visit history, 
current and past medical history, comorbidities, HIV status, medications, alcohol, and TB 
treatment.  They will be advised that they can decline to answer any question they 
consider too personal. 
• 
a sputum sample (expectorated) will be obtained for smear and culture at the laboratory 
participants will have weight measured 
• 
Blood will be drawn for a CBC with differential and platelet count, serum or plasma 
creatinine, ALT, total bilirubin, and blood glucose  
• 
a urine or serum pregnancy test (if patient is a woman of child-bearing potential) 
• 
review of medications since screening/consenting visit to assess whether subject 
continues to meet study eligibility criteria. 
• 
review of interval TB treatment since screening/consenting visit to assess whether 
subject continues to meet study eligibility criteria. 
• 
Targeted symptom assessment 
• 
Focused clinical assessment – including vitals such as temperature, heart rate, resting 
rate, and blood pressure 
• 
10 cc of blood (BD 10 cc Serum Separator Tube (SST) per S29 Biomarker specimen 
protocol for Biomarker 
• 
At least 20 cc of urine for Biomarker, freeze as soon as possible in -70 degree C.  
• 
EKG   
• 
Karnofsky score 
 
The randomization eligibility form will be filled out and the data submitted to the study Data 
Center. The Data Center will then certify that the patient is eligible for randomization. Following 
this, the Randomization Center will assign the study levofloxacin dose (see section 6.2). Study 
drug treatment will be initiated during the randomization visit for participants who meet eligibility 
criteria. The randomization visit (and initiation of study drug treatment) should occur as soon as 
feasible after study treatment assignment. Instructions for administering study drugs are 
provided in the “Administration of Study Drugs” section. Participants who do not meet eligibility 
criteria will be referred to a local source of TB care.  The study team will work in concert with the 
local source of TB care to provide timely, medically appropriate TB-related care.   
A log will be maintained of persons who are screened, randomized or withdrawn. 
7.3 
Follow-up 
 
Visits listed below are protocol-specified study visits.  Safety of study participants will be 
enhanced further by providing study medication doses by directly observed therapy (DOT).  In 

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this context, participants will be queried about signs/symptoms potentially related to drug toxicity 
at the time of each medication dose per standard TB treatment DOT practices.  Should 
signs/symptoms potentially related to drug toxicity be recognized at any time, then further 
evaluation including laboratory testing may be performed at the discretion of the treating 
clinician.   
 
Study Visits at:  
 
Week 1 
• 
Targeted symptom assessment  
• 
Focused clinical assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
Review DOT log 
 
Week 2 
• 
Targeted symptom assessment  
• 
Focused clinical assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Complete blood count with differential and platelets 
• 
Serum or plasma creatinine, alanine aminotransferase (ALT), total bilirubin 
• 
Review DOT log 
 
Week 2-4 (one 24 period in this interval) 
• 
Dietary history based on recall (in-patient & out-patient) 
• 
Seven blood samples for PK evaluation (see section 8.2.2 – may entail inpatient stay)  
 
Week 3 
• 
Targeted symptom assessment 
• 
Focused clinical assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
Review DOT log 
 
 
 

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Week 4 
• 
Targeted symptom assessment 
• 
Focused clinical assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Complete blood count with differential and platelets 
• 
Serum or plasma creatinine, alanine aminotransferase (ALT), total bilirubin, blood 
glucose 
• 
a urine or serum pregnancy test (if patient is a woman of child-bearing potential) 
• 
EKG 
• 
Review DOT log 
 
Week 5 
• 
Targeted symptom assessment 
• 
Focused clinical assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
Review DOT log 
 
Week 6 
• 
Targeted symptom assessment 
• 
Focused clinical assessment  
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Complete blood count with differential and platelets 
• 
Serum or plasma creatinine, alanine aminotransferase (ALT), total bilirubin 
• 
Review DOT log 
 
Week 7 
• 
Targeted symptom assessment  
• 
Focused clinical assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
Review DOT log 

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Week 8 
• 
Targeted symptom assessment 
• 
Focused clinical assessment  
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Complete blood count with differential and platelets 
• 
Serum or plasma creatinine, alanine aminotransferase (ALT), total bilirubin, blood 
glucose 
• 
Serum and urine for biomarker studies 
• 
a urine or serum pregnancy test (if patient is a woman of child-bearing potential) 
• 
Review DOT log 
• 
EKG 
 
Week 10 
• 
Targeted symptom assessment 
• 
Focused clinical assessment  
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Review DOT log 
 
Week 12 
• 
Targeted symptom assessment 
• 
Focused clinical assessment  
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Complete blood count with differential and platelets 
• 
Serum or plasma creatinine, alanine aminotransferase (ALT), total bilirubin, blood 
glucose 
• 
a urine or serum pregnancy test (if patient is a woman of child-bearing potential) 
• 
Review DOT log 
• 
EKG 
 
Week 16 

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• 
Targeted symptom assessment 
• 
Focused clinical assessment  
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Complete blood count with differential and platelets 
• 
Serum or plasma creatinine, alanine aminotransferase (ALT), total bilirubin, blood 
glucose 
• 
a urine or serum pregnancy test (if patient is a woman of child-bearing potential) 
• 
Review DOT log 
• 
EKG 
 
Week 20 
• 
Targeted symptom assessment 
• 
Focused clinical assessment  
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Complete blood count with differential and platelets 
• 
Serum or plasma creatinine, alanine aminotransferase (ALT), total bilirubin, blood 
glucose 
• 
A urine or serum pregnancy test (if patient is a woman of child-bearing potential) 
• 
Review DOT log 
• 
EKG 
 
Week 24 
• 
Targeted symptom assessment  
• 
Focused clinical assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Complete blood count with differential and platelets 
• 
Serum or plasma creatinine, alanine aminotransferase (ALT), total bilirubin, blood 
glucose 
• 
a urine or serum pregnancy test (if patient is a woman of child-bearing potential) 
• 
Review DOT log 
• 
EKG 

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MDR-TB treatment following completion of study phase: Following completion of the study, 
subjects will continue OBR according to local protocol, and the blinded levofloxacin dose will be 
replaced by the standard fluoroquinolone in use for MDR-TB treatment at that site at the 
standard recommended dose. The study will not provide OBR for either the study phase or the 
post-study phases of MDR-TB treatment, nor will it provide fluoroquinolone for the post-study 
phase of MDR-TB treatment.    
7.4 
Final Study Visit 
The final study visit will occur 4 weeks after completion of study phase therapy. Assessments at this visit 
will include: 
• 
Targeted symptom assessment 
• 
Focused clinical assessment  
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
One sputum obtained for culture  
• 
Complete blood count with differential and platelets 
• 
Serum or plasma creatinine, alanine aminotransferase (ALT), total bilirubin 
 
7.5 
Early Termination Visit 
 
For study subjects who withdraw from the study treatment early, a final study visit will be 
performed 4 weeks after termination, with the same items as the Final study visit, unless the 
subject withdraws consent for all further participation. 
7.6 
Unscheduled Visit 
 
Unscheduled visits can be initiated by either patient or provider and will be recorded on the 
“Unscheduled visit” form. 

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8 
STUDY PROCEDURES/EVALUATIONS 
Study subjects will be compensated for their time and travel to and from study visits.  The form 
and amount of compensation will be in accordance with local guidelines and subject to local IRB 
approval. 
8.1 
Clinical Evaluations 
 
Randomized patients will have directly observed therapy (DOT) every day for 24 weeks (168 
doses). DOT will be observed by study staff or trained community observers and documented in 
a log book. Study visits will be weekly during the first 8 weeks, at 10 weeks, 12 weeks and then 
monthly at weeks16, 20, 24, and 4 weeks after the end of treatment with study drug. At each 
study visit, a focused clinical assessment – including vitals such as temperature, heart rate, 
resting rate, and blood pressure – will be conducted and evidence of any toxicities obtained by 
interview and examination. Patient height will be documented at randomization and patient 
weight will be assessed at randomization and at all study visits.  Standardized questions on 
toxicity and tolerability will be posed to each patient at study visits and recorded in source 
documentation and on the Follow-up Visit Form. 
 
Review of symptoms since last visit: Visits listed in Appendix A-Schedule of Events are 
protocol-specified study visits.  At each study visit, a symptom assessment will be conducted.  
Patients will be queried about targeted symptoms potentially related to drug toxicity at each 
follow-up visit.   Patients will be asked whether they have experienced any of the following since 
the last study visit: fevers, sweats, cough, rash, itching, phototoxicity, jaundice, nausea, 
vomiting, diarrhea, abdominal pain, loss of appetite, numbness/tingling of extremities, 
headache, dizziness, insomnia, joint pain, musculo-skeletal pain or tendon rupture, or new 
infections,.  In addition, patients will be asked whether they have had other symptoms that are 
not listed above.   The reported symptoms will be recorded on the Targeted Symptom 
Assessment page of the patient’s CRF.  Should symptoms potentially related to drug toxicity be 
recognized at any follow-up visit, further evaluation including laboratory testing may be 
performed at the discretion of the treating clinician.  Furthermore, the patients will be assessed 
for concomitant medications, including warfarin, theophylline, benzodiazepines, and 
phenylpropanolamine. 
 
8.2 
Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations 
A pregnancy test will be done during screening, randomization, and at weeks 4, 8, 12, 16, 20, 
and 24. In addition, HIV serology, and a chest X-ray will be undertaken at the screening visit. 

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Screening, randomization and study visits during weeks 2, 4, 6, 8,12,16, 20 and 24 will include 
obtaining a complete blood count with differential and platelets, specified blood chemistries and 
a directed physical examination,. An expectorated spot sputum sample will be obtained at 
screening, randomization and weeks 2, 4, 6, 8, 10, 12, 16, 20, and 24. If a first negative culture 
is obtained at week 24, a specimen will also be collected at week 28 to assess conversion at 
week 24. EKG readings will be taken during weeks 4, 8, 12, 16, 20 and 24. In this study, we will 
also collect serum and urine from all participants at randomization and at week 8, for storage as 
part of future biomarker discovery and qualification sub-studies.   
 
Obtaining sputum specimens: A single spontaneously expectorated sputum will be collected 
at screening, randomization (day 1), 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, and 
monthly thereafter through week 24, and at four weeks after the end of study regimen. A 
minimum of 5 ml of sputum must be collected up through week 4, and a minimum of 3 ml at 
subsequent time points.  A sputum specimen will be defined as unobtainable (and negative for 
analytic purposes) if no sputum can be obtained. 
 
Laboratory aspects of sputum analysis: For each study site, a single laboratory will be 
designated as the site’s study laboratory, and all study-related sputum specimens must be sent 
to that laboratory. Specimens should be delivered to the laboratory on the same day of 
collection. Specimens must be stored in the refrigerator and transported in a cool box if delivery 
to the laboratory is >2 hours from the time of collection. For details of processing of sputum 
specimens see study laboratory manual of procedures. 
 
Sputum specimens will be used for AFB smears, solid culture on Middlebrook 7H11S 
medium, and liquid culture using the MGIT 960 system. The identification of M. tuberculosis 
(MTB) complex will be performed at the site laboratory for the first positive culture only. The 
time-to-positive (TTP) culture in the MGIT system will be determined for all MTB complex 
positive MGIT cultures. All microbiology tests will be done in accordance with Clinical 
Laboratory Standards Institute guidance for sputum processing, smear microscopy, culture 
techniques, and identification of mycobacteria (Guidance documents M22-A3, M24-A, and M48-
P). AFB smears will be scored by the World Health Organization (WHO) standard scale 
(Negative, scanty positive, 1+, 2+, 3+).  
 
Drug Susceptibility Testing: Susceptibility testing of first-line (INH, rifampin, ethambutol, 
pyrazinamide) and second-line drugs, including ofloxacin, will be done on M. tuberculosis- 
positive cultures of specimens collected at screening visit per local protocols.  Isolates from 
screening visit and last positive culture (if after month 3) will be sent to CDC at the conclusion of 
the study. At CDC, MICs for levofloxacin on randomization specimen and final isolate (for those 
subjects still culture positive at month 4 or later) will be performed by the method of Heifets, et 
al.76 CDC will also perform in vitro PZA susceptibility testing on all screening or baseline 
isolates.     

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8.2.2 Special Assays or Procedures 
Pharmacokinetic sampling: sampling will take place in one 24 hour period between the 14th 
day through the 28th day from the start of study regimen. Depending on the site, this may entail 
an overnight inpatient stay for study participants. On the day of PK sampling, study drugs will be 
administered in the morning at the time the patients usually take their dose.  Study drugs will be 
swallowed with 200 cc of water after being NPO for 8 hours and no food will be ingested for the 
next two hours.  A breakfast and light meal will be provided two and six hours after 
administration of study drugs.  The timing and content of meals, snacks, and concurrent 
medications taken by each subject on the day of the pharmacokinetic study will be recorded.  
 
The blood specimen will be obtained at randomization prior to the ingestion of drugs. All blood 
samples will be collected in reference to a single directly observed dose of study phase drugs.  
The reference dose used for PK sampling should be preceded by two daily study drug doses 
given approximately 24 hours apart during the preceding 48 hours.  Patients who experience 
emesis during the course of the pharmacokinetic sampling and vomit within 2 hours of dosing 
will be rescheduled for another PK sampling within two weeks. Patients should abstain from 
consuming any alcohol for 48 hours prior to the PK study period and until after the last PK 
sample is collected.   
       
Five ml of venous blood for determination of levofloxacin plasma concentrations will be collected 
before dosing (time 0) and at 1, 2, 4, 8, 12, and 24 hours after administration of the morning 
dose of study drug treatment on one day between days 14 and 28 of treatment. Patients will 
have received a minimum of 3 consecutive daily doses prior to the blood collections.     
 
Participants will be interviewed to obtain additional information about medical and social history, 
recent weight loss or weight gain, concomitant medications on the day prior to and the days of 
PK sampling, gastrointestinal symptoms, and timing of meals, snacks and medications relative 
to study drug dosing.   
 
PK samples will be temporarily stored in the local laboratory before being shipped to the 
University of Florida for PK analysis. 
 
HIV testing: Patients will have HIV testing performed at study entry unless such testing has 
been previously documented to be positive or has been performed and documented to be 
negative within the previous 3 months. HIV test results will be given only to the patient (and to 
those to whom it may be required by law) and kept with other study records in a secure place. 
With their permission, HIV-infected patients will be referred to local sources of HIV care, as 
appropriate. HIV-indeterminate patients will be given a follow-up appointment for re-testing. 
 
HIV-infected study subjects who are eligible for antiretroviral regimen according to national 
guidelines pertaining to their study site should be referred to local sources of care for such 
regimen. The study is not performing CD4 counts as part of the study protocol except at the 

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randomization visit.  The study protocol allows the co-administration of antiretroviral agents 
when clinically indicated. Patients who have antiretroviral regimen initiated during the study 
phase should be observed closely for the possible occurrence of severe immune reconstitution 
syndromes. 
 
Management of subjects randomized but subsequently determined to have isolates that 
are rifampin or isoniazid susceptible or ofloxacin-resistant based on culture and 
susceptibility results: Because of the relatively slow growth of M. tuberculosis in culture, the 
results of sputum mycobacterial cultures and phenotypic drug susceptibility testing are rarely 
available at the time of initiation of MDR TB treatment.  Therefore for this study we plan to 
randomize patients based on the result of the MTBDRplus and MTBDRsl tests. Patients whose 
screening/consenting or randomization/baseline cultures demonstrate isoniazid or rifampin 
susceptibility or ofloxacin resistance will be discontinued from the study treatment and referred 
to the local TB control program for treatment with a regimen appropriate for their disease. 
Similarly, patients whose screening and baseline cultures are both negative will be discontinued 
from the study treatment and referred to the local TB control program for treatment with a 
regimen appropriate for their disease. Such patients will not be included in the modified 
intention-to-treat study population. However, all such patients will have a study visit at 4 weeks 
after discontinuation of the study regimen for assessment of delayed toxicity and will be 
included in the safety database.  
8.2.3 Specimen Preparation, Handling, and Shipping 
8.2.3.1 
Instructions for Specimen Preparation, Handling, and Storage 
These instructions can be found in the study MOP 
8.2.3.2 
Specimen Shipment 
• 
Specimens for the Central Mycobacteriology Laboratory will be shipped to the CDC, 
Atlanta GA. 
• 
Specimens for the Central Clinical Pharmacology laboratory will be shipped to the 
University of Florida in Gainesville FL 
• 
Specimens for the Central Specimen Repository will be shipped to the University of 
California, San Francisco, CA, USA. 
 
Detailed instructions can be found in the study MOP. 

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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
 
Primary Safety Endpoint – the primary safety endpoint will be the number of grade 3, 4 and 5 
adverse events (AEs), occurring up to and including the time on study drug plus four weeks post 
study drug completion. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
9.2.1 Adverse Events 
Adverse Event:  ICH E6 defines an AE as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product regardless of its causal 
relationship to the study treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of medicinal (investigational) product.  The occurrence of an AE may come to the 
attention of study personnel during study visits and interviews of a study recipient presenting for 
medical care, or upon review by a study monitor. If the primary care team suspects an adverse 
event between study visits, this will trigger an unscheduled study visit to assess the potential 
adverse event.   
 
All AEs will be captured on the Adverse Event (AE) Case Report Form (CRF).  Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority to make a 
diagnosis, which would include MD, PA, Nurse Practitioner, DO, or DDS), and time of 
resolution/stabilization of the event.  All AEs occurring while on study must be documented 
appropriately regardless of relationship.  All AEs will be followed to adequate resolution.  
 
Any medical condition that is present at the time that the patient is screened should be 
considered as baseline and not reported as an AE.  However, if it deteriorates at any time 
during the study, it should be recorded as an AE. 
 
All AEs must be graded for severity and relationship to study product.  
 
FDA defines an AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
 
A serious adverse event is defined as an AE meeting one of the following conditions:  
• 
Death during the period of protocol defined surveillance  

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• 
Life threatening event (defined as a subject at immediate risk of death at the time of the 
event)  
• 
An event requiring inpatient hospitalization or prolongation of existing hospitalization 
during the period of protocol defined surveillance  
• 
Results in congenital anomaly or birth defect  
• 
Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.  
 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon appropriate 
medical judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
  
All serious adverse events will be:  
• Recorded in a timely and proper manner, and reported to the relevant entities.  
• Followed through resolution or stabilization by a study clinician  
• Reviewed and evaluated by a study clinician 
 
Severity of Event: The severity of each adverse event will be determined using the Common 
Terminology Criteria for Adverse Events v3.0 (CTCAE) published August 9, 2006 or the most 
updated version of this document, which can be found at 
http//ctep.cancer.gov/forms/CTCAEv3.pdf.  Any events that are not listed in this toxicity table will 
be graded by the local PI as follows: 
 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
Grade 2 
Moderate 
Minimal, local or noninvasive intervention 
indicated; limits age-appropriate instrumental 
ADL.  
Grade 3 
Severe 
Medically significant but not immediately life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limits self-
care ADL.  
Grade 4 
Life-threatening 
Consequences; urgent intervention indicated. 
Grade 5 
Death                          Related to AE. 
 

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Relationship to Study Products: Any AE that occurs in a patient will be assessed for 
relationship to the study drug as outlined in Appendix C.  A causal relationship means that the 
drug caused (or is reasonably likely to have caused) the AE. This usually implies a relationship 
in time between the drug/study agent and the AE⎯for example, the AE occurred shortly after 
the patient received the drug/study agent.   
 
Whether to re-challenge the patient with study drug or not will be left to the discretion of study 
staff in combination with the primary providers for the patient in conjunction with the patient.  
Re-challenges will be documented by recording when patient resumed study drug and any 
subsequent AE’s.  Experience from re-challenge may be used for design of a re-challenge 
protocol for a subsequent larger study, if it is warranted based on the results of this pilot study. 
 
For all AEs, the principal investigator or his/her designee who examines and evaluates the 
patient will determine the adverse event’s causality based upon the temporal relationship to 
administration of the study agent(s), the pharmacology of the study agent(s), and his/her clinical 
judgment. 
 
The following scale will be used to reflect the PI’s or his/her designee’s judgment as to the 
relationship between the study agent/intervention and the AE: 
• 
Definitely Related: The AE is clearly related to the study agent – follows a reasonable 
temporal sequence from administration of the study agent, follows a known or expected 
response pattern to the study agent that is confirmed by improvement on stopping or 
worsening/reappearance of the event in repeated exposure and that could not be 
reasonably explained by the known characteristics of the patient’s clinical state. 
• 
Probably Related:  The adverse event and administration of study agent are reasonably 
related in time or follows a known pattern of response, and the adverse event is more 
likely explained by study agent than other causes. 
• 
Possibly Related: AE follows a reasonable temporal sequence from administration of the 
study drug/intervention, follows a known or expected response pattern to the suspected 
drug, but that could readily have been produced by a number of other factors. 
• 
Probably not Related:  A potential relationship between study agent and the adverse 
event could exist (i.e., the possibility cannot be excluded), but the adverse event is most 
likely explained by causes other than the study agent (e.g., could readily have been 
produced by the patient’s clinical state or could have been due to environmental or other 
interventions) 
• 
Not Related:  AE is clearly not related to the study agent – another cause of the event is 
most plausible or a clinically plausible, temporal sequence is consistent with the onset of 
the event and the study medication administration or event is biologically implausible. 
 

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9.2.2 Procedures to be Followed in the Event of Abnormal Laboratory Test Values or Abnormal 
Clinical Findings 
Changes in laboratory values are reported as AEs if they are clinically significant (i.e., if some 
action or intervention is required or if the investigator judges the change to be beyond the range 
of normal physiological fluctuation) or if they are a change in grade as indicated in the Common 
Terminology Criteria for Adverse Events.  Should a patient call a study clinician to report an 
adverse event, it will be determined at that time if an extra visit(s) will be scheduled, and 
appropriate medical advice will be provided.  All actions taken by the investigator after observing 
an AE should be documented, including increased monitoring of the patient/study participant, 
suspension of the treatment, etc. Additionally, all calls will be documented in the patient/study 
participant’s study chart, and discussed with the principal investigator. 
 
All serious and non-serious AEs reported in this study will be followed until resolution or until the 
investigator and the treating physician are in agreement that the AE has stabilized and no more 
follow-up is required. This requirement indicates that follow-up may be required for some events 
after the patient discontinues participation from the study. 
 
In the event that the patient’s study medication is stopped due to an AE, it must be recorded on 
the CRF as such.  The patient should be followed and treated by the investigator until the 
abnormal parameter or symptom has resolved or stabilized. It is up to the clinician to determine 
that the AE is either resolved, or that it has reached a stable state, after which no further follow-
up is necessary. There should be documentation to support that determination. 
9.3 
Reporting Procedures 
 
Any AE, whether or not considered related to the study drug, or whether considered non-serious 
or unexpected, that occurs between the times a patient signs the informed consent form and the 
time s/he departs the study (for any reason) must be fully and completely documented on the 
Adverse Event (AE) Case Report Form (CRF) and in the patient/study participant’s clinical 
chart.  The start date, the stop date, the severity of each reportable event, and the principal 
investigator’s or his/her designee’s judgment of the AEs relationship to the study 
agent/intervention will also be recorded on the Adverse Event CRF.  
 
Internal Reporting Requirements: All deaths and life-threatening SAEs which occur during the 
course of this investigation, whether or not considered to be related to the study agent or 
considered to be an expected event associated with the study agent, will result in a preliminary 
report that is submitted the Independent Safety Monitor (ISM) with a copy to the DMID and 
study sponsor’s pharmacovigilance group within 24 hours of awareness. The ISM will provide 
an independent written assessment of the SAE to the DMID Medical Monitor and study 
sponsor’s pharmacovigilance group within 2 business days after receipt of this preliminary 
report. This reporting timeline has been determined to account for the time it may take the 

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treating doctors working with the patients to report to the local study staff who in turn will report 
to DMID.  
 
Adverse event reporting requirements for this protocol are as follows: 
1. Local Investigators must provide a preliminary report to local IRB after becoming aware 
of a patient death or a potentially life-threatening serious adverse event.  This 
preliminary report must be followed by a progress report within 8 days. 
2. Investigators must provide a final report to the local IRB and regulatory authorities within 
15 days after becoming aware of an inpatient hospitalization (other than elective), a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect. 
9.3.1 Serious Adverse Events 
All SAEs which occur during the course of this investigation, whether or not considered to be 
related to the study agent or considered to be an expected event associated with the study 
agent, will result in a preliminary report that is submitted within 24 hours of site awareness to the 
ISM, Pharmacovigilance Group of Macleods Pharmaceuticals at safety@macleodspharma.com 
and the DMID Pharmacovigilance Group, at the following address:  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20814, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
The DMID medical monitor and clinical protocol manager will be notified of the SAE by the 
DMID Pharmacovigilance Group.  The DMID medical monitor will review and assess the SAE 
for regulatory reporting and potential impact on study subject safety and protocol conduct.  
 
At any time after completion of the study, if the investigator becomes aware of an SAE that is 
suspected to be related to study product, the investigator will report the event to the DMID 
Pharmacovigilance Group.  
 
Note: All AEs, including SAEs, occurring within the reporting period will be documented on the 
appropriate Case Report Forms (CRFs). For the purposes of adverse event reporting, 
hospitalization for the protocol-specified PK evaluation will not be a reportable SAE. 
9.3.2 Regulatory Reporting for Studies Not Conducted Under DMID-Sponsored IND 
This study will be conducted under an IND held by the product manufacturer, Macleods 
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submitted within 24 hours of site awareness to MacLeods Pharmaceuticals, Ltd. At any time 
after completion of the study, if the investigator becomes aware of an SAE that was not 
previously reported, the investigator will also report this event to MacLeods Pharmaceuticals, 
Ltd. 
 
9.3.3 Reporting of Pregnancy 
Pregnancy is not a contraindication to levofloxacin treatment for MDR-TB, but the safety of 
treatment with levofloxacin at investigational doses in pregnancy cannot be assured. Therefore, 
study subjects who become pregnant during the trial will have their study treatment discontinued 
and replaced with standard doses of levofloxacin. Subjects who become pregnant will be 
followed for the duration of the pregnancy and infants followed for 6 months after birth. This will 
be reported to the sponsor, study leadership, IRB, and regulatory agencies.  
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
 
AEs will be followed until resolution or stabilization even if this extends beyond the study-
reporting period.  Resolution of an AE is defined as the return to pretreatment status or 
stabilization of the condition with the expectation that it will remain chronic.  
 
9.5 
Guidance for Temporary Discontinuation of Study Drug 
 
When it is unclear whether the AE is associated with levofloxacin, study levofloxacin/placebo 
may be discontinued while re-challenge with other drugs or study levofloxacin/placebo is 
performed (See Appendix C: Toxicity Management Algorithm).  If it is determined that study 
levofloxacin/placebo was not the cause of the AE, it should be restarted. Restarting the daily 
study dose as half dose twice daily is acceptable and will be considered to be continuation of 
the protocol-assigned dose. Such temporary discontinuation will not be considered a study 
endpoint unless the duration of the discontinuation makes it impossible for the patient to 
complete the required 168 doses in 200 days. 
9.6 
Safety Oversight 
9.6.1 Independent Safety Monitor (ISM) 
An ISM will be appointed at each study site. 
 
The ISM is a physician located near the investigator site with relevant expertise whose primary 
responsibility is to provide independent safety monitoring in a timely fashion. This ISM is 
identified by the investigator site and approved by the DMID. The ISM will review SAEs and 

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other AEs as needed and provide an independent assessment to DMID. The study site will have 
an ISM with experience in infectious diseases and/or internal medicine. 
9.6.2 Data and Safety Monitoring Board (DSMB) 
DMID will organize the DSMB. The Data Coordinating Center (DCC) will provide the appropriate 
reports for DSMB review. The DSMB will meet semiannually to assess safety and efficacy data 
on each arm of the study.   
 
The DSMB will also review aggregate safety data for increased rate of occurrence of serious 
suspected adverse reactions. If more than 50% of patients in any dose arm have permanently 
discontinued treatment for any reason before completing 24 weeks of treatment at the time of 
review, the DSMB may recommend that randomization to that arm be terminated. In addition to 
the semiannual meeting, the DSMB will review safety and tolerability of all doses three months 
after 40 patients have been randomized and again three months after 60 patients have been 
randomized. The DSMB will advise DMID of its recommendations after each meeting. 
9.6.3 Halting Rules 
In addition to the above, subsequent review of serious, unexpected, and related AEs by the 
Medical Monitor, DSMB, IEC/IRB, the sponsor(s), or the FDA or relevant local regulatory 
authorities may result in suspension of further trial interventions/administration of study product 
at a site. The FDA and study sponsor(s) retain the authority to suspend additional randomization 
and study interventions/administration of study product for the entire study, as applicable. 

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10 
CLINICAL MONITORING 
10.1 Site Monitoring Plan 
 
Under the U01 mechanism, site monitoring is the responsibility of the investigators. To ensure 
that human subject protection, study procedures, laboratory procedures, study intervention 
administration, and data collection processes are of high quality and meet sponsor, CGP/ICH, 
and regulatory guidelines, and that the study is conducted in accordance with the protocol and 
sponsor SOPs, the study will be monitored by Westat, Inc.  
 
In brief, site visits will be made at standard intervals as defined by the Site Monitoring Plan. 
Monitoring visits will include, but are not limited to, review of regulatory files, accountability 
records, case report forms, informed consent forms, medical and laboratory reports, and 
protocol compliance. Study monitors will meet with investigators to discuss any problems and 
actions to be taken and document visit findings and discussions. See detailed site monitoring 
plan for details. The details of the site monitoring process for this study are given in a separate 
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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
 
Hypothesis 1a: Increasing AUC/MIC of levofloxacin will be associated with shorter time to 
sputum culture conversion 
 
Hypothesis 2a: Increasing AUC of levofloxacin will be associated with increased proportion of 
Subjects with Grade 3 or 4 Adverse Events 
 
Hypothesis 2b: Increasing AUC of levofloxacin will be associated with decreased frequency of 
completion at assigned dose. 
 
Hypothesis 3. An algorithm including patient age, sex, race, height, weight, and creatinine will 
accurately predict serum levofloxacin AUC. 
11.2 Sample Size Considerations 
 
Hypothesis 1a. (Efficacy; continuous exposure, continuous outcome). 
The sample size should be sufficient to test the first hypothesis that there is an association 
between AUC/MIC and time-to-treatment-success. A total of 62 evaluable patients will allow a 
correlation of -0.40 to be detected with 90% power. Ρ=-0.40 is considerable to be moderate 
correlation.  
 
This sample size calculation is based on the Pearson correlation coefficient (ρ) between two 
normally distributed variables (the ratio AUC/MIC and log time to sputum culture conversion) 
and the null hypothesis to be tested is H0: ρ=0. The calculations use the Fisher transformation of 
the correlation coefficient and the expected time to conversion with the lowest dose of 
levofloxacin as equal to that observed by Holtz.[8] In the Holtz study, 50% of patients with MDR-
TB converted their sputum culture to negative on solid medium by 2 months and 75% had 
converted by 3 months; therefore, we have planned more frequent culture sampling during 
weeks 0-12 (every 2 weeks) and less frequent sampling during weeks 13-24 (every 4 weeks). 
 
Table 6 shows the required evaluable patients to detect the specified Pearson correlation 
coefficient (ρ) with the specified power, based on a two-sided significance concentration of 5% 
(=0.05).  
 
 

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Table 6. Required number of evaluable patients to detect specified Pearson correlation 
coefficient with specified power 
ρ 
Power 
80% 
85% 
90% 
95% 
-0.35 
62 
71 
82 
101 
-0.40 
47 
54 
62 
76 
-0.45 
37 
42 
40 
59 
-0.50 
30 
33 
38 
47 
 
 
Hypothesis 2a (Safety; continuous exposure, dichotomous outcome). 
The sample size calculation is based on the same methodology and estimates of mean AUC as 
for the tolerability endpoint below (Hypothesis 2b). It is informative to estimate what power will 
be available with 79 evaluable subjects to test whether there is a relationship between the AUC 
and whether a patient has experienced a grade 3, 4 or 5 adverse events (AEs), occurring up to 
and including the time on study drug plus four weeks post study drug completion. Table  7 
shows the detectable odds ratio with 79 evaluable subjects under 80% and 90% power using a 
two-sided significance level of 5% (=0.05). With 79 evaluable subjects, therefore, if the 
proportion with mean AUC having a grade 3, 4 or 5 AE is 30% (p1), there will be 80% power to 
detect an association if the proportion at mean AUC + 1 SD is 46% (p2) or 90% power if the 
proportion is 49%.  
 
Table 7. Detectable odds ratio with 79 evaluable subjects 
 
Power 
p1 
Proportion with 
mean AUC 
having a grade 
3, 4 or 5 AE 
p2 
Proportion with 
mean AUC + 1 
SD  having a 
grade 3, 4 or 5 
AE 
Detectable Odds 
Ratio 
80% 
0.20 
0.35 
0.46 
0.25 
0.41 
0.48 
0.30 
0.46 
0.50 
0.35 
0.51 
0.52 
0.40 
0.56 
0.53 
90% 
0.20 
0.38 
0.40 
0.25 
0.44 
0.43 
0.30 
0.49 
0.45 
0.35 
0.54 
0.46 
0.40 
0.58 
0.47 
 

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Hypothesis 2b (Tolerability; continuous exposure, dichotomous outcome). 
The sample size should also be sufficient to test the second hypothesis that there is a 
relationship between the AUC and whether a patient has completed 6 months of treatment at 
the assigned dose. It is expected that the proportion of treatment completion at the mean will be 
85% and 70% when the AUC increases by one standard deviation (SD). A total of 79 evaluable 
patients will therefore be required to detect this difference (Table 8). 
 
The sample size calculation is based on the logistic regression of a binary response variable 
(whether the patient has completed 6 months of treatment with the assigned dose) on a 
continuous, normally distributed variable (AUC). The null hypothesis to be tested is H0:OR=1 
where OR is the odds ratio of whether a patient has completed 6 months of treatment at 
different concentrations of AUC. The sample size calculation is based on the normal 
approximation formulas given in Hsieh FY, et al..77 
 
Table 8 shows the required evaluable patients to detect the specified odds ratio under various 
conditions, with a one-sided significance concentration of 5% (=0.05) and power of 80%.  
 
Based on previously published data,72-73 the estimated mean AUC will be approximately 140 
mg, with a standard deviation of about 65 mg. p1 corresponds to the proportion of those with 
mean AUC (140mg) completing treatment and p2 corresponds to the proportion of those with 
mean + 1 SD (205mg) completing treatment.  
 
Table 8. Required number of evaluable patients to detect specified odds ratio 
p1 
Proportion 
with mean 
AUC 
completing 
treatment 
p2 
Proportion 
with mean 
AUC + 1 
SD  
completing 
treatment 
Detectable 
Odds Ratio 
Evaluable 
patients 
0.50 
0.35 
0.538 
82 
0.50 
0.40 
0.667 
191 
0.60 
0.45 
0.545 
90 
0.60 
0.50 
0.667 
199 
0.75 
0.60 
0.500 
88 
0.75 
0.65 
0.619 
183 
0.85 
0.70 
0.412 
79 
0.85 
0.75 
0.529 
153 
0.95 
0.80 
0.211 
69 
0.95 
0.85 
0.298 
113 
 

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Sample Size Adjustment 
It was originally expected that as many as 25% of randomized subjects would be lost to follow-
up with regard to the efficacy endpoint, based on experience in other MDR-TB clinical trials of 
this design (McNeeley, David, personal communication). For the tolerability endpoint, it was 
expected that a total of 20% of the randomized patients would be lost to follow-up, since 
subjects who stop their study drug dose because of intolerability would have met the endpoint 
for tolerability and will thus not be “lost” with regard to this endpoint. Because on review in 
December 2015, lost to follow up was approximately 33%, we are now planning to randomize 
120 patients. For endpoint 2, we will randomize 120 subjects, yielding 80 evaluable subjects.  
For endpoint 1, 120 patients with 33% Lost to follow-up will yield 80 evaluable subjects, greater 
than the 62 required. The sample size calculations are meant to take into account additional 
patients randomized then excluded or lost to follow up. However, if the number of such patients 
is such that the lost to follow up proportion exceeds 33%, additional subjects will be randomized 
to replace those who were lost. This sample size will give: 
• 
95% power to evaluate hypothesis 1 assuming a correlation of -0.4 or 88% power 
assuming a correlation of -0.35. 
• 
80% power to evaluate hypothesis 2a assuming that the proportion of Grade 3,4 or 5 
AEs at the mean will be 30% and 54% when the AUC increases by one SD.  
• 
80% power to evaluate hypothesis 2b assuming that the proportion of treatment 
completion at the mean will be 85% and 70% when the AUC increases by one SD.  
 
Aim 3 
It is not straightforward to determine how many patients will be required to develop a dosing 
algorithm to achieve the AUC associated with maximal efficacy and acceptable safety and 
tolerability (Aim 3). Experience from other similar studies can, however, give information about 
likely sample sizes required.  
 
A demographic prediction model linking demographic characteristics of patients taking a single 
dose of levofloxacin with pharmacokinetic parameters has been previously developed.73 In that 
study, the authors used data from 172 patients to develop the model and 100 patients to train 
the model. In the training data set of only 100 patients, the resulting model was relatively robust 
for predicting clearance from plasma for levofloxacin, a proxy for AUC, R2 = 0.40. Dose of 
treatment is likely to be a much stronger predictor of AUC than demographic characteristics and 
therefore it is likely that the 80 evaluable patients that will be available in the present study will 
be sufficient to develop a dosing algorithm for aim 3 including important covariates in the 
prediction model. 
 
 
 

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11.3 Planned Interim Analyses (if applicable) 
 
Adaptive Design to Limit Intolerance 
The Data and Safety Monitoring Board (DSMB) will review tolerability of all doses three months 
after 40 patients have been randomized and again three months after 60 patients have been 
randomized. If more than 50% of patients in any dose arm have permanently discontinued 
treatment because of toxicity or intolerability before completing 24 weeks of treatment, the 
DSMB will recommend that randomization to that arm be terminated.  The total sample size will 
remain the same, and patients subsequently randomized into the trial will be randomized 
equally between the remaining study arms.  
 
11.4 Final Analysis Plan 
 
Analysis Plan of Primary objectives 
Patients who complete study drug treatment will be included in the per protocol analysis. The 
primary analyses will be conducted on all randomized patients that have received at least one 
dose of trial medication, applying the principle of intention to treat (ITT), as far as is practically 
possible, given any missing data. There will, however, be a small number of subjects lost post-
randomization because of anticipated delays in availability of testing for isoniazid, rifampin and 
ofloxacin resistance and subjects with no positive culture for M. tuberculosis from samples taken 
at screening or randomization. Thus, a modified intention to treat (MITT) analysis will be 
undertaken with the MITT population defined as subjects randomized with a positive culture at 
screening or baseline, phenotypic resistance to isoniazid and rifampin, and phenotypic 
susceptibility to ofloxacin. This MITT population will be used for evaluation of both efficacy and 
tolerability (but not safety). The results will be adjusted for creatinine and HIV status. 
 
1. Efficacy  The primary efficacy outcome is time to culture conversion on solid media as 
defined in section 3.2.1. The primary efficacy exposure is the ratio of AUC/MIC. It is expected 
that time to culture conversion follows a log-normal distribution8 and therefore times will be log-
transformed. The patient’s levofloxacin exposure (AUC) as assessed by pharmacokinetic 
measurements divided by the minimum inhibitory concentration of levofloxacin required to kill 
90% of the patient’s isolate (AUC/MIC90) will be the exposure variable. Because there could still 
be as much as one tube dilution error in the assay, which could lead to wide variation in 
AUC/MIC ratios, we will perform the MIC assays in triplicate and average the findings, giving us 
increased precision and avoiding the misclassification introduced by rounding to the nearest 
power of 2. Log transformation will also be explored as a method for smoothing the exposure 
values. Linear regression will be used to calculate the Pearson correlation coefficient between 
AUC/MIC and log-transformed time to culture conversion. The relationship will be plotted on a 
scatter plot of AUC/MIC against time to culture conversion curve on the log scale. Missing times 
for patients that do not culture convert and missing AUC/MIC will be imputed in secondary 

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sensitivity analyses to evaluate the effect of missing data. The primary objective is to determine 
whether there is sufficient evidence to reject the null hypothesis that the Pearson correlation 
coefficient is equal to zero.  
 
A time-to event analysis will also be performed. The exposure variable will be the patient’s 
levofloxacin exposure (AUC) as assessed by pharmacokinetic measurements divided by the 
minimum inhibitory concentration of levofloxacin required to kill 90% of the patient’s isolate 
(AUC/MIC90), averaged across three assays. We will use time-to-event analysis to evaluate the 
relationship between the exposure variable and time to conversion; if the proportional hazards 
assumptions are met, Cox proportional hazards models will be employed to evaluate the crude 
and adjusted effects. Measured covariates will include site, HIV co-infection, baseline bacillary 
load (as measured by time to detection in liquid culture), previous MDR treatment and 
cavitation, and dosing schedule (single daily or split). Since we expect randomization of study 
subjects to lead to balanced distribution of OBR drugs—including less effective ones—across 
study arms, we do not expect to need to control for the composition of the OBR. If, however, the 
distribution is imbalanced, we will adjust for composition of the OBR. If Cox models are used, 
the effect estimate will be the hazard ratio, which can be interpreted as the change in rate of 
culture conversion as the AUC/MIC changes by one unit (and all other variables are held 
constant, in the adjusted analysis). Persons discontinuing levofloxacin due to adverse events 
will be censored in the time to event analysis of time to culture conversion; they will therefore 
contribute time until they are censored. This anticipated loss is accounted for in the sample size 
estimates. 
 
We will also perform a comparison of the responses of persons who have an AUC/MIC o>100to 
those who have an AUC/MIC ratio of <100. We will first compare these two groups with regard 
to the time to sputum culture conversion as a continuous outcome using non-parametric tests.  
We will also dichotomize the outcome (culture conversion by week 12: yes/no) and evaluate the 
predictive value of a cutoff of 100 using receiver-operator curve analysis, constructing a model 
that adjusts for other predictors of this outcome, as described by Drusano and colleagues.60 
 
 
2a. Safety. Exposure is AUC and the primary safety outcome is the number of grade 3, 4 and 5 
adverse events (SAEs), occurring up to and including the time on study drug plus four weeks 
post study drug completion. The number of events will be plotted against the AUC of the 
individual in whom those events occurred. Correlation between AUC and number and severity 
of events will be assessed. The resulting relationship will be used to identify an AUC at which 
greater than 25% of patients would be expected to have grade 3, 4, or 5 adverse events.  
 
Time to event methods will be used to compare the incidence of SAEs between dosing groups 
and to evaluate whether SAEs tend to accumulate earlier when higher doses of levofloxacin are 
taken.   
 

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2b. Tolerability. The primary tolerability outcome is completion of 24 weeks of study drug 
regimen as defined in section 3.2.1. The primary tolerability exposure is AUC.  
 
Logistic regression will be used to model the association between these variables with AUC 
included as a continuous covariate. If the distribution of AUC is skewed then the AUC will be log 
transformed. Other transformations will be explored as appropriate. The primary objective is to 
determine whether there is sufficient evidence to reject the null hypothesis that the odds ratio of 
discontinuation for a unit increase in AUC is equal to 1. Model parameters will also be used to 
estimate the AUC associated with 25% intolerability.   
 
3. Construction of Dosing Algorithms.  
Choice of target. The target AUC/MIC that produces maximal efficacy and the highest AUC that 
is associated with acceptable safety and tolerability will be determined from the results of the 
studies outlined in primary Objectives 1 (efficacy), 2a (safety) and 2b (tolerability) above. The 
target choice will be accomplished by first examining the shape of the AUC/MIC to time-to 
culture conversion relationship to see if continued increases in AUC/MIC are associated with 
continued decreases in time to culture conversion, or if this relationship plateaus (or reverses 
direction), which would indicate that further increases in AUC would not be associated with 
increased efficacy.  If the relationship shows that the effect of AUC/MIC plateaus, then the 
preliminary choice of target will be that AUC.  If it does not plateau, then the preliminary choice 
will be the highest achievable AUC.  This preliminary target will then be examined for safety and 
tolerability, defined above as not having a significantly increased proportion of grade 3,4 or 5 
AEs and having at least 75% of patients able to tolerate the AUC for 6 months. If the maximal 
safe dose and the maximal tolerable dose exceed the preliminary target, then the preliminary 
target will be the primary final target.  If not, then the lower of the three (preliminary target, 
maximal safe dose and maximal tolerable dose) will be the primary final target. If the maximal 
effective dose exceeds the tolerability threshold but not the safety threshold, then a second 
algorithm will be constructed to predict the dose likely to achieve the maximal effective 
threshold. This algorithm may be preferred in clinical situations where the willingness to tolerate 
side effects (and reduce levofloxacin dose as needed) is greater.         
 
Construction of algorithms. We will use linear regression to develop dosing algorithms that will 
identify the highest safe and tolerable doses of levofloxacin (in mg/Kg) that a given patient 
should receive to achieve the AUC Target. Analyses by ANCOVA will identify covariates or 
factors that may affect levofloxacin exposure like drug dose, patient height, weight, age, sex and 
race. Demographic and clinical terms will be adjusted for drug dosage, and significant factors 
combined into a multivariable model with interactions of terms in the main effects model 
assessed for significance.48   Results will be adjusted for creatinine clearance, (calculated as 
previously described78 and HIV status and other demographic or clinical variables that are 
associated with AUC in univariate analyses. The tolerability algorithm will be constructed to yield 
a distribution of AUC values such that 95% of subjects would be expected to have an AUC 
equal to or less than the Target AUC. The efficacy algorithm will be constructed to yield a 

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distribution of AUC values such that 95% of subjects would be expected to have an AUC equal 
to or greater than the Target AUC. Use of these dosing algorithms will facilitate optimization of 
levofloxacin dosing without the need to determine levofloxacin serum concentrations. 
 
Analysis Plan for Secondary Objectives 
 
1.Determine which levofloxacin AUC/MIC provides the shortest time to sputum culture 
conversion in liquid medium. Analyses will be performed as described under Primary 
analysis 1 above, but with liquid culture results substituted for solid medium culture 
results.  
 
2.Determine if baseline PZA susceptibility is associated with shorter time to sputum 
culture conversion after controlling for levofloxacin AUC. Linear regression will be used 
to evaluate the relationship between PZA susceptibility at randomization and log 
transferred time to sputum culture, adjusted for levofloxacin AUC and other predictors of 
time to sputum culture conversion. 
 
3. Describe the differences in safety and efficacy between assigned study dose groups. 
The study is not powered to detect differences between the dosing groups in terms of 
efficacy or safety. This analysis will therefore be focused on description, rather than 
hypothesis testing. The median time to culture conversion with interquartile range will be 
presented by dosing group to describe differences in the primary efficacy endpoint. The 
number of grade 3, 4 and 5 adverse events (AEs) and the number of patients completing 
treatment will also be tabulated by dosing group to describe differences in safety and 
tolerability. Other secondary measures will also be summarized by randomized group to 
further describe any differences. 
 
 
 
 

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
Appropriate medical and research records will be maintained for this trial, in compliance with 
ICH E6 GCP, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects.  
 
The following individuals and groups will have access to study records:  
 
 Members of the study team  
 IRBs that review the study (including IRB members, staff, and legal counsel)  
 Office of Human Research Protections 
 Macleods Pharmaceuticals, Ltd. 
 FDA  
 DMID/NIAID/NIH  
 Regulatory Agencies in Peru & South Africa 
 
Authorized representatives of the sponsor(s), DMID, and regulatory agencies indicated above 
will be permitted to examine (and when required by applicable law, to copy) clinical records for 
the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress.  
 
Documentation of source data is necessary for the reconstruction, evaluation, and validation of 
clinical findings, observations, and other activities during a clinical trial. Source documents are 
where participant information is first recorded. This includes medical records such as clinic 
progress notes, hospital charts, informed consent forms, and prescriptions, as well as laboratory 
reports and results of diagnostic testing, for which there may be additional primary source 
documentation within the relevant departments. Source documents also include any written 
and/or documented verbal communication between the clinical investigator and participant or 
clinical investigator and non-study health provider regarding the present and/or past medical 
history of the participant. Source documentation also includes tools developed for capturing 
study-specific data. (see MOP Section 6.4.1 for further details). 
 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
The investigational site is responsible for conducting routine quality assurance (QA) and quality 
control (QC) activities to internally monitor study progress and protocol compliance.  The 
Principal Investigator will provide direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. The Principal Investigator will ensure all study personnel are 
appropriately trained and applicable documentations are maintained on site.  
 
Each site will prepare and follow a site-specific Quality Management Plan. This plan will ensure 
that data are accurately collected and that errors are promptly recognized and corrected. These 
plans are described in detail in the individual plans.  
 
The clinical site monitors will verify that the clinical trial is conducted according to protocol, and 
that data are generated, documented (recorded), and reported in compliance with the protocol, 
Good Clinical Practice, and the applicable regulatory requirements.   
 
Refer to protocol Section 10.1 for the Site Monitoring Plan and Section 15.1 for Data 
Management Responsibilities, 
 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
The protection of human research subjects will be assured throughout the study execution and 
reporting.  
 
14.1 Ethical Standard 
 
The investigators will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6; 62 Federal Regulations 25691 (1997). In addition, the investigators will ensure that this 
study is conducted in full conformity with the current revision of the Declaration of Helsinki, or 
with the International Conference for Harmonizing Good Clinical Practice (ICH-GCP) regulations 
and guidelines, whichever affords the greater protection to the subject. In addition, this study will 
be conducted in accordance with South African and Peruvian standards. 
 
14.2 Institutional Review Board 
 
Before they are placed into use, the study protocol and informed consent documents will be 
reviewed and approved by IRBs of all involved institutions (Boston University, CDC, Harvard 
University, MRC, University of Florida, University of Arkansas, University of California – San 
Francisco, South Africa and Peru) unless the institution decides that it is not engaged in human 
subjects research. Any amendments to the protocol or consent materials will be reviewed and 
approved by the IRBs engaged in human subjects research before they are placed into use.  
(See page 4 for a listing of IRBs) 
 
14.3 Informed Consent Process 
 
Informed consent is a process that will be initiated prior to the individual’s agreeing to participate 
in the study and will continue throughout the individual’s study participation. Extensive 
discussion of risks and possible benefits of this therapy will be provided by study staff to 
potential subjects (and, with permission from potential subjects, their families). Potential 
subjects will receive counseling about study objectives and procedures, potential toxicities, and 
the informed consent process. Consent forms describing in detail the study interventions & 
products, study procedures and risks will be given to the subject and written documentation of 

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informed consent will be required prior to starting intervention/administering study product. 
Consent forms will be IRB approved, will contain all the elements required by the ICH E6 
Guideline for Good Clinical Practice and any additional elements required by local regulations. 
Forms for use in Peru will be written in Spanish; English versions will be available for IRB and 
sponsor review. The subject will be asked to read and review the document. Upon reviewing the 
document, the person obtaining consent will explain the research study to the subject and 
answer any questions that may arise. For subjects who speak and understand the language 
used in the consent document, but are unable to read or write, all of the information in the 
consent form will be communicated verbally, in the presence of an adult witness who is not a 
member of the study team; informed consent requires the signature or mark of the subject. The 
subject will sign or mark the informed consent document prior to any procedures being done 
specifically for the study. The subjects will have the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. The subjects may withdraw consent 
at any time throughout the course of the trial. A copy of the signed and dated informed consent 
document will be given to the subjects for their records. The rights and welfare of the subjects 
will be protected by emphasizing, to subjects, that the quality of their medical care will not be 
adversely affected if they decline to participate in this study.  
 
During the informed consent process, the subject will receive information about compensation 
for study participation. Specifically, subjects will not be paid for study participation, but their 
expenses and time will be reimbursed. Study subjects may receive vouchers for transportation 
to the health center/research facility, and monthly food baskets for the duration of time they are 
in the study. They will also receive meals while in the inpatient research facility for PK studies. 
 
14.4 Informed Consent/Assent Process (in Case of a Minor) 
 
Not applicable. All study subjects will be ≥ 18 years of age.  
14.5 Exclusion of Women, Minorities, and Children (Special Populations) 
 
Children will be excluded from this study for three reasons. First, children under the age of 5 
years have increased levofloxacin excretion, so that they will not achieve levofloxacin AUC 
similar to other study subjects in their dose category, increasing variability in the exposure 
variable and increasing sample size. Second, the smallest tablet form of levofloxacin available is 
250 mg, and dosing persons under 40 kg is not practical with this formulation; therefore, all 
persons less than 40 kg have been excluded from the study because it is not be possible to 
preserve the blinding. Third, children with pulmonary TB often do not produce sputum; since 
following the decline of M. tuberculosis in sputum is a major outcome of the study, persons who 
do not produce sputum are also excluded.  
 

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Pregnant women will be excluded from this study because of the lack of evidence on the safety 
and tolerability of high-dose levofloxacin among fetuses.  
14.6 Subject Confidentiality 
 
This study will be performed in accordance with U.S., South African and Peruvian standards for 
protection of privacy of identifiable health information. All study records will be managed in a 
secure and confidential fashion. Study records will be maintained in locked cabinets, and 
computer records will be password protected. Access to study records will be restricted to 
specified team members. Methods for secure data handling are detailed below in Section 15.  
 
The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the Investigators, including but not limited to, case 
report forms and pharmacy records for the subjects in this study. The clinical study sites will 
permit access to such records. 
14.7 Study Discontinuation 
 
In the event that the study is discontinued (e.g. by the investigators and/or regulatory groups), 
subjects on study phase treatment will continue to receive TB treatment in accordance with 
national guidelines. Treatment will be offered free of charge, as guaranteed through the public 
health system in South Africa and Peru.  
14.8 
Future Use of Stored Specimens 
 
These types of specimens will be stored:  M. tuberculosis isolates, serum and urine.  Specimens 
collected for storage will be labeled with study identification number and collection date, and will 
not be labeled with participant name. Serum and urine will be collected at randomization and at 
week 8 for storage as part of biomarker discovery and qualification studies. These sera will be 
stored at -70˚C and may be tested for biomarkers of tuberculosis treatment response. 
M. tuberculosis isolates:  baseline and treatment failure M. tuberculosis isolates will be shipped 
to the University of California, San Francisco laboratory and stored.  Stored baseline and 
treatment failure M. tuberculosis isolates will be used for study-related drug susceptibility 
testing.  In addition, stored M. tuberculosis isolates may be used for M. tuberculosis strain typing 
in order to assess whether persistently positive cultures (for an individual participant) are due to 
failure of TB treatment, laboratory contamination, or re-infection.  Participant consent for stored 
specimens will be part of the study Informed Consent Form (ICF) which will be asked for during 
the Screening/Consenting visit. 

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15 DATA HANDLING AND RECORD KEEPING 
Data handling and record keeping will be performed according to procedures that will be 
developed in a detailed Data Management Plan. The following types of forms will be used in this 
trial: 
 
 Informed consent forms for participation, in English and translated into Spanish  
 Eligibility screening forms  
 Data collection forms that document screening, randomization, study visits, follow-up 
visit, adherence, and specimen collection  
 Administrative forms that document participant deaths, termination from study drugs, 
and work up and treatment of AEs and treatment failure  
 
A participant’s name will be collected only one time, and this information will be kept on a form 
that does not contain any test results, and that is filed separately from forms that do contain test 
results. Each participant will be assigned a unique study ID number. This number will be 
recorded on each data collection form and clinical specimen to facilitate linkage of data. The 
study ID number will be used on data collection forms; names and other obvious identifiers will 
not be used on data collection forms.  
 
All data collection forms will be stored in locked files in a secure area. Access to study records 
and data files will be limited to study personnel, the NIH and its designees, the FDA, and local 
regulatory authorities.  
 
All forms will be reviewed prior to data entry for accuracy, consistency, and completeness by 
designated study staff.  
 
For banked specimens, the study ID number, date of collection, specimen volume, and freezer 
location will be recorded on the laboratory requisition forms and entered into the computer.  
 
15.1 Data Management Responsibilities 
 
The on-site principal investigator and the data manager will be responsible for the accuracy, 
completeness, and storage of source records and study data collection forms. The study team 
and data entry staff will review source documents and laboratory reports to ensure accuracy 
and completeness. The site staff will maintain logs to record dates of completed and upcoming 
clinic visits and specimen collections.  
 

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15.2 Data Capture Methods 
 
All forms will be entered via Remote Data Capture (RDC) and verified according to procedures 
that will be developed in a Data Management Plan, SOPs, and Work Instructions.  
 
15.3 Types of Data 
 
Data for this study will include safety, laboratory (microbiology), and clinical data. Safety data 
will be recorded in the clinical database for this study.  
 
15.4 Timing/Reports 
 
The timing of reports will be detailed in the Data Management Plan. Briefly, the DSMB will 
review safety and tolerability of all doses three months after 40 patients have been randomized 
and again three months after 60 patients have been randomized; if any dose is found to exceed 
the safety or tolerability guidelines, the DSMB will recommend that randomization to that study 
arm be terminated. Reports for the DSMB will be prepared for the DSMB according to a 
schedule determined at the first convened DSMB meeting. Data coding will occur at the time of 
data collection; ongoing logical data queries will be performed.  
 
15.5 Study Records Retention 
 
Within 2 years of completion of the study, identifiers excluding the study ID number will be 
deleted from computerized and paper data files. Study records will be maintained by the 
investigator for a minimum of 5 years following discontinuation of the study. The FDA and DMID 
will be notified prior to study records being destroyed.  
 
15.6 Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements. The noncompliance may be either on the part of 
the subject, the investigator, or the study site staff. As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly.  
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
according to the guidelines of the IND sponsor. All deviations from the protocol must be 

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addressed in study subject source documents. Protocol deviations must be sent to DMID and 
the local IRB in accordance with standard procedures.  

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16 PUBLICATION POLICY 
 
Following completion of the study, the investigators plan to publish the results of this research in 
a scientific journal. The International Committee of Medical Journal Editors (ICMJE) member 
journals have adopted a trials-registration policy as a condition for publication. This trial will be 
registered in a public trials registry such as ClinicalTrials.gov before patient enrollment is 
initiated. It is anticipated that the results of this study will be submitted for publication in a peer-
reviewed scientific journal. Authorship will be extended to the following individuals: study 
investigators, site PIs, and other individuals having major contribution to the study design, 
implementation, data analysis, and preparation of the written manuscript.  
 
Prior to submission for presentation or publication, any materials derived wholly or in part from 
this study must be submitted to the study PI(s), site PI, and all co-authors for review.  

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Medicine 2006;144:650-9. 
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Mitchison D. Assessment of new sterilizing drugs for treating pulmonary 
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Weiner M, Prihoda TJ, Burman W, et al. Evaluation of time to detection of 
Mycobacterium tuberculosis in broth culture as a determinant for end points in treatment 
trials. J Clin Microbiol 2010;48:4370-6. 
64. 
Davies G, R B, SH K, LJ A. Use of Nonlinear Mixed-Effects Analysis for Improved 
Precision of Early Pharmacodynamic Measures in Tuberculosis Treatment. Antimicrobial 
Agents and Chemotherapy 2006;50:3154-6. 
65. 
Davies G, SH K, LJ A. Optimal sampling strategies for early pharmacodynamic 
measures in tuberculosis. Journal of Antimicrobial Chemotherapy 2006;58:594-600. 
66. 
Esptein M, NW S, AL D, S B, WN R, B H. Time to detection of Mycobacterium 
tuberculosis in sputum culture correlates with outcome in patients receiving treatment 
for pulmonary tuberculosis. Chest 1998;113:379-86. 
67. 
Joloba M, JL J, al e. Quantitative sputum bacillary load during rifampin-containing 
short course chemotherapy in human immunodeficiency virus-infected and non- infected 
adults with pulmonary tuberculosis. Int J Tuberc Lung Dis 2000;4:528-36. 
68. 
Perrin F, MC L, TD M, SH G. Biomarkers of treatment response in clinical trials of 
novel antituberculosis agents. Lancet Infectious Diseases 2007;7:481-90. 

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69. 
Hesseling AC, Walzl G, Enarson DA, et al. Baseline sputum time to detect ion 
predicts month two culture conversion and relapse in non-HIV-infected patients. Int J 
Tuberc Lung Dis 2010;14:560-70. 
70. 
Wispelwey B. Clinical implications of pharmacokinetics and pharmacodynamics 
of fluoroquinolones. Clin Infect Dis 2005;41 Suppl 2:S127-35. 
71. 
Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. A common 
mechanism of cellular death induced by bactericidal antibiotics. Cell 2007;130:797-810. 
72. 
Peloquin CA, Hadad DJ, Molino LP, et al. Population pharmacokinetics of 
levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis. 
Antimicrob Agents Chemother 2008;52:852-7. 
73. 
Preston SL, Drusano GL, Berman AL, et al. Levofloxacin population 
pharmacokinetics and creation of a demographic model for prediction of individual drug 
clearance in patients with serious community-acquired infection. Antimicrob Agents 
Chemother 1998;42:1098-104. 
74. 
World Health Organization. Guidelines for the programmatic management of drug-
resistant tuberculosis. Emergency update 2008. 2008. 
75. 
Thwaites GE, Bhavnani SM, Thi Hong Chau T, et al. A randomised 
pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous 
meningitis. Antimicrob Agents Chemother 2011. 
76. 
Heifets LB, Iseman MD, Lindholm-Levy PJ. Ethambutol MICs and MBCs for 
Mycobacterium avium complex and Mycobacterium tuberculosis. Antimicrob Agents 
Chemother 1986;30:927-32. 
77. 
Hsieh FY, Bloch DA, Larsen MD. A simple method of sample size calculation for 
linear and logistic regression. Stat Med 1998;17:1623-34. 
78.  
Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16:31-41. 

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APPENDIX A: SCHEDULE OF EVENTS* 
 
Event 
Screening/ 
Consenting 
Visit 
Randomization
/ Baseline 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
10 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28** 
Clinical 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent‡ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History, demographics 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted symptom 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Focused clinical assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky Score 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of previous/interval 
TB treatment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DOT Log Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum smear 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum culture  
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
DNA-based susceptibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry and hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Serum/urine for bank 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
HIV serology / history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
PK evaluation+ 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
*weekly visits to occur on the day 6,7,or 8 days after the expected date for the previous visit    
** or 4 weeks after completion of medication  
+at any time between week 2 and week 4 
‡ Includes futures use permission for serum/urine bio-repository  
 
 
 

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APPENDIX B: KARNOFSKY SCALE 
 
Able to carry on normal activity 
100 
Normal; no complaints; no evidence of disease 
 
 
90 
 
 
Able to carry on normal activity; minor signs or 
symptoms of disease 
 
80 
 
 
Normal activity with effort; some signs or 
symptoms of disease 
Unable to work; able to live at home and care for 
most personal needs; a varying amount of 
assistance is needed 
70 
 
 
Cares for self; unable to carry on normal activity or 
to do active work 
 
60 
 
 
Requires occasional assistance but is able to care for 
most of his/her needs 
 
50 
 
 
Requires considerable assistance and frequent 
medical care 
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly 
40 
 
 
Disabled; requires special care and assistance 
 
30 
 
 
 
Severely disabled; hospitalization is indicated 
although death is not imminent 
 
20 
 
Very sick; hospitalization necessary; active 
supportive treatment is necessary 

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10 
 
 
Moribund; fatal process progressing rapidly 
 
0 
Dead 
 
 
 

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APPENDIX C: TOXICITY MANAGEMENT ALGORITHM 
Sign/symptom 
Other 
Potential 
Causal Agent 
Management Strategy  
Grade 1 
Management Strategy  
Grade 2 
Management 
Strategy Grade 3 
Dizziness, 
restlessness, 
anxiety, 
insomnia or 
other sleep 
disorder 
Efavirenz, 
Cycloserine, 
Terazadone 
Stop Efavirenz (or reduce dose); 
If not on Efavirenz, stop 
Cycloserine/ Terazadone; if 
symptom does not subside in 3 
days, stop levo; if symptom 
does not subside in 3 days, 
restart levo and look for other 
causes 
Same as Grade 1 
Same as Grade 1 
Headache 
Cycloserine, 
Terazadone 
Stop  Cycloserine/ Terazadone; 
attribute to levo if symptom 
does not subside in 3 days; if 
symptom does not subside in 3 
days, restart levo and look for 
other causes;  if symptom 
directly follows administration 
of meds, give levo in afternoon 
and keep rest of regimen in 
morning 
Same as Grade 1 
Same as Grade 1 
Paranoia, 
depression, 
hallucinations, 
psychosis 
Cycloserine, 
Terazadone 
Stop  Cycloserine/ Terazadone; 
attribute to levo if symptom 
does not subside in 3 days 
Same as Grade 1 
Same as Grade 1 

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Abdominal pain 
Ethionamide, 
PAS, PZA 
If symptom directly follows 
administration of meds, give 
levo in afternoon and keep rest 
of regimen in morning; if not, 
stop  Ethionamide, then PAS, 
then PZA and then levo 
Same as Grade 1 
Same as Grade 1 
Nausea, 
vomiting, 
diarrhea 
Ethionamide, 
PAS, AZT 
If symptom directly follows 
administration of meds, give 
levo in afternoon and keep rest 
of regimen in morning; if not, 
stop  Ethionamide, then PAS 
and then levo 
Evaluate for C. difficile 
colitis; manage as in 
Grade 1 
Evaluate for C. 
difficilecolitis; 
manage as in 
Grade 1 
Peripheral 
neuropathy, 
paresthesias, 
weakness, 
tingling, 
numbness 
INH, 
stavudine, 
didanosine, 
Linezolid 
Stop stavudine or didanosine if 
patient taking these agents; then 
stop Linezolid if patient is on 
Linezolid; if not, and patient is 
on INH, then add or increase B6; 
if symptom does not resolve 
following this, then stop INH; 
attribute to levo if patient not on 
Linezolid and symptom does not 
subside in 7 days after 
discontinuation of INH 
Same as Grade 1 
Same as Grade 1 
Hypersensitivity 
(rash, itching, 
urticaria) 
Cycloserine, 
Terizidone,  
Ethionamide,  
PAS, INH, 
PZA, 
Nevirapine, 
abacavir,; less 
commonly 
Give Benadryl and continue all 
meds 
If on nevirapine or 
abacavir, stop these 
first. If not, stop INH 
first, then PZA, then 
Ethionamide, then PAS, 
then 
Cycloserine/Terizidone 
Stop all meds 
and reintroduce 
sequentially, 
starting with 
levo after 
symptoms abate 

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(all grade 4 toxicities will be 
study endpoints, whether judged 
related to levo or not) 
 
efavirenz or 
etravirine 
Arthralgia, 
myalgia 
PZA 
Obtain uric acid level and hold 
PZA.  If symptom does not 
resolve, treat with analgesics 
and continue meds  
Same as Grade 1 
Obtain uric acid 
level and hold 
PZA.  If 
symptom does 
not resolve, hold 
FQ for 3 days 
and determine if 
symptoms 
improve.  
Elevated LFTs  
Ethionamide,  
PAS, INH, 
PZA, 
nevirapine 
Stop INH first, then PZA, then 
Ethionamide, then PAS, then 
levo 
Stop all meds and 
reintroduce 
sequentially, starting 
with levo after LFTs 
normalize 
Stop all meds 
and reintroduce 
sequentially, 
starting with 
levo after LFTs 
normalize 
Elevated or 
decreased Blood 
Glucose  
 
Obtain fasting Glucose; observe 
Stop levo 
Stop levo 
Decreased WBC 
 
Observe 
Stop levo for 3 days 
and re-evaluate 
Stop levo  for 3 
days and re-
evaluate 
Decreased 
Hemoglobin 
 
Observe 
Stop levo for 3 days 
and re-evaluate 
Stop levo  for 3 
days and re-
evaluate