Conditions: Pulmonary Tuberculosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 157
Healthy volunteers: no

Brief summary:
Assess the mycobactericidal activity of PA-824 (given at 200 mg daily) when added to first-line tuberculosis (TB) treatment (isoniazid, pyrazinamide, and a rifamycin antibiotic) over 12 weeks of treatment. Funding Source - FDA Office of Orphan Products Development (OOPD)

Detailed description:
Phase IIB, 12-week, open-label, single-site, randomized clinical trial with three treatment groups. Patients with drug-sensitive TB will all receive once daily isoniazid and pyrazinamide for 8 weeks followed by 4 weeks of daily isoniazid. In addition, Arm 1 participants will receive PA-824 200 mg daily and rifampin 600 mg daily for 12 weeks. Arm 2 participants will receive PA-824 200 mg daily and rifabutin 300 mg daily for 12 weeks. Arm 3 participants (control group) will receive rifampin for 12 weeks and ethambutol for 8 weeks. Patients will be screened within 1 week of TB diagnosis, will receive 12 weeks of study treatment and will return for follow-up visits at 4, 12, and 36 weeks after study treatment completion. All patients will be referred to the local TB treatment program after completion of study treatment to finish their 24-week TB treatment course.

Arms:
arm 1: PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks arm 2: PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks arm 3: Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks

Interventions: intervention 1: PA-824 intervention 2: Rifampin intervention 3: Rifabutin intervention 4: Pyrazinamide intervention 5: Ethambutol intervention 6: Isoniazid
Intervention descriptions: intervention 1: 200 mg QD intervention 2: 600 mg QD intervention 3: 300 mg QD intervention 4: 25mg/kg QD intervention 5: 15mg/kg QD intervention 6: 300 mg QD

Protocol document:
Prot_SAP_000.pdf: 
PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                           Version 6.0 7 February 2018 
Page 1 of 56 
 
 
A Phase 2 Randomized, Open-Label Trial of PA-824-Containing Regimens 
versus Standard Treatment for Drug-Sensitive Sputum Smear-Positive 
Pulmonary Tuberculosis  
 
NCT02256696 
 
Study Protocol containing Statistical Analysis Plan 
 
7 February 2018  
 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 2 of 56 
 
 
 
 
 
 
A Phase 2 Randomized, Open-Label Trial of PA-824-Containing Regimens versus Standard Treatment for 
Drug-Sensitive Sputum Smear-Positive Pulmonary Tuberculosis 
 
Protocol No: NA_00093014 
Johns Hopkins University IRB no:  NA_00093014 
 
U.S. Investigators:   
Kelly E. Dooley – Johns Hopkins University – Co-Principal Investigator 
Nikhil Gupte, Johns Hopkins University – Statistician and Co-Investigator 
Grace Barnes, Johns Hopkins University – Study Coordinator 
 
South Africa Investigators:  
Rodney Dawson – University of Cape Town – Site Principal Investigator 
Helen McIlleron – University of Cape Town – Co-Investigator and Pharmacologist 
Bronwyn Hendricks – University of Cape Town – Co-Investigator 
 
 
 
Version Number 6.0 
07 February 2018 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 3 of 56 
 
 
 
STUDY TEAM 
Principal Investigator, United States 
Kelly E. Dooley, MD, PhD 
Associate Professor of Medicine, Pharmacology & Molecular Sciences 
Divisions of Clinical Pharmacology and Infectious Diseases 
Johns Hopkins University Center for Tuberculosis Research 
600 N. Wolfe Street, Osler 527 
Baltimore, MD 21287 
Phone 443-287-0517 
Fax 410-614-9978 
Email kdooley1@jhmi.edu 
 
Co- Investigator, United States 
Susan E. Dorman, MD 
Associate Professor of Medicine and International Health 
Johns Hopkins University Center for Tuberculosis Research 
1550 Orleans Street, Room 1M-06 
Baltimore, MD 21231 
Phone 410-502-2717 
Fax 410-955-0740 
Email dsusan1@jhmi.edu 
 
Co-Investigator, Study Coordinator, United States 
Grace Barnes, BSN, MPH 
Johns Hopkins University Center for Tuberculosis Research 
1550 Orleans Street 
CRB-2, 1M 
Baltimore, MD 21287-0014 
Phone 410-614-3812 
Email glbarnes@jhmi.edu 
 
Co-Investigator, Biostatistician, United States/India 
Nikhil Gupte, MSc, MPhil, PhD 
Center for Global Health and Education, Johns Hopkins University School of Medicine & 
BJ Medical College and Sassoon General Hospitals 
Jai Prakash Narayan Road 
Pune, India 411001 
Phone +91 98220-70853 
Email ngupte1@jhmi.edu 
 
Site Principal Investigator, Cape Town 
Rodney Dawson, MB ChB,FCP (SA), Cert. Pulm.(SA) 
Centre for TB Research Innovation, University of Cape Town Lung Institute 
P.O.Box 34560 
Groote Schuur 7937, South Africa 
Phone +27214066864 
Fax +27214067770 
Email rodney.dawson@uct.ac.za 
 
Co-Investigator, Cape Town 
Helen M. McIlleron, MB ChB, PhD 
Head, Pharmacokinetic Unit, Division of Clinical Pharmacology 
Department of Medicine 
University of Cape Town 
Email helen.mcIlleron@uct.ac.za 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 4 of 56 
 
 
 
Co-Investigator, Cape Town 
Bronwyn Hendricks, MB,ChB 
Centre for TB Research Innovation, University of Cape Town Lung Institute 
P.O.Box 34560 
Groote Schuur 7937, South Africa 
Phone +27214047747 
Fax +27214047770 
Email bronwyn.hendricks@uct.ac.za 
 
 
Co-Investigator, Cape Town 
Kim Narunsky 
Centre for TB Research Innovation, University of Cape Town Lung Institute 
P.O.Box 34560 
Groote Schuur 7937, South Africa 
Phone +27 21 406 6605 (Office) 
Fax +27214047770 
Email Kim.Narunsky@uct.ac.za 
 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 5 of 56 
 
TABLE OF CONTENTS 
 
STUDY TEAM ............................................................................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................................................. 4 
1 
PROTOCOL SYNOPSIS .................................................................................................................................. 7 
2 
STUDY SCHEMA .............................................................................................................................................. 9 
3 
OBJECTIVES .................................................................................................................................................. 10 
4 
INTRODUCTION ........................................................................................................................................... 10 
4.1 
SCIENTIFIC BACKGROUND ............................................................................................................................... 10 
4.2 
STUDY RATIONALE ........................................................................................................................................... 23 
4.3 
RATIONALE FOR SELECTION OF DOSE AND REGIMENS ................................................................................. 24 
5 
DESIGN ............................................................................................................................................................ 24 
5.1 
STUDY TREATMENT (FIRST 12 WEEKS) ............................................................................................................ 24 
5.2 
NONEXPERIMENTAL CONTINUATION PHASE TREATMENT  ............................................................ 25 
5.3 
ENDPOINTS ........................................................................................................................................................ 26 
5.4 
STUDY DRUG DESCRIPTIONS ........................................................................................................................... 26 
5.4.1 
PA-824 ................................................................................................................................................... 26 
5.4.2 
Rifampin ................................................................................................................................................. 27 
5.4.3 
Rifabutin ................................................................................................................................................. 28 
5.4.4 
Isoniazid ................................................................................................................................................. 29 
5.4.5 
Pyrazinamide ......................................................................................................................................... 29 
5.4.6 
 Ethambutol ............................................................................................................................................ 30 
5.5 
STUDY DRUGS SUPPLY AND ACCOUNTABILITY .............................................................................................. 31 
5.6 
RANDOMIZATION .............................................................................................................................................. 31 
6 
POPULATION ................................................................................................................................................. 31 
6.1 
GENERAL CONSIDERATIONS ............................................................................................................................ 31 
6.2 
SPECIAL POPULATIONS .................................................................................................................................... 31 
6.2.1 
Children, Pregnant Women, and Breast-Feeding Women .................................................................... 31 
6.2.2 
Prisoners ................................................................................................................................................ 31 
6.2.3 
HIV-Positive Individuals ........................................................................................................................ 32 
6.3 
INCLUSION CRITERIA ....................................................................................................................................... 32 
6.4 
EXCLUSION CRITERIA ...................................................................................................................................... 33 
7 
STUDY SCHEDULE ....................................................................................................................................... 34 
7.1 
SCREENING VISIT ............................................................................................................................................. 34 
7.2 
BASELINE VISIT ................................................................................................................................................ 35 
7.3 
STUDY VISITS WEEKS 0-12 ............................................................................................................................... 35 
7.4 
STUDY VISITS WEEKS 13-24 AND AFTER TREATMENT ................................................................................... 36 
7.5 
EARLY WITHDRAWAL ....................................................................................................................................... 37 
7.6      Unscheduled ………………………………………………………………………………………………….37 
8 
STUDY PROCEDURES .................................................................................................................................. 37 
8.1 
INFORMED CONSENT PROCESS ....................................................................................................................... 37 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 6 of 56 
 
 
8.2 
ADMINISTRATION OF STUDY DRUGS ............................................................................................................... 38 
8.3 
OBTAINING SPUTUM SPECIMENS .................................................................................................................... 38 
8.4 
LABORATORY ASPECTS OF SPUTUM ANALYSIS ............................................................................................. 38 
8.5 
DRUG SUSCEPTIBILITY TESTING ..................................................................................................................... 38 
8.6 
ELECTROCARDIOGRAMS .................................................................................................................................. 38 
8.7 
OPHTHALMOLOGIC EXAMINATIONS ................................................................................................................ 38 
8.8 
REVIEW OF SYMPTOMS SINCE LAST STUDY VISIT ........................................................................................ 39 
8.9 
CONCOMITANT MEDICATIONS ........................................................................................................................ 39 
8.10 MANAGEMENT OF SUBJECTS DEEMED PROTOCOL INELIGIBLE BASED ON CULTURE RESULTS ..............  39 
8.11 MANAGEMENT OF SUBJECTS THAT ARE NOT PROTOCOL-CORRECT  ........................................................... 39 
8.12 COMPENSATION OF STUDY SUBJECTS ............................................................................................................ 40 
8.13 STEADY STATE PHARMACOKINETIC ASSESSMENT ........................................................................................ 40 
8.14 MANAGEMENT OF HIV-POSITIVE SUBJECTS ................................................................................................. 40 
8.15 PROCEDURES TO MAXIMIZE COMPLIANCE WITH STUDY VISITS ................................................................... 40 
9 
ASSESSMENT OF SAFETY AND TOLERABILITY ................................................................................. 41 
9.1 
SAFETY AND TOLERABILITY ENDPOINTS ....................................................................................................... 41 
9.2 
SAFETY EVALUATION ....................................................................................................................................... 41 
9.3    INTERIM EFFICACYAND PK ANALYSIS……………………………………………………………………..41 
9.4 
EARLY STOPPING RULES ................................................................................................................................. 42 
9.5 
STUDY TREATMENT DISCONTINUATION CRITERIA ........................................................................................ 42 
9.6 
SUBJECT STUDY WITHDRAWAL CRITERIA ...................................................................................................... 42 
9.7 
ADVERSE EVENTS .............................................................................................................................................. 43 
                   9.7 .1    DEFINITIONS .................................................................................................................................... 43 
                   9.7.2    ASSOCIATION AND ATTRIBUTION/CAUSALITY  ................................................................................. 43 
                   9.7.3    SEVERITY .......................................................................................................................................... 44 
                   9.7.4    REPORTING ....................................................................................................................................... 45 
                   9.75   PREGNANCY ........................................................................................................................................ 46 
9.8 
CLINICAL MANAGEMENT OF ADVERSE EVENTS .............................................................................................. 46 
                  9.8 .1    LIVER TOXICITY ................................................................................................................................. 46 
                  9.8.2    CARDIAC RHYTHM DISTURBANCES  ............................................................................................... 47 
                  9.7.3     OTHER TOXICITIES .......................................................................................................................... 46 
10 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................................................. 48 
10.1 HYPOTHESIS ...................................................................................................................................................... 48 
10.2 DATA ANALYSIS ................................................................................................................................................ 48 
10.3 SAMPLE SIZE ..................................................................................................................................................... 49 
11 
HUMAN SUBJECTS PROTECTIONS ......................................................................................................... 49 
11.1 INSTITUTIONAL REVIEW BOARD INVOLVEMENT ........................................................................................... 49 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 7 of 56 
 
11.2 INFORMED CONSENT………………………………………………………….................................................50 
11.3 CONFIDENTIALITY .............................................................................................................................................. 5 
 
11.4 SPECIAL POPULATIONS .................................................................................................................................... 50 
11.5 ETHICAL ISSUES IN DOING THIS TRIAL IN SOUTH AFRICA ........................................................................... 50 
11.6 FUTURE USE OF STORED SPECIMENS .............................................................................................................. 50 
12 
MONITORING AND DATA HANDLING……………................................................................................51 
13    REFERENCES .................................................................................................................................................. 53 
 
APPENDIX A:  SCHEDULE OF EVALUATIONS 
 
APPENDIX B: KARNOFSKY SCALE 
 
APPENDIX C:  INVESTIGATOR'S BROCHURE, PA-824  
 
APPENDIX D:  TABLE FOR GRADING SEVERITY OF ADULT ADVERSE EVENTS 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 8 of 56 
 
1   PROTOCOL SYNOPSIS  
Protocol Title: 
A Phase 2 Randomized, Open-Label Trial of PA-824-Containing Regimens 
versus the Standard Regimen for the Treatment of Drug Sensitive Sputum 
Smear-Positive Pulmonary Tuberculosis 
Treatment Indication: 
Pulmonary Tuberculosis (TB) 
Trial Objective: 
Assess the mycobactericidal activity of PA-824 (given at 200 mg daily for 12 
weeks) when added to first-line TB treatment (isoniazid, pyrazinamide, and a 
rifamycin antibiotic)  after 12 weeks of treatment 
Trial Design: 
Open-label, randomized clinical trial in three treatment groups.  Patients with 
drug-sensitive TB will all receive once daily isoniazid and pyrazinamide for 8 
weeks followed by 4 weeks of daily isoniazid. In addition, Arm 1 participants 
will receive PA-824 200 mg daily and rifampin 600 mg daily for 12 weeks. 
Arm 2 participants will receive PA-824 200 mg daily and rifabutin 300 mg 
daily for 12 weeks.  Arm 3 participants (control group) will receive rifampin 
for 12 weeks and ethambutol for 8 weeks.    Patients will be screened following 
TB diagnosis, will receive 12 weeks of study treatment and will return for 
follow-up visits at 4, 12, and 36 weeks after study treatment completion. All 
patients will be referred to the local TB treatment program to complete their 
24-week TB treatment course. 
Patient Population: 
A total of approximately 183 male and female patients, newly diagnosed with 
sputum smear positive pulmonary tuberculosis aged 18 years or older.  
Treatment arms: 
Study participants will be randomized 1:1:1 to receive one of the following: 
 
Arm 
Weeks 0-8 
Weeks 9-12 
Weeks 13-24* 
1 
PaHRZ 
PaHR 
HR 
2 
PaHRbZ 
PaHRb 
HR 
3 (standard Rx) 
EHRZ 
HR 
HR 
*Note: During Weeks 13-24, patients will receive standard TB treatment 
through local TB programs.  
 
PA-824 (Pa):   
200 mg once daily (7/7) 
Rifampin (R):  
600 mg once daily (7/7) 
Rifabutin (Rb):  
300 mg once daily (7/7) 
Isoniazid (H):   
300 mg once daily (7/7) 
Ethambutol (E) and Pyrazinamide (Z) will be given at standard 
doses, according to weight bands (see Section 5.1) 
 
Criteria for evaluation: 
 
Primary Endpoints:  
(1) Time to sputum culture conversion in liquid media, defined as the time from the start of treatment until the 
first negative sputum culture, over 12 weeks 
(2) Proportion of subjects with a severe adverse event (defined as grade 3, 4, or 5 adverse event) 
Secondary Endpoints:  
(1) Discontinuation of study treatment for any reason 
(2) Time to sputum culture conversion in solid media, defined as the time from the start of treatment until the 
first negative sputum culture, over 12 weeks 
(3) Proportion of participants with sputum culture conversion at 8 weeks or at 12 weeks (separately, on solid 
and liquid media). 
(4) The rate of change in time to sputum culture positivity (TTP) through 12 weeks in the Mycobacterial Growth 
Indicator Tube (Bactec MGIT960) system in sputum over 12 weeks in participants, which may be described 
with linear, bi-linear or non-linear regression of TTP on time 
(5) Pharmacokinetics (PK) of PA-824 delivered at a dose of 200 mg once daily in the context of concomitant 
rifampin- or rifabutin-containing treatment 
(6) Pharmacokinetic/pharmacodynamic (PK/PD) relationship between PA-824 exposures (area under the 
concentration-time curve (AUC) or maximum concentration (Cmax)) and outcomes (time to culture 
negativity or rate of change in TTP over 12 weeks) using non-linear mixed effects modeling 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 9 of 56 
 
Study site: 
Study subjects will be recruited from the University of Cape Town inpatient wards and outpatient clinics. 
Study duration: 
Duration of study: It is estimated that 18 months will be required for recruitment and enrollment of study 
subjects. The estimated duration of participation for each study subject is 12 months, including 3 months (12 
weeks) of experimental phase TB treatment, 3 months (12 weeks) of non-experimental conventional 
continuation phase TB treatment, and an additional 6 months for follow-up for TB relapse. For those in Arms 1 
and 2, a post-treatment ophthalmology follow-up 12 weeks after stopping PA-824 will be performed. 
 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 10 of 56 
 
2 
STUDY SCHEMA 
 
 
 
 
 
 
 Adults with new sputum smear-positive 
pulmonary TB 
 
PA-824 200 mg 
Isoniazid 
Rifampin 
Pyrazinamide 
Once daily for 56 doses
Randomization 1:1:1 
 
Continue TB treatment with conventional continuation phase regimen. 
Study visits at 4 and 6 months 
 
PA-824 200 mg 
Isoniazid 
Rifabutin 
Pyrazinamide 
Once daily for 56 doses
ETHAMBUTOL  
Isoniazid 
Rifampin 
Pyrazinamide 
Once daily for 56 doses
          
 
 
 
PA-824 200 mg 
Isoniazid 
Rifampin 
Once daily for 28 doses
PA-824 200 mg 
Isoniazid 
Rifabutin Once daily for 28 
doses 
Isoniazid 
Rifampin 
Once daily for 28 doses
Collect sputa for solid and liquid cultures at days 0, 7, 14, 21, 28, 42, 56, 70, 84. 
Safety visits at Days 7, 14, 21, 28, 42, 56, 70, 84  
Semi-Intensive PK analysis at Day 14 & Sparse PK analysis at Days 28, 56, 84 
Weeks 0-8 
Weeks 9-12 
Weeks 13-24 
 
Post-treatment 
Post-treatment follow-up visit at 12 
months 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 11 of 56 
 
 
 
3 
OBJECTIVES 
 
3.1 
Primary objectives 
(1) To compare the efficacy of the test regimens, using the intermediate endpoint of time to culture conversion on 
liquid medium, to the efficacy of standard treatment 
(2) To compare the safety and tolerability of each test regimen to the safety and tolerability of standard treatment 
 
3.2 
Secondary objectives 
 
(1) To compare the discontinuation rate of study treatment, by arm 
(2) To compare the efficacy of each regimen, using the intermediate endpoint of time to culture conversion on solid 
medium, to the efficacy of standard treatment 
(3) To compare the proportion of participants in each arm who convert sputum cultures to negative with the control 
arm after 8 and 12 weeks of treatment (on liquid medium and on solid medium) 
(4) To compare the rate of change in TTP through 12 weeks, comparing the test regimens to standard treatment 
(5) To describe the steady-state pharmacokinetics of PA-824 among patients with pulmonary TB receiving co-
administered isoniazid, rifampin or rifabutin, and pyrazinamide 
(6) To evaluate the relationship between PA-824 pharmacokinetics (AUC and Cmax) and treatment outcomes, as 
measured by time-to-culture conversion or rate of change in TTP over time among participants in the 
experimental treatment arms  
 
4 
INTRODUCTION 
 
4.1  
Scientific background 
 
Tuberculosis (TB) as a Global Health Problem: The Need for Novel Treatment Regimens 
Tuberculosis (TB) continues to be a global public health threat. In 2011, there were an estimated 8.7 million incident 
cases of TB and 1.4 million deaths.(1)  TB control efforts are hampered by the lengthy, complex treatment regimens 
necessary for cure without relapse. Although the current regimens and drugs have been very successful in controlled 
clinical trials resulting in the permanent cure of more than 95% of trial participants, treatment of drug-sensitive TB 
takes 6 months to complete.  In practice, treatment completion and cure rates vary by country, with poor adherence 
most likely to occur after the second month of treatment.  The full application of the directly observed therapy short 
course (DOTS) strategy is becoming more and more difficult in the developing countries of the world where TB 
incidence is high, countries that are also battling to control the HIV epidemic.  As a result of poor treatment 
adherence, drug resistance is becoming more common, and multidrug-resistant (MDR) TB has emerged as a 
worldwide epidemic with approximately 440,000 cases and 150,000 deaths per year (2). Shorter treatment duration 
can decrease the logistical burden and expense of extended therapy, improve adherence, and help prevent the 
emergence of acquired drug resistance. An urgent research priority is, thus, to evaluate new drugs and new 
combination regimens that can shorten treatment duration for drug-sensitive TB, both for the benefit of individual 
patients and to improve TB control from a public health standpoint. PA-824, a nitroimidazole with impressive activity 
against Mycobacterium tuberculosis (MTB) in in vitro and mouse models and in early phase clinical trials, holds 
promise as a novel anti-tuberculosis agent. 
 
Nitroimidazoles for the treatment of TB 
 
Tuberculosis in humans is an extremely complex disease that primarily affects the lung in discrete consolidated foci 
known as granulomas.  In contrast to murine models of TB disease, human disease is characterized by discrete types 
of lesions including both aerobic (cavities) and anaerobic (caseous necrotic nodules) areas. The bacteria found in these 
different areas represent metabolically distinct populations against which individual TB drugs have varying 
activity(3). In TB-infected rabbits and non-human primates that have necrotic lesions similar to those seen in human 
TB disease, nitroimidazoles have been demonstrated to be highly efficacious against TB(4), presumably because of 
their activity against “persister” organisms, those M. tuberculosis subpopulations that are phenotypically resistant to 
first-line drugs like isoniazid and rifampin but can be killed by TB drugs that have activity against the anaerobic sub-
populations thought to cause relapse if TB treatment is stopped too early.  Metronidazole, for example, is active in 
vitro against M. tuberculosis maintained under anaerobic conditions, but demonstrated little to no activity in mouse  


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 12 of 56 
 
 
models of TB treatment (5).  However, in the rabbit and primate models, the drug was highly efficacious (4,6). More 
importantly, in a recent clinical trial involving 31 patients, metronidazole shortened the time to sputum culture 
conversion among patients with MDR-TB receiving a standard MDR-TB regimen compared to placebo, but two-
month culture conversion proportions among those who did and did not receive metronidazole were not statistically 
different (7). High resolution CT and positron emission tomography (PET) testing suggested that resolution of TB 
lesions over 2-6 months was associated with successful treatment outcome, but these results require confirmation in a 
larger population of patients with TB.  Metronidazole causes unacceptably high rates of peripheral neuropathy (7), and 
it is dosed three times a day, so is not a good candidate drug for treatment of drug-sensitive TB; also, it has activity 
against TB that is limited to TB in anaerobic conditions.  Delamanid (previously OPC-67683) , another nitroimidazole 
under development for the treatment of TB, increased 2-month culture conversion from 30% to 45% when given at a 
dose of 100 mg twice daily or 200 mg twice daily and added to standard treatment among patients with MDR-TB (8).  
However, long-term favorable outcomes assessed over 24 months were only improved among those patients who 
received extended treatment with delamanid for 6 months (versus those that received the drug for <2 months)(9).  
Delamanid, a twice-a-day drug, has never been tested among patients with drug-sensitive TB who are receiving first-
line drugs with good sterilizing activity (like rifamycins and pyrazinamide).  
 
PA-824 is a nitroimidazole with potent in vitro activity against MTB with minimum inhibitory concentrations (MIC) 
for antibiotic-susceptible and drug-resistant strains ranging from 0.015 to 0.25 (10,11), a narrow spectrum of activity 
limited to the M. tuberculosis complex, and no demonstrable cross-resistance with marketed TB drugs. In vitro, PA-
824 has activity against metabolically active as well as non-replicating M. tuberculosis isolates (11). Thus, PA-824 
may be expected to have both bactericidal and sterilizing activity, the latter being the key to treatment shortening. The 
mechanism of action of PA-824 has not been fully elucidated, but it appears to inhibit oxidation of hydroxymycolate 
to ketomycolate, thus interfering with cell wall biosynthesis (10). However, it has other, less specific, activity. PA-824 
is a prodrug, like its cousin, metronidazole. It is activated by M. tuberculosis via reduction to a des-nitroimidazole 
metabolite by a deazaflavin (F420)-dependent nitroreductase (10). Once the compound is enzymatically reduced to its 
des-nitroimidazole metabolite, reactive nitrogen species including nitric oxide are generated which poison M. 
tuberculosis’ respiratory apparatus and likely contribute to the drug’s lethal effects, particularly in nonreplicating 
bacilli (12). The preclinical and clinical data suggesting that PA-824 may play an important role in TB treatment 
shortening are provided in detail below. 
 
PA-824 has been studied in three 14-day early bactericidal activity (EBA) trials to date.  In EBA studies, quantitative 
sputum cultures are collected daily over the course of 7-14 days among patients with pulmonary TB receiving 
monotherapy or combination therapy to detect differences in microbiologic activity among doses, drugs, or regimens 
(13,14). Typically, these studies are used as dose-finding trials to determine which drugs or combinations should be 
tested in Phase 2B trials (longer-duration studies, in which regimens are tested over 2-3 months).  In two EBA studies, 
PA-824 monotherapy has demonstrated substantial mycobactericidal activity (15,16). The efficacy data from the TB 
Alliance-sponsored study PA-824-CL-007 indicated that all doses of PA-824 (200, 600, 1000 and 1200 mg) produced 
an equivalent decrease in sputum CFU counts over the 14-day treatment period; no difference could be discerned 
among the PA-824 treatment groups (17).  In study PA-824-CL-010, an EBA study with a similar design to study PA-
824-CL-007 except for the use of lower doses of PA-824 (50, 100, 150 and 200 mg/day), results indicated that PA-824 
treatment resulted in a measurable dose-dependent mycobactericidal activity over the dose range studied, and 
supported a clinical dose of 100-200 mg per day (16).  In study NC-001-(J-M-Pa-Z), an EBA study with multiple 
treatment combinations, preliminary results suggested that the three drug combination of PA-824 (200 mg per day), 
moxifloxacin and pyrazinamide (PaMZ) had similar or better activity to standard first-line TB treatment.  This 
combination was just tested in a Phase 2B trial (NC-002) for drug-sensitive and MDR-TB with PA-824 given at doses 
of 100 mg or 200 mg (18).  NC-002 was recently completed; 207 subjects were enrolled, including 60 randomized to 
M-PA100-Z,  62 randomized to M-PA200-Z, and 59 to HRZE. In addition, 26 subjects with MDR-TB were treated 
with M-PA200-Z. . Preliminary results are as follows:  In the M-PA200-Z arm,  8-week culture conversion was 94% 
on solid media and 71% on liquid media; in the M-PA-100-Z arm, 8-week culture conversion was 85% on solid media 
and 67% on liquid media. This is compared to 87% (solid) and 38% (liquid) culture conversion at 8 weeks in the 
control arm (unpublished data courtesy of TB Alliance). Phase 2A and 2B trials of PA-824, thus, support testing of 
this drug at doses of 100 mg or higher once daily. Preclinical studies suggest that adding PA-824 to standard first-line 
TB drugs may shorten the time needed to cure TB to less than 6 months(19), and this must be studied clinically in a 
Phase 2B trial prior to evaluation of a regimen of PA-824 and standard first-line TB drugs (isoniazid, a rifamycin 
antibiotic, and pyrazinamide) in a Phase 3 treatment-shortening study. Middle-duration (2-3 months) treatment studies 
have historically served as stepping stones to pivotal Phase 3 trials in development of new TB treatment regimens.  


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 13 of 56 
 
 
PA-824 
 
Preclinical Studies 
 
Please see the Investigator’s Brochure (Appendix C) for full details of preclinical and clinical studies to date.  
 
Microbiology 
 
In vitro studies have demonstrated that the minimum inhibitory concentration (MIC) of PA-824 against a variety of 
drug-sensitive MTB isolates is similar to the MIC of isoniazid (MIC of PA 824, ≤0.015 to 0.25 µg/mL; MIC of 
isoniazid, 0.03 to 0.06 µg/mL) (10,11) . PA-824 was efficacious in vitro against drug-resistant clinical isolates of M. 
tuberculosis with MIC values ranging from 0.03 to 0.53 µg/mL.  The minimum effective dose (MED) of PA-824 was 
12.5 mg/kg/day in a mouse model of TB (20).  The MED is defined as the lowest dose able to prevent the 
development of macroscopic lung lesions and splenomegaly.  The minimum bactericidal dose (MBD) was 100 
mg/kg/day in the same mouse model.  The MBD is defined as the lowest dose able to reduce the lung TB colony 
forming unit (CFU) counts by 99%.  The magnitude of CFU reduction by PA-824 at this dose is similar to that seen 
with the highest dose of isoniazid tested in the same study (25 mg/kg/day). 
 
 
 
Nonclinical Safety Studies 
 
The non-clinical safety evaluation of PA-824 includes pharmacology, pharmacokinetics, toxicology and metabolism 
studies that were conducted in accordance with current ICH guidelines. 
 
Metabolite analyses in rats, monkeys, and humans indicate an overall similar metabolic profile in these species with 
some differences among minor metabolites.  These studies have confirmed that rats and monkeys are appropriate 
species for the toxicology program. 
 
PA-824 was negative in all genotoxicology studies performed.  One of its metabolites (M50) that is found in rat, 
monkey, and human plasma was positive in a screening Ames assay. M50 is not a major metabolite in humans, and 
the exposure relative to parent drug is higher in the rat (24%) and monkey (18%) than in humans (6%).  
 
PA-824-induced effects in respiratory, CNS, and cardiovascular safety pharmacology studies were generally mild and 
reversible; effects were most prominent at 450 mg/kg/day.  PA-824 is a weak inhibitor (IC50=20uM) of the hERG 
channel.  In a telemetry monkey study, in the dose range 50-450 mg/kg, there was no or minor prolongation of the QT 
interval, depending on the method of correction.  The weight of evidence suggests that there should be no effect on 
QT in the concentration range being explored in the clinical studies. 
 
Repeat-dose toxicology studies with PA-824 have been conducted in male and female rats (14 days to 6 months) and 
in male and female monkeys (7 days to 3 months).  In all studies, dose-dependent reduced food consumption and 
reduced weight gain or weight loss were noted.  In addition, testicular atrophy was observed in rats while cataracts 
were observed by indirect ophthalmoscopy in both rats and monkeys. In general, toxicity in both rat and monkey was 
significantly greater when exposures exceeded approximately 300 μg•hr/mL in the 14-day studies and approximately 
200 μg•hr/mL in the 3-month studies.  
Reproductive toxicology studies show that PA-824 is not teratogenic in rats or rabbits.  In the rat fertility study, dose-
dependent reduced fertility rates, due to decreased sperm numbers and decreased motility, were observed at doses of 
30 mg/kg and greater.  This effect was partially reversible.  As in the 3-month rat toxicology study, irreversible 
testicular lesions were not observed at 30 mg/kg, only at 100 and 300 mg/kg. 
To more fully characterize the cataract and male reproductive system findings, a 3-month monkey study in sexually 
mature males (0, 50, 150, 300 mg/kg/day) and a 6-month rat study (0, 30, 100, 300 mg/kg) in males and females were 
conducted.  Ocular assessments were conducted in a much more careful and systematic manner than in the initial 3-
month toxicology studies described above. In each of the later studies, all ophthalmologic examinations were 
conducted by a single ophthalmologist, using both indirect ophthalmoscopy and slit-lamp biomicroscopy.  Animals 
were screened before dosing to ensure no animal had cataracts at baseline, and then monthly during dosing and 
recovery.    In this monkey study, although similar drug exposures were attained as in the original 3 month monkey  


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 14 of 56 
 
 
 
study, no cataracts or testes effects (semenology, organ weights, histopathology, or hormones [testosterone, follicle-
stimulating hormone, Inhibin B]) were observed at any point during dosing or during a 20-week recovery period.  PA-
824 does not appear to cause cataracts or testicular toxicity in monkeys.  In the 6-month rat study, PA-824 caused 
irreversible cataracts at 100 mg/kg from Day 118 of the study in males and females. In contrast to the original 3-month 
rat report, rats in this more carefully conducted study developed cataracts while on drug but not during recovery.  The 
NOAEL was 30 mg/kg for cataracts and 10 mg/kg for testicular toxicity.  Rats that developed cataract and testicular 
toxicity also experienced marked decreases in body weight gain and food consumption.  The AUC safety multiples 
(relative to the exposures obtained at the anticipated clinical dose of 200 mg/day) for cataract are ~1.5x in the rat; in 
the monkey at the highest dose tolerated, where there were no cataracts in the second well conducted study, the 
multiple is at least 3.7x.  
 
To summarize, cataracts have been detected in multiple animals from two similar rat studies at mid-to-high doses.  In 
contrast, the finding of cataracts in one monkey study could not be confirmed in a follow-up study.  Thus, both 
cataracts and the testicular effects appear to be species-limited. 
 
Preclinical efficacy 
 
In an experimental murine model of TB, PA-824 was shown to have bactericidal activity during the early phase of TB 
treatment and sterilizing activity during the continuation phase of TB therapy when given as monotherapy (20). 
Further, when given with isoniazid, it prevented the development of isoniazid mutants.  Subsequent studies 
demonstrated that substitution of PA-824 for pyrazinamide or rifampin (the two key sterilizing drugs in first-line TB 
treatment) was detrimental, and addition of PA-824 to standard treatment with isoniazid, rifampin, and pyrazinamide 
did not appear to provide additional benefit (21).  In a subsequent study, substitution of PA-824 for isoniazid in a 
regimen containing rifampin and pyrazinamide reduced the treatment time required for cure from 6 months to 4 
months, and the two-drug combination of PA-824-PZA was particularly potent (22).  These mouse models, though, do 
not develop necrotic lesions, so the full anaerobic activity of PA-824 may not be realized, as was the case with 
metronidazole. In the “Kramnik” mouse model, in which C3H3B/FeJ mice develop hypoxic, necrotic lesions with 
their TB disease, Pa-824 added significantly to moxifloxacin plus pyrazinamide (MZ), but the combination of Pa-M-Z 
was not better than standard treatment with rifampin, isoniazid, and pyrazinamide (RHZ) (23). If findings in the 
mouse model are indicative of the human experience, retaining a rifamycin in the regimen and capitalizing on the 
synergistic activity of pyrazinamide and PA-824 is a promising treatment-shortening strategy.  
 
Clinical Studies 
 
Nine Phase 1 and four Phase 2 clinical trials with PA-824 have been completed.  A Phase 2A EBA trial evaluating the 
combination of PA-824 plus moxifloxacin plus pyrazinamide showed that this combination had excellent early 
bactericidal activity (18), and the follow-on two-month Phase 2B trial of PA-824 at doses of 100 or 200 mg plus 
moxifloxacin plus pyrazinamide is complete, and preliminary efficacy results are described above.  Table 1 provides a 
high-level summary of the completed and ongoing studies.  Full details of the completed clinical studies are provided 
in the current Investigator’s Brochure (Appendix C).  
 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                           Version 6.0 7 February 2018 
Page 15 of 56 
 
Table 1 PA-824 Clinical Studies to Date 
 
 
 
 
Study 
Design 
PA-824  
Dose Levels (mg) 
Enrolled 
(active 
and 
control) 
Key Safety/Efficacy Findings 
Phase I 
CL-001 
Double-blind, placebo-
controlled, single-dose, dose-
escalating, PK and safety 
study  
0, 50, 250, 500, 
750, 1000, 1250, 
1500 
53  
 
• Well tolerated; no dose-limiting AEs or abnormal laboratory results; no 
effects on ECG, vital signs, or PE.  
CL-002 
Double-blind, placebo-
controlled 7-day multidose, 
escalating, PK and safety 
study 
0, 200, 600, 1000 
24  
 
• Well tolerated; no effects on ECG, vital signs, or PE. 
• After 5 days’ dosing at 1000 mg/d, progressive moderate creatinine 
elevation: reversed during 7-day washout period.   
• No consistent effect on BUN.   
• A planned 1400-mg cohort not enrolled. 
CL-003 
Open-label, single-dose, food 
effects 
1000 
16  
 
 
• Well tolerated; no dose-limiting AEs or abnormal laboratory results; no 
effects on ECG, vital signs, or PE. 
• Treatment-emergent AEs affecting more than one subject occurred more 
frequently after dosing in the fed condition than the fasted condition, and 
more frequently among women than men. 
• Bioavailability is 3.5-to-4.5-fold higher when PA-824 is administered 
within 30 minutes of a high-fat, high-calorie meal than when it is 
administered after an overnight fast. 
CL-004 
Open-label, single-dose, 
ADME 
~860, oral 
suspension [benzyl-
14C]PA-824 
6  
 
• Well tolerated; no dose-limiting AEs or abnormal laboratory results; no 
effects on ECG, vital signs, or PE. 
• No significant radioactivity captured as [benzyl-14C]CO2.   
• ~91% of dose recovered (~65% in urine; ~26% in feces) 
Plasma: parent drug and one major metabolite.  
Urine: little or no parent drug; multiple major metabolites. 
• Feces: minimal unchanged parent drug; numerous low-abundance 
metabolites. 
CL-005 
Double-blind, 8-day 
multidose, renal effects  
0, 800, 1000 
47  
 
• Well tolerated; no dose-limiting AEs or abnormal laboratory results; no 
effects on ECG, vital signs, or PE 
• As anticipated, serum/plasma creatinine levels increased significantly (up to 
~ 40%) during treatment; reversed during 7-day washout period. 
• No effect during treatment on GFR, ERPF, FF, BUN or UA 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 16 of 56 
 
Study 
Design 
PA-824  
Dose Levels (mg) 
Enrolled 
(active 
and 
control) 
Key Safety/Efficacy Findings 
CL-006 
Open-label, multidose, DDI 
400 
14 
• Well tolerated; no dose-limiting AEs  
• For midazolam, the geometric mean ratio of Day 17 (midazolam+Pa-
824) vs. Day 1 (midazolam alone) for Cmax was 0.84 and AUC(0-
infinity) was 0.85  
• For the 1-hydroxy midazolam metabolite, the corresponding geometric 
mean ratio for Cmax was 1.05 and AUC(0-infinity) was 1.11  
CL-008 
Open-label, single-dose, ADME 
~1100, oral 
suspension 
[imidazooxazine-1
4C]PA-824 
6  
 
• Well tolerated; no dose-limiting AEs or abnormal laboratory results; no 
effects on ECG, vital signs, or PE. 
• No significant radioactivity captured as [imidazooxazine-14C]CO2.   
• ~91% of dose recovered (~53% in urine; ~38% in feces) 
Plasma: parent drug.  
Urine: little or no parent drug; multiple major metabolites. 
Feces:  unchanged parent drug and numerous low-abundance metabolites. 
CL-009 
Open-label, single-dose, food 
effects 
50 and 200 
 32 
 
• Well tolerated; no dose-limiting AEs 
• In the presence of high fat, high calorie diet, Cmax and AUC of the 50-
mg dose increased 1.40-fold and 1.45-fold respectively, whereas for the 
200-mg dose, Cmax increased 1.76-fold and AUC increased 1.88-fold. 
ACTG A5306 
Open-label, multidose DDI with 
efavirenz (EFV), ritonavir-
boosted lopinavir (LPV/r), or 
rifampin 
200 mg 
52 
• Well tolerated; no dose-limiting AEs 
• In the presence of efavirenz, on average, AUC is reduced 35%; with 
LPV/r, AUC is reduced 15%; with rifampin, AUC is reduced 60% 
 
Phase II 
CL-007 
Partially double-blinded (blinded 
as to PA-824 dose), 14-day 
multidose, extended early 
bactericidal activity 
200, 600, 1000, 
1200 
• 69  
• Overall well tolerated with relatively few AEs and no dose-limiting AEs 
or laboratory findings.  No clinically significant effects on ECG, vitals, 
or PE noted. 
• Two SAEs occurred during study, both were considered possibly related 
to TB disease (hemoptysis). 
• PA-824 treatment produced a measurable decrease in log CFU, with the 
magnitude of effect equivalent for all doses. 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 17 of 56 
 
CL-010 
Partially double-blinded (blinded 
as to PA-824 dose), 14-day 
multidose, extended early 
bactericidal activity 
50, 100, 150, 200 
• 69  
• Well tolerated. 
• PA-824 treatment produced a measurable decrease in log CFU with 
some evidence of dose dependence. 
NC-001- 
(J-M-Pa-Z) 
Partially double-blinded (blinded 
as to combination within Pa or J 
containing arms), 14-day 
multidose, extended early 
bactericidal activity 
200 
• 85 
• Well tolerated. 
• PA-824 plus moxifloxacin plus pyrazinamide combination treatment 
produced a decrease in log CFU at least comparable to that of the 
Rifafour e-275Ò control group. 
NC-002-
(Pa-M-Z) 
Open-label, partially randomized 
(patients with drug-sensitive TB 
are randomized; patients with 
MDR-TB are assigned), 2-month 
multidose 
100, 200 
• 230 
Based on preliminary results: 
• Well tolerated 
• Among patients with drug-sensitive disease, eight-week culture results 
on liquid media favored the experimental arms over the standard 
treatment arm (isoniazid, rifampin, pyrazinamide, ethambutol) 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 18 of 56 
 
• 
Phase 1 
 
In these trials, PA-824 has been administered in doses ranging from 50 to 1500 mg as 50 or 200 mg 
tablets or as an oral suspension.  PK parameters have largely been consistent in each study and can be 
summarized as follows:  
• 
PA-824 is moderately rapidly absorbed, with median Tmax values across subjects and dose levels 
ranging from 4 to 7 hours.   
• 
The mean half-life for elimination (t½) across subjects and dose levels was approximately 16 - 25 
hours.  
• 
Exposure increased approximately linearly but less than dose-proportionally, with increasing doses 
up to approximately 600 – 1000 mg, while higher doses achieved minimal additional increases in 
either Cmax or AUC.   
Two studies using radiolabeled PA-824 in an oral-suspension formulation have been conducted to 
investigate the metabolism and excretion patterns of PA-824 in humans: Study PA-824-CL-004, which 
used [benzyl-14C] PA-824 and Study PA-824-CL-008, which used [imidazooxazine-14C] PA-824. The mass 
balance results from the two studies were very similar.  In each study, the majority (53-65%) of radioactivity 
was excreted in the urine; an additional 26-38% was collected in the feces such that approximately 91% of 
the administered dose was ultimately recovered in the excreta.   
Radioprofiling and metabolite identification work have been completed on samples from the two human 
studies as well as from analogous work in rat and monkey using both radiolabeled PA-824 preparations.  
The metabolism of PA-824 proceeds via a combination of reductive metabolism (~20 – 25% of the dose) 
and oxidative metabolism (remainder of the characterized metabolites). The metabolic profile of PA-824 
in vivo was qualitatively similar in the three species, with quantitative differences being minor. No human 
unique metabolites were detected and there is no one single metabolic path that can be considered major. 
Furthermore, there are no major metabolites in human plasma.   
Study PA-824-CL-006, a drug-drug interaction study with midazolam to assess the extent of CYP3A 
inhibition by PA-824, results indicate that dosing of PA-824 400 mg once daily for 14 days did not have a 
major effect on the exposure of midazolam or its major metabolite 1-hydroxy midazolam.  For 
midazolam, the geometric mean ratio of Day 17 (midazolam+PA-824) vs. Day 1 (midazolam alone) for 
Cmax was 0.84 and AUC was 0.85.  For the 1-hydroxy midazolam metabolite, the corresponding 
geometric mean ratio for Cmax was 1.05 and AUC was 1.11.  The data suggests that PA-824 does not 
cause clinically significant drugs interactions with drugs metabolized by CYP3A.   
Study PA-824-CL-009, a food effects study using lower doses of PA-824 (200 mg and 50 mg), results 
indicate that the food effect observed is dependent on the PA-824 dose administered.  When a single dose 
of PA-824 was administered with a high fat, high calorie meal, Cmax and AUC of the 50 mg dose 
increased 1.40-fold and 1.45-fold respectively, whereas for the 200 mg dose, Cmax increased 1.76-
fold and AUC increased 1.88-fold. 
In the NIH-sponsored study ACTG A5306, a drug-drug interaction study with efavirenz, ritonavir-
boosted lopinavir, or rifampin among healthy volunteers, results indicate that efavirenz reduces PA-824 
AUC approximately 35%, lopinavir/ritonavir reduces AUC 15%, and rifampin reduces AUC 65%.  
Subjects were not co-administered isoniazid, an inhibitor of metabolizing enzymes, or other TB drugs. 
 
• 
Phase 2 
 
Study PA-824-CL-007 examined the effects of 14 days’ treatment with PA-824 monotherapy at doses 
ranging from 200 to 1200 mg/day on TB participants’ lung bacterial load measured as logCFU (log of 
Colony Forming Units) in the sputum.  Four groups of approximately 15 men and women received 200, 
600, 1000, or 1200 mg/day PA-824.  An additional group of eight participants received the standard 
South African 4-drug combination TB treatment (Rifafour® e-275, comprised of a fixed-dose 
combination of isoniazid, rifampin, pyrazinamide and ethambutol).  This group was included to provide 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 19 of 56 
 
control for the microbiological techniques used to measure lung TB bacterial burden. The efficacy data 
from this study indicated that all doses of PA-824 including the lowest dose, 200 mg, produced a 
measurable and equivalent decrease in sputum CFU counts over the 14-day treatment period; no 
difference could be discerned among the PA-824 treatment groups (Figure 1) (17). 
 
 
 
Figure 1 PA-824-CL-007 Mean Group logCFU Values Over Time 
 
 
Study PA-824-CL-010 was an EBA study with a similar design to study PA-824-CL-007 except for the 
use of lower doses of PA-824 (50, 100, 150 or 200 mg/day).  Results indicate that PA-824 treatment 
resulted in a measurable dose-dependent mycobactericidal activity, with the 50 mg dose demonstrating 
less activity than the 100, 150 and 200 mg doses, which were all equivalent (Figure 2) (16) .The results of 
the 200 mg and Rifafour arms were also consistent with the results for those same dose arms in study PA-
824-CL-007, indicating these EBA studies are highly reproducible when conducted at these clinical and 
laboratory sites, and supported the choice of doses of 100 mg and 200 mg, PO, once per day, as the 
clinical doses of PA-824 tested in the eight-week Phase 2B NC002 trial.  
 
 
 
 
 
 
 
 
 
 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 20 of 56 
 
 
 
Figure 2 PA-824-CL-010 Error Bar Plot over Treatment for Daily Mean EBA  
 
 
Study NC-001-(J-M-Pa-Z) was a 2-week EBA study that assessed the two-week EBA of the following 
drug combinations: PA-824 plus pyrazinamide, PA-824 plus pyrazinamide plus moxifloxacin, along with 
two other non-PA-824 containing combinations.  The two-week EBA activity of PA-824 plus 
pyrazinamide plus moxifloxacin was at least comparable to that of Rifafour (HRZE) (18). 
 
Study NC-002 (Pa-M-Z) is a recently-completed 2-month study evaluating moxifloxacin plus PA-824 
100mg plus pyrazinamide versus moxifloxacin plus PA-824 200mg plus pyrazinamide versus standard 
treatment (HRZE) among patients with drug-sensitive TB and PA-824 200mg plus moxifloxacin plus 
pyrazinamide among a small group of patients with MDR TB that had isolates sensitive to pyrazinamide. 
Preliminary efficacy results suggest that both experimental arms had higher 8-week culture conversion 
rates than the standard of care arm on liquid media; solid media results were similar in all arms.  Final 
results are expected in mid-2014. The experimental regimens were safe and well-tolerated. These results 
suggest that PA-824 at doses of 100 mg and 200 mg daily is effective in combination regimens for TB.  
 
Clinical Safety 
 
Across the clinical studies with PA-824 completed to date, a total of 649 subjects have been exposed to 
PA-824, including 289 healthy subjects across the  Phase 1 studies and 360 subjects with newly 
diagnosed smear positive pulmonary TB across the Phase 2 studies. Among the 289 healthy subjects, 174 
received exposure to a single dose of PA-824 ranging from 50 to 1500 mg and 115 received exposures to 
repeated daily doses of PA-824 (50 to 1000 mg) for up to 14 days. The 360 subjects with newly 
diagnosed smear positive pulmonary TB were exposed to PA-824 either as a single agent at daily doses of 
50 to 1200 mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin 
pyrazinamide and/or clofazimine) at a dose of 100 mg or 200 mg for up to 56 days.   
 
Safety has been fully evaluated for the studies with final clinical study reports, and the safety evaluation is 
preliminary from the recently completed Phase 2B 8-week NC-002 study.   
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 21 of 56 
 
 
 
Safety in Completed Studies of Dosing up to 2 Weeks Duration 
 
The overall safety profile from these completed clinical studies in healthy subjects and TB patients 
through 2 weeks of dosing indicated that orally-administered PA-824 was well tolerated when 
administered alone or a part of a multi-drug anti-TB regimen. In the Phase 2 studies, PA-824-CL-007, 
PA-824-CL-010 and NC-001-(J-M-Pa-Z), the overall frequency of treatment-emergent adverse events 
(TEAEs) during the 2-week treatment period was similar for the PA-824 treatment groups and for the 
standard first-line treatment for TB, Rifafour® e-275. In these Phase 2 studies, the overall frequency of 
TEAEs with PA-824 did not appear dose related when given at doses ranging from 50 to 200 mg/day in 
Study CL-010 or from 200 to 1200 mg/day in Study PA-824-CL-007. In Study NC-001-(J-M-Pa-Z), the 
three-drug regimen of moxifloxacin + PA-824 + pyrazinamide was associated with a slightly higher 
frequency of reported treatment-emergent adverse events (TEAEs) (60%) than were the two-drug 
regimens of PA-824 + pyrazinamide (53%) or PA-824 + TMC207 (47%).  
 
Reported TEAEs across the 330 subjects exposed to PA-824 in completed clinical studies with final study 
reports thus far have generally been mild in intensity, with only about 3% of subjects (one healthy 
volunteer, nine subjects with pulmonary TB) having a TEAE that was assessed as severe. Almost all 
TEAEs resolved without sequelae. Five of the 330 subjects (all with pulmonary TB) exposed to PA-824 
in the completed studies had a TEAE that met the criteria for being considered serious (pneumothorax, 
pneumonia, worsening pulmonary TB, hemoptysis, and neurocysticercosis). Each of the serious adverse 
events (SAEs) reported thus far in subjects exposed to PA-824 were assessed as unrelated to study 
treatment, and for two of these subjects, the SAE occurred more than 30 days after the last dose of PA-
824.   
 
TEAEs led to discontinuation from study treatment and/or from the study for 10 of the 330 subjects 
exposed to PA-824 (one healthy subject; nine subjects with pulmonary TB). Five of the nine subjects with 
pulmonary TB who were discontinued due to a TEAE were receiving PA-824 as part of a multi-drug 
regimen (three were on moxifloxacin + PA-824 + pyrazinamide). For five subjects, the TEAE leading to 
discontinuation was detected upon laboratory evaluations (alanine aminotransferase [ALT] increased in 
three subjects; ECG abnormalities [QTc prolonged; Wolff-Parkinson-White syndrome]) and the subjects 
were asymptomatic. Of the remaining five TEAEs leading to discontinuation, four were assessed as 
unrelated to study treatment (SAEs of hemoptysis, pneumothorax, neurocysticercosis; urinary tract 
infection [subject discontinued to take protocol-disallowed medication]). The remaining TEAE leading to 
discontinuation was a generalized rash in a healthy subject that presented approximately 32 hours after 
the final PA-824 dose (1000 mg/day).  
 
In Phase 1 studies, headache was the most common TEAE. Among the 42 subjects across these studies 
who received a PA-824 dose of 200 mg (anticipated maximum clinical dose) or less, 10 (24%) reported 
headache.  The incidence of headache in subjects treated with placebo in Phase 1 studies PA-824-CL-001 
and PA-824-CL-002 was 31% and 22%, respectively.  In the Phase 2 studies in subjects with pulmonary 
TB, in studies PA-824-CL-007 and PA-824-CL-010, headache was reported for three of the 122 subjects 
exposed to PA-824 as a single agent. In Study NC-001-(J-M-Pa-Z) seven of the 45 subjects exposed to 
PA-824 as part of a multi-drug regimen in reported headache. 
 
 
Gastrointestinal disorder TEAEs (primarily nausea and vomiting) and skin and subcutaneous tissue 
disorder TEAEs (mainly rash) were the most frequently-reported TEAEs in the Phase 2 studies. 
Gastrointestinal disorder TEAEs were reported for 13 of the 122 subjects (11%) treated with PA-824 
across Studies PA-824-CL-007 and PA-824-CL-010 and for four of the 45 subjects (16%) treated with a 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 22 of 56 
 
PA-824-containing regimen in Study NC-001-(J-M-Pa-Z). None of these TEAEs were severe or serious, 
or resulted in discontinuation. Skin and subcutaneous tissue disorder TEAEs were reported for 18 of the 
122 subjects (15%) across Studies PA-824-CL-007 and PA-824-CL-010, and for three of the 45 subjects 
(7%) treated with PA-824 in Study NC-001-(J-M-Pa-Z). Although treatment with PA-824 did appear to 
be associated with skin-related TEAEs, such as pruritus or rash, these events tended to be mild in 
intensity and generally resolved without sequelae. Across the 11 clinical studies with PA-824 completed 
to date (including 8 Phase I studies), only one skin-related TEAE (generalized rash) was severe and 
resulted in discontinuation from the study. None were serious. 
 
No other clinically significant changes in laboratory parameters (hematology, clinical chemistry, and 
urinalysis) have been noted with PA-824 in the Phase 1 or 2 clinical studies. As indicated above, three of 
the 45 subjects (7%) exposed to a PA-824-containing regimen in Study NC-001-(J-M-Pa-Z) were 
withdrawn from treatment due to an elevation in ALT levels. The rate of discontinuation for this 
laboratory TEAE in this study was similar to that for bedaquiline-containing regimens (2/30, 7%). 
Moreover, none of the three subjects discontinued for increased ALT levels in Study NC-001-(J-M-Pa-Z) 
had associated symptoms, and in all cases, ALT levels resolved upon discontinuation of treatment. No 
other hepatic-related TEAEs have been reported in clinical studies with PA-824, and evaluation of hepatic 
laboratory parameters (ALT, aspartate aminotransferase [AST], total bilirubin) did not suggest any 
clinically significant changes in these parameters with PA-824. 
 
The initial 3-month nonclinical toxicology studies in rats and monkeys reported the development of 
cataracts during both treatment and recovery in rats dosed with PA-824 300 mg/kg/day and during the 3-
month recovery period in monkeys in the PA-824 450/300-mg/kg/day group. As a result, the 
Investigational New Drug (IND) application for PA-824 was placed on full clinical hold by the Food and 
Drug Administration (FDA) on 09 April 2008 until additional nonclinical and clinical data were provided. 
Following submission of nonclinical data from two repeat toxicology studies in rat and monkey, cross-
species metabolism comparisons, clinical information on ophthalmologic evaluations in subjects who had 
participated in multi-dose clinical studies PA-824-CL-005 and PA-824-CL-007, and expert opinions from 
an independent Ophthalmology Review Board (ORB), the clinical hold was lifted in July 2009. In 
addition, the FDA requested planned ophthalmologic examinations in future clinical studies. Since the 
clinical hold was lifted, five additional clinical studies have been conducted, each of which included 
prospectively-planned ophthalmologic evaluations (slit-lamp examinations, visual acuity testing) predose 
and at 3- or 6-months after the final dose of study treatment (Studies PA-824-CL-010, PA-824-CL-006, 
PA-824-CL-009, NC-001-(J-M-Pa-Z) and NC-002-(M-Pa-Z). Mild lenticular opacities were noted upon 
ophthalmological slit lamp testing in 2 of the 152 subjects exposed to PA-824 across these five studies; 
both subjects were asymptomatic.  
 
Rat toxicology studies demonstrated testicular toxicity although there was no evidence of testicular 
toxicity in mature male monkeys evaluated with PA-824 dosing over 3 months.  To gather more 
information in male subjects regarding male reproductive hormones, serum testosterone, LH and FSH 
were measured in all male subjects in Study NC-002-(M-Pa-Z) at baseline and at the end of 8 weeks of 
exposure to PA-824 and the control H-R-Z-E therapy. 
 
Preliminary Safety from Completed Phase 2b 8-Week Study NC-002 
 
Preliminary data analyses of the study indicate that a total of 207 subjects were enrolled, with 60 
randomized to M-PA100-Z, 62 randomized to M-PA200-Z, and 59 to HRZE.  An additional 26 subjects 
were treated in the M-PA200-Z MDR arm.  In this study 88% of all subjects had a treatment emergent 
adverse event (TEAE), including 87% in the M-PA100-Z group, 92% in the M-PA-Z group, 85% in the 
Rifafour group and 89% in the M-PA-Z MDR group.  Adverse events were graded according to the NIH 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 23 of 56 
 
Division of Microbiology and Infectious Diseases Adult Toxicity Table.  TEAEs by grade were 
comparable by grade across the arms of the trial, as demonstrated in the table below. 
 
NC-002 Adverse Events by DMID Grade 
 
 
 
 
 
 
 
 
 
 
 
Eleven serious adverse events (SAEs) were reported in 9 subjects, with one subject in each of the M-
PA100-Z and the Rifafour groups, and 7 subjects in the M-PA200-Z group.  The subject in the M-PA100-
Z group died of an unknown cause 39 days after a single dose of study drug regimen, and the death was 
not considered related to study drug by the investigator or the sponsor.  Four other SAEs were considered 
not related to study drug, including a pneumothorax, a bone fracture, dyspnea requiring hospitalization, 
and second degree heart block considered on evaluation to be existing prior to entry into the trial.  SAEs 
considered possibly related or related to the study drug regimen included hyperuricemia likely secondary 
from pyrazinamide, drug-induced hepatitis, and elevated liver enzymes.  One subject had an episode of 
agranulocytosis that resolved after the study drug regimen was stopped, and one subject had a seizure 
witnessed by the family and was discontinued from the study. 
 
The protocol required that subjects with hepatic enzyme ALT or AST elevations greater than 3X the 
Upper limit of Normal (ULN) have study drug discontinued.  Consequently, 25 subjects were withdrawn 
from the study across the study arms for elevations in hepatic enzymes.  Among patients in the M-PA100-
Z, M-PA200-Z, ,and HRZE arms, 4/60, 5/62, and 4/59 had ALT values higher than 5 times the upper 
limit of normal; among patients with MDR-TB receiving a regimen of M-PA200-Z, 2 of 26 did.   
 
Additional preliminary safety findings of special focus from NC-002 are noted below. 
 
Ophthalmologic Evaluations – All subjects received ophthalmologic evaluations including visual acuity 
testing and slit lamp examinations at baseline and 3 months after completion of study drug dosing.  The 
ophthalmologists were trained in grading 3 regions of the lens using the AREDS2 grading system across a 
range of 0-4.  All subjects enrolled with the required zero score grade for all regions of the lens except for 
1 subject who was blind in one eye.  Among all subjects in the trial, 4 subjects had lens evaluations with a 
grade of greater than zero.  One subject in the M-PA100-Z group and 3 subjects in the M-PA200-Z group 
had grades of 0.5 or 1.0 in a single eye in one of the 3 zones of the lens.  It is unlikely these findings 
represent a drug-induced lens opacity given the low incidence, the unilateral nature of all findings and the 
differing zone locations of the findings.  It is common in persons with no clinical abnormalities to have 
grades of 0.5 – 1.0+ in the AREDS2 rating on a slit lamp evaluation. 
 
Reproductive Hormone Evaluations – Preclinical toxicology studies had noted that rats dosed with PA-824 
developed testicular toxicity, although a 3 month study in mature monkeys did not identify any drug related 
testicular toxicity.  In Study NC-002 men were evaluated with plasma samples for the reproductive 
hormones LH, FSH and Testosterone at baseline and at the end of the dosing period.  If the study drug 
regimen caused testicular toxicity, the most sensitive measure from these hormones would be an increase 
in levels of FSH.  Among subjects in the M-PA100-Z group the mean baseline FSH was 9.027 U/L which 
Severity
Statistic
M-PA100-Z 
(N=60)
M-PA200-Z 
(N=62)
Rifafour 
(N=59)
M-PA200-Z 
MDR (N=26)
Total 
(N=207)
Grade 1
N     (%)
43 (71.7)% 48 (77.4%)
46 (78.0%)
18 (69.2%)
155 (74.9%)
Grade 2
N     (%)
25 (41.7%) 31 (50.0%)
27 (45.8%)
13 (50.0%)
96 (46.4%)
Grade 3
N     (%)
18 (30.0%) 20 (32.3%)
15 (25.4%)
6 (23.1%)
59 (28.5%)
Grade 4
N     (%)
3 (5.0%)
9 (14.5%)
6 (10.2%)
2 (7.7%)
20 (9.7%)


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 24 of 56 
 
decreased to 8.338 U/L at the end of therapy.  Among subjects in the M-PA200-Z group the mean baseline 
FSH was 6.531 U/L at baseline and this decreased to a mean of 6.061 at the end of therapy.  Men in the 
Rifafour group had a mean baseline of 7.394 U/L which decreased to 6.714 at the end of therapy.  This 
gives relative reassurance that the M-PA-Z regimen is not likely to cause testicular toxicity in men.  
 
Electrocardiographic Conduction Interval Changes – Subjects in NC-002 had supine resting ECGs taken at 
baseline, Day 4 and weekly through the 8 week dosing period and 2 weeks after the end of dosing.  All 
ECGs were read by a central cardiology service.  No subjects had a corrected QT interval (QTcF) greater 
than 500 msec during the study. A small number of subjects had asymptomatic increases in QTcF from 
baseline over 60 msec:  Two in the M-PA100-Z group, 4 in the M-PA200-Z group, none in the Rifafour 
group and 2 in the M-PA200-Z MDR group.  An evaluation of the mean change from baseline across all 
post-baseline ECGs notes increases of 11.1 msec in the Rifafour group, 11.1 in the M-PA100-Z group, 17.8 
msec in the M-PA200-Z group and 6.7 in the M-PA200-Z MDR group.  Of note, many subjects were 
tachycardic at baseline with their active pulmonary MTB and had heart rates decrease over the first week 
of therapy, which complicates interpretation of heart-rate corrected calculated QT..  In addition, PA-824 
was always given with moxifloxacin in NC-002, and moxifloxacin is known to prolong QTc modestly. 
 
4.2 
Study rationale 
 
PA-824 is an investigational drug with bactericidal and sterilizing activity against M. tuberculosis that has 
significant potential as a treatment-shortening drug when used as part of combination TB therapy. The 
nitroimidazoles are of particular interest because of their activity against “persisters,” those bacteria that 
are hard to kill and lead to relapse when TB is not treated for a long enough duration. Data from 
preclinical studies suggest that PA-824 is synergistic with pyrazinamide and that regimens including PA-
824, rifampin, and pyrazinamide shorten the treatment duration required for cure from 6 months to 4 
months.  Although these results are promising, it is important to note that the pathophysiology of TB 
disease in humans and the mouse model differ substantially, and new regimens must be tested rigorously 
in humans to discover their true treatment-shortening potential.  PA-824 is a once-daily, well-tolerated 
nitroimidazole that is in Phase 2 development. The proposed study would answer the following question:  
In a combination regimen that includes isoniazid, pyrazinamide, and a rifamycin, drugs with proven 
activity against TB, will addition of PA-824 improve the activity of the regimen?. While trials involving 
combinations of multiple investigational drugs for TB are under consideration and are likely to be 
informative, trials substituting one drug for another may also help us learn about the individual 
contributions of investigational drugs to regimens so that prioritizing drugs and drug combinations for 
Phase 3 trials can be done efficiently and effectively.  Historically, adding rifampin to TB treatment 
resulted in a 20% difference in 8-week culture conversion (on solid media) and allowed for shortening of 
treatment duration from 18 months to 9 months; the addition of pyrazinamide increased the 8-week 
sputum culture conversion rate by 13% and allowed for treatment shortening from 9 to 6 months (24).  In 
modern-day Phase 2B TB treatment trials, about 80-85% of patients with pulmonary TB convert their 
sputum cultures (on solid media) to negative by the end of 2 months of treatment, and culture conversion 
on liquid media at 2 months is about 65-70%. Trial endpoints with more discriminatory power than the 
binary 2-month culture conversion proportion, such as time to culture conversion or quantitative culture 
results over time, will be needed to inform Phase 3 trials(25). In addition, modalities that allow us to 
expand our evaluations of treatment response beyond the microbiology of sputum samples, such as CT 
scans, may be important as biomarkers of TB treatment response. Last, though many TB treatment trials 
have ended at 2 months, the time between 2 and 3 months of treatment is likely to provide important 
additional data about sputum culture clearance that can help us figure out which drugs and regimens 
among the many moving forward in clinical studies have the most promise of being an effective 3-4 
month regimen.  
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 25 of 56 
 
 
 
4.3 
Rationale for selection of doses and regimens 
 
In this study, PA-824 will be substituted for ethambutol, a drug that generally does not provide additional 
activity when given together with isoniazid, rifampin, and pyrazinamide to treat drug-sensitive TB. The 
role of ethambutol, given at its minimal effective dose because of optic toxicity that is related to dose and 
cumulative exposure, in TB treatment is to protect companion drugs against the development of resistance 
(26). PA-824 also protects against isoniazid resistance, as noted in the Background section above. 
Isoniazid is the drug with the highest bactericidal activity (1-2 log reductions in sputum colony counts are 
generally seen after 2 days of dosing) (27), driving down bacterial burden quickly, and rifamycin 
antibiotics (rifampin or rifabutin) and pyrazinamide are the drugs with the highest sterilizing activity of 
all TB drugs evaluated to date. This study is designed to see if the addition of PA-824 to this combination 
can increase its potency further given its activity against “persisters”, with an eye towards treatment 
shortening.   
 
The dose of PA-824 selected for this study is based on data from the dose-ranging EBA studies described 
above in which increases in dose above 200 mg did not increase the activity of the drug and doses 
between 100 mg and 1000 mg produced similar results (17). In addition, preclinical studies suggest that 
PA-824’s activity against M. tuberculosis is time-dependent, and human pharmacodynamic simulations 
based on Phase 1 data predict that 200 mg per day produces free drug time above mean inhibitory 
concentration (T>MIC) values near the target for maximal observed bactericidal effect, as determined in 
the mouse model (28).  The PK/PD parameter that correlates best with treatment effect and the target 
value for that parameter in humans have not been determined. At a dose of 200 mg, the median %T>MIC 
is 99%.  Further, preliminary 8-week NC-002 study results demonstrated that PA-824 at doses of 100 mg 
and 200 mg given together with moxifloxacin and pyrazinamide had higher two-month culture conversion 
rates on liquid media than standard treatment with isoniazid, rifampin, pyrazinamide, and ethambutol. 
This supports further testing of doses of 100 mg and 200 mg. However, preliminary results from a recent 
Phase I drug-drug interaction (DDI) study suggested that PA-824 at a dose of 200 mg given on an empty 
stomach with rifampin resulted in PA-824 exposures that are similar to a dose of about 100 mg given 
without rifampin. However, the combined effects of isoniazid, an inhibitor of metabolizing enzymes, and 
rifampin on PA-824 have not been tested. In Arm 1, PA-824 will be given at a dose of 200 mg together 
with rifampin, pyrazinamide, and isoniazid. In Arm 2, PA-824 will be given at a dose of 200 mg together 
with rifabutin, a drug with comparable efficacy to rifampin that is a significantly less potent inducer of 
metabolizing enzymes (29,30), plus pyrazinamide, and isoniazid (for example, among patients with TB 
and HIV requiring antiretroviral therapy, rifabutin is commonly substituted for rifampin to avoid drug 
interactions). Exposures to PA-824 are expected to be higher in Arm 2 than in Arm 1, and this will allow 
us to evaluate concentration-effect relationships when PA-824 is added to an effective first-line regimen. 
PA-824 will be given with food, which is expected to boost exposures, so exposures should be higher 
than in the DDI study of rifampin plus PA-824 because drugs were taken on an empty stomach in that 
trial.  
 
5 
DESIGN 
 
5.1 
Study treatment (First 12 Weeks) 
 
“Study treatment “is defined as the TB treatment given for the first 12 weeks, during the experimental 
phase of the trial.  These 12 weeks of study treatment includes the Intensive Phase (first 8 weeks) of TB 
treatment and four weeks of the Continuation Phase. This study will be a prospective, open-label Phase 
2B clinical trial.  Adult pulmonary TB suspects who meet eligibility criteria will be randomized to receive 
one of the following three regimens 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 26 of 56 
 
 
 
Arm 
Weeks 0-8 
(Intensive phase) 
Weeks 9-12 
(First 4 weeks of the continuation phase) 
1 
PaHRZ 
PaHR 
2 
PaHRbZ 
PaHRb 
3 (standard Rx) 
EHRZ 
HR 
 
 
Vitamin B6 (pyridoxine) 50 mg will be administered with each dose of isoniazid 
 
All treatment will be administered once daily, 7 days per week.  Study medication doses will be directly 
observed by study personnel, a designated healthcare worker, or a lay treatment supervisor who is aware 
of the study protocol and has received training in study procedures.  
 
PA-824 will be given at a dose of 200 mg once daily, recommended to be taken with food.  Exact doses 
of the other study medications are given in Table 2 below.  Pyrazinamide and ethambutol doses should be 
based on weight at the time of study entry, and should not be increased if weight increases during the 
intensive phase. 
 
The duration of the intensive phase of therapy will be determined by the number of doses ingested, not by 
calendar time.  Patients will complete the intensive phase when they have had 56 doses.  The total 
duration of study treatment will be determined by the number of doses ingested, not by calendar time.  
Patients will complete study treatment when they have had 84 doses.    
  
    
Table 2. Doses of isoniazid, rifampin, pyrazinamide, and ethambutol during the intensive phase 
 
Drug 
Dose 
Isoniazid 
300 mg 
Rifampin 
600 mg 
Rifabutin 
300 mg 
Pyrazinamide 
 
     < 55 kg 
1000 mg 
     ≥ 55-75 kg 
1500 mg 
     > 75 kg 
2000 mg 
Ethambutol 
 
     < 55 kg 
800 mg 
     ≥ 55-75 kg 
1200 mg 
     > 75 kg 
1600 mg 
 
 
 
5.2 
Non-experimental continuation phase treatment 
Study follow-up will continue during the non-experimental component of the continuation phase 
of TB treatment (Weeks 13-24).  Since study endpoints will already have been reached by Week 
12 and data collected, the composition and duration of non-experimental continuation phase 
treatment will not affect study results.   
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 27 of 56 
 
After completing the experimental phase of therapy, patients in all study arms will be treated 
with standard, non-experimental continuation phase treatment in accordance with South African 
care standards.   
 
5.3 
Endpoints 
 
Primary Endpoints:  
(1) Time to sputum culture conversion in liquid media, defined as the time from the start of treatment 
until the first negative sputum culture, over 12 weeks 
(2) Proportion of subjects with a severe adverse event (defined as grade 3, 4, or 5 adverse event) 
 
Secondary Endpoints:  
(1) Discontinuation of study treatment for any reason. 
(2) Time to sputum culture conversion in solid media, defined as the time from the start of treatment 
until the first negative sputum culture, over 12 weeks 
(3) Proportion of participants with sputum culture conversion at 8 weeks or at 12 weeks (separately, on 
solid and liquid media). 
(4) The rate of change in time to sputum culture positivity (TTP) through 12 weeks in the Mycobacterial 
Growth Indicator Tube (Bactec MGIT960) system in sputum over 12 weeks in participants, which 
may be described with linear, bi-linear or non-linear regression of TTP on time 
(5) Pharmacokinetics (PK) of PA-824 delivered at a dose of 200 mg once daily in the context of 
multidrug treatment for TB 
(6) Pharmacokinetic/pharmacodynamic (PK/PD) relationship between PA-824 exposures (area under the 
concentration-time curve (AUC) or maximum concentration (Cmax)) and outcomes (time to culture 
negativity or rate of change in TTP over 12 weeks) using non-linear mixed effects modeling 
 
5.4  
Study drug descriptions 
5.4.1  PA-824 
 
PA-824 is an investigational nitroimidazole being developed for the treatment of TB. It interferes with 
cell wall biosynthesis and may have other mechanisms of action as well in nonreplicating bacteria. 
 
PA-824 Pharmacokinetics:  At a dose of 200 mg, steady state PK parameters are as follows: Cmax 1.7 
mcg/mL, time to maximum concentration (Tmax) 4.5 hours, half-life (t1/2) 16.0 hours, AUC0-tau 30.2 
mcg*h/mL, and CL/F 6.7 L/h. Food increases bioavailability, particularly at higher doses, with a high-fat, 
high-calorie meal increasing Cmax of a 200 mg dose by 75% and AUC by 88% when compared to the 
fasting state (31). After being absorbed, PA-824 is extensively metabolized (<5% is recovered as parent 
drug in urine and feces) to multiple metabolites. In the human, the metabolism of [14C]-PA-824 proceeds 
via a combination of reductive metabolism (~20–25% of the dose) and oxidative metabolism (remainder 
of the dose). No single metabolite is predominant, and the most prominent component in the plasma is 
radiolabelled parent drug. The drug and its metabolites are largely eliminated in the urine (53-65%) and 
feces (26-38%). Clearance is not time- or dose-dependent. 
 
Drug-Drug Interactions:  Liver microsome studies were performed to assess the potential of PA-824 to 
inhibit or induce human cytochrome P450 (CYP) isoenzymes (31). PA-824 did not induce isoforms 3A4, 
2C9, or 2E1 in vitro but is a weak competitive inhibitor of CYP3A in other experiments. PA-824 also 
inhibited 2C8, 2C9, and 2C19. PA-824 is not a substrate for 2C9, 2C19, or 2D6. It is 20% metabolized by 
3A4. In a clinical drug interaction study using midazolam as a CYP3A probe, PA-824 dosed at 400 mg 
daily decreased midazolam Cmax and AUC0-inf by 16% and 15%, respectively, a difference not likely to be 
clinically significant. In a drug interaction study with efavirenz, a CYP2B6 substrate, preliminary results 
suggest that PA-824 did not change efavirenz concentrations; efavirenz reduced PA-824 AUC by about 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 28 of 56 
 
35% (32). Rifampin reduced PA-824 concentrations by about 65%. Ritonavir-boosted lopinavir reduced 
PA-824 concentrations modestly (about 15%), and PA-824 did not alter lopinavir concentrations 
appreciably. Participants in the drug interaction study did not take isoniazid, a known inhibitor of 
metabolizing enzymes, with rifampin, so the combined effects of the two drugs on companion drug 
concentrations are unknown. 
 
Dosage:  PA-824 is being studied in subjects with TB at doses of 100 mg and 200 mg daily to be 
administered orally for the treatment of human TB. PA-824 is available in tablet form containing 50 mg, 
100 mg, or 200 mg of PA-824.  
 
Tolerability:  In the clinical trials of PA-824 to date, multiple dosing of PA-824 has extended for as long 
as 56 days.  As described in detail above, the most common side effects or AEs associated with PA-824 
exposure include: 
Headache 
Benign, isolated and reversible elevations of serum creatinine 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea) 
Skin and subcutaneous tissue disorders 
 
Refer to section 4.1 for detailed safety information related to PA-824. 
 
5.4.2 
Rifampin 
 
Rifampin is a semi-synthetic rifamycin derivative that is highly active against mycobacteria, most gram-
positive bacteria, and some gram-negative bacteria. It is bactericidal for both intracellular and 
extracellular microorganisms. By inhibiting prokaryotic DNA-dependent RNA polymerase, it suppresses 
the early elongation of the nucleotide chain in RNA synthesis.  
 
Pharmacokinetics:  Rifampin is normally absorbed completely when taken orally, but food delays 
absorption. After 1.5 to 2 hours, a 600 mg dose yields a peak blood level of 8-20 mcg/mL. The half-life of 
rifampin varies from 2 to 5 hours, and it is shortened by approximately 20-40% after the first week of 
daily treatment because of the induction of hepatic microsomal enzymes. The half-life is unaffected by 
renal impairment but is increased by liver disease or biliary obstruction. Rifampin is deacetylated to an 
enterohepatically recirculated active metabolite, and 50% to 60% is excreted in the feces. Up to 30% of a 
dose is excreted in the urine. Approximately 85% of circulating rifampin is bound to plasma proteins, and 
is widely distributed throughout the body.  
 
Drug-drug interactions:  Rifampin is an inducer of a number of hepatic enzymes involved in the 
metabolism of drugs and some hormones. This enzyme induction causes more rapid elimination (and 
potential loss of efficacy) of many drugs. Medications for which concomitant rifampin is contraindicated 
include: HIV-1 protease inhibitors (other than ritonavir), delavirdine, cyclosporine, tacrolimus, 
itraconazole, and ketoconazole.For many other medications, the dose can be increased to compensate for 
the effect of rifampin. 
 
Dosage:  The recommended dose of rifampin for the treatment of TB during the intensive phase is 600 
mg. Rifampin is available in 150 mg or 300 mg capsules. In this study, rifampin will be provided at a 
dose of 600 mg daily. 
 
Tolerability:  In the usual daily dose of 600 mg, rifampin is well tolerated. It often causes harmless but 
disconcerting red-orange discoloration of tears, sweat, saliva, feces, and urine. Less than 4% of TB 
patients experience significant adverse reactions to rifampin. Gastrointestinal AEs are the most common, 
and they include epigastric distress, anorexia, nausea, vomiting, cramps, and diarrhea. Hepatitis rarely 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 29 of 56 
 
occurs in persons who have normal baseline hepatic function. The incidence of hepatitis may be increased 
for older persons and those who have chronic liver disease or alcoholism, but remains substantially lower 
than that for pyrazinamide or isoniazid. Rifampin can cause a flu-like syndrome of fever, chills, and 
myalgia, although this is uncommon using the 600 mg dose given daily or thrice-weekly. In a very small 
proportion of patients the flu-like syndrome is associated with interstitial nephritis, acute tubular necrosis, 
thrombocytopenia, hemolytic anemia, and shock. There may be changes in menstruation. 
 
5.4.3 
Rifabutin 
 
Rifabutin is a semisynthetic ansamycin antibiotic derived from rifamycin S.  It inhibits DNA-dependent 
RNA polymerase and is active against E. coli, Bacillus subtilis, Mycobacerium avium, M. intracellulare, 
and M. tuberculosis.  
 
Pharmacokinetics:  Following a single oral dose, rifabutin is rapidly absorbed reaching peak 
concentrations in 2 to 3 hours.  Peak concentrations increase proportionally with dose over the range of 
300 mg, 600 mg, 900 mg, and 1200 mg.  The terminal half-life is approximately 38 hours. Rifabutin has 
high lipophilicity with an apparent steady-state distribution volume of 9.3L/kg.  It is 85% protein-bound, 
and protein binding is concentration-independent.  Following 28 days of oral dosing of rifabutin, the 
steady-state AUC is lower than the first dose AUC at each of the four dose levels.  At the 300 mg daily 
dose, the AUC was approximately 30% lower on day 28 than on day 1.  The modest decrease in AUC 
following 4 weeks of administration of rifabutin is presumed to be due to auto-induction of its 
metabolism.  Bioavailability of rifabutin is about 20% following the first dose and 12% after multiple 
doses.  High-fat meals slow the rate of absorption but do not alter the extent of absorption.  Following the 
oral administration of 14C-rifabutin (solution), 52.9% of the administered dose was excreted in the urine, 
predominantly as metabolites and 29.4% of the administered dose was recovered in feces.  Rifabutin was 
the primary circulating compound with 31-OH rifabutin and 25-O-desacetyl-rifabutin produced by 4 
hours.  The 25-O-desacetyl metabolite has antimicrobial activity equal to the parent on a molar basis but 
the AUC ratio of parent to metabolite is approximately 10:1.  Rifabutin undergoes extensive metabolism, 
along with 31-OH and 25-O-desacetyl-rifabutin, three other urinary metabolites have been identified.  
Based on the urinary metabolites, the primary routes of metabolism are deacetylation and oxidation; 
CYP3A plays a role in rifabutin metabolism. 
 
Drug-drug interactions:  Rifabutin is chemically related to rifampin, a potent inducer of P450 enzymes, 
including those of the CYP3A family.  Rifabutin appears to induce P450 enzymes as well, although not as 
potently as RIF, as judged by effects on markers of P450 activity in humans. Thus, when given together 
with companion drugs that are metabolized by P450 enzymes, induction of metabolism is expected, 
though the magnitude of the drug interaction, if any, is generally not clinically significant.  In addition, 
rifabutin is a CYP3A substrate. Drugs that inhibit CYP3A4 can increase rifabutin concentrations.  
 
Dosage:  The recommended dosage for rifabutin is 300 mg once daily. Dose adjustments are necessary 
for patients with severe renal impairment or for patients taking certain concomitant drugs. For this study, 
RBT will be given at a dose of 300 mg once daily, during the experimental phase, the standard treatment 
dose for TB. 
Tolerability:  In two pivotal trials (n=566 rifabutin and n=550 placebo), clinical adverse events occurring 
at >1% of patients include rash, gastrointestinal intolerance and neutropenia.  Discoloration of urine 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 30 of 56 
 
occurred in >30% of patients on RBT.  In <1% of the patients, flu-like syndrome, hepatitis, chest pressure 
and pain with dyspnea and skin discoloration occurred.  Increased alkaline phosphatase, SGOT, and 
SGPT occurred similarly in the rifabutin and placebo groups.  There were no reported incidences of 
hyperbilirubinemia noted in the reports of these studies.  Incidence of neutropenia is more common with 
rifabutin than with placebo.  Uveitis is rare when given at 300 mg per day, but dose-limiting uveitis 
occurs at higher doses. 
 
5.4.4   Isoniazid 
 
Isoniazid is the hydrazide of isonicotinic acid and is one of the primary drugs for TB treatment.  The 
activity of isoniazid is limited to the mycobacteria of the M tuberculosis complex; it is bactericidal for 
rapidly dividing organisms and bacteriostatic for “resting” bacilli.  The probable mechanism of action is 
the inhibition of the biosynthesis of mycolic acids, a component of the mycobacterial cell wall.   
 
Isoniazid Pharmacokinetics:  Isoniazid is generally well absorbed; food and antacids decrease the rate, 
but not the extent of absorption. The peak blood levels of isoniazid, 3 to 5 mcg/ml, are obtained 30 
minutes to 2 hours after ingestion of routine doses.  It diffuses into all body fluids and cells and penetrates 
into the caseous material of a tuberculoma or pulmonary cavity.  In the liver, it is acetylated to inactive 
metabolites, and 75% to 95% of the dose is excreted as inactive metabolites in the urine within 24 hours.  
Isoniazid clearance rates depend on 2 metabolic phenotypes, slow and fast acetylation. The isoniazid 
AUC among persons who have fast acetylation is 30% to 50% of that among persons who have slow 
acetylation.  Because isoniazid is well tolerated over a wide range of therapeutic doses, a single dose per 
body mass is recommended.  Persons who have rapid acetylation achieve effective concentrations, while 
persons who have slow acetylation do not experience increased toxicity.  Half-life (t1/2) may vary from 1 
hour in fast acetylators (t1/2 < 90min) to 3 hours in slow acetylators (t1/2 >90min). 
 
Isoniazid Drug-drug interactions:  Isoniazid decreases the clearance of some medications that are 
metabolized in the liver (particularly carbamazepine, phenytoin, diazepam).   
 
Isoniazid Toxicity:  The total incidence of all adverse effects from isoniazid is approximately 5%, many 
of which do not require discontinuation of the drug.  Peripheral neurotoxicity is dose dependent and it is 
uncommon (<0.2%) at conventional doses. The risk of peripheral neuritis increases for persons who are 
malnourished or predisposed to neuritis by other illnesses.  Concomitant administration of pyridoxine 
(vitamin B6) is recommended for these persons and will be given to all patients receiving isoniazid in this 
trial.  Other nervous system reactions are rare at normal doses, and they include convulsions, 
encephalopathy, optic neuritis, memory impairment, and psychosis.  Gastrointestinal adverse effects 
include nausea, vomiting, and epigastric distress.  Asymptomatic elevation of aminotransferases is 
common and occurs in 10-20% of persons receiving isoniazid. However, idiosyncratic severe hepatic 
reactions are uncommon but are more likely in older persons (up to 2.3% hepatitis incidence in persons 
more than 50 years old), and may be life threatening.  Daily consumption of alcohol increases the risk of 
isoniazid-associated hepatotoxicity by approximately 4-fold.  The risk of isoniazid-induced hepatotoxicity 
may also be increased in the postpartum period. The prodromal symptoms of hepatotoxicity are anorexia, 
nausea, vomiting, fatigue, malaise, and weakness; persons who take isoniazid and have these symptoms 
should stop therapy and be evaluated immediately.  
 
5.4.5   Pyrazinamide 
 
Pyrazinamide is an analog of nicotinamide and has unique activity against M tuberculosis, allowing the 
duration of treatment to be decreased from 9 months to 6 months (assuming rifampin is used throughout).  
The mechanism of action of pyrazinamide remains unknown. 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 31 of 56 
 
 
Pyrazinamide Pharmacokinetics.  Pyrazinamide is well-absorbed from the gastrointestinal tract and 
widely distributed into all tissues. Usual doses are 15-30 mg/kg/d, up to 2 gm/d.  Peak serum 
concentrations of about 45 mcg/ml are achieved approximately 2-3 hours after a dose. Food and antacids 
do not significantly affect the absorption of pyrazinamide.  The half-life of pyrazinamide is approximately 
9-10 hours, and is prolonged in the presence of hepatic insufficiency.  Pyrazinamide is metabolized to 
pyrazinoic acid by the hepatic microsomal enzyme pyrazinamide deamidase.  Approximately 40% of a 
dose is recovered in the urine as pyrazinoic acid and an additional 4% is excreted in the urine as the 
unchanged parent drug.  The remaining drug is thought to be excreted in the bile.   
 
Pyrazinamide Drug-drug interactions:  There are no known clinically significant drug-drug interactions 
involving pyrazinamide. 
 
Pyrazinamide Toxicity:  The most frequent side effects are skin rash, gastrointestinal intolerance, 
hepatotoxicity (1.3%), arthralgias (1-7%), hyperuricemia due to blockade of urate excretion (up to 66%), 
and rarely acute gouty arthritis.  These side effects are seldom dose-limiting. Asymptomatic elevations in 
serum uric acid are frequent, usually occur during the first or second month of treatment, and are self-
limited and require no specific treatment. Minor arthralgias also may occur during pyrazinamide 
treatment and can usually be treated with salicylates or non-steroidal inflammatory agents such as 
indomethacin while continuing the drug.  The most common serious side effect of pyrazinamide is 
hepatotoxicity.   
 
5.4.6   Ethambutol 
 
Ethambutol is an ethylene derivative of butane that interferes with cell wall synthesis in mycobacteria; 
other bacteria are uniformly resistant to ethambutol.  In the treatment of human TB, ethambutol is 
effective in preventing the emergence of drug resistant strains, although it has no sterilizing activity at 
clinically-tolerated doses. 
 
Ethambutol Pharmacokinetics:  Ethambutol is well absorbed from the gastrointestinal tract, reaching peak 
serum concentrations of 3-5 mcg/ml in normal volunteers 2-4 hours after a dose.  Food slows absorption 
and decreases the peak serum concentration by 10-20%, but has no effect on the total systemic exposure 
(AUC).  Antacids decrease both the peak serum concentration and AUC, and so should not be 
administered at the same time.  Ethambutol is primarily eliminated by the kidneys as unchanged drug; the 
serum half-life averages 4 hours.   Patients with renal insufficiency are prone to accumulation of the drug 
and the resultant toxicity. 
 
Ethambutol Drug-drug interactions:  There are no known drug–drug interactions involving ethambutol. 
 
Ethambutol Toxicity:  Ethambutol is usually well-tolerated with low rates of skin rash, nausea, vomiting, 
or diarrhea.  Fever, allergic reactions, abdominal pain, mental status changes, peripheral neuropathy, and 
increased liver function tests have rarely been associated with ethambutol.  Adverse events occur in less 
than 2% of patients receiving ethambutol at the 15 mg/kg dose and include decreased visual acuity 
(0.8%), rash (0.5%) and asymptomatic hyperuricemia. The most common serious side effect of 
ethambutol is retinal toxicity, often first perceived as a decrease in color perception.  Patients receiving 
ethambutol should be instructed about symptoms of ocular toxicity.  If stopped promptly, permanent 
visual loss is rare among patients with ethambutol-related retinal toxicity.  Rates of retinal toxicity are 
very low when the drug is given for relatively short periods, as is the case in this study. 
 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 32 of 56 
 
5.5 
Study drug supply and accountability 
 
PA-824, formulated as 200 mg tablets, will be obtained from the Global Alliance for TB Drug 
Development (“TB Alliance”). Rifampin, rifabutin, isoniazid, pyrazinamide, and ethambutol will each be 
obtained from local suppliers compliant with Good Manufacturing Practice Regulations.  The investigator 
will acknowledge receipt of and keep an inventory of all study drug supplied for this study.  Study staff 
has the responsibility to assure that study drugs are dispensed to patients in compliance with the protocol.  
Procedures for drug handling and storage will be described in the study site SOPs.  
 
5.6 
Randomization  
 
This will be a randomized trial.  Trial randomization will be computer-generated.  Eligible patients (who 
meet all of the inclusion criteria and none of the exclusion criteria) will be randomized in a 1:1:1 ratio to 
the study arms.     
 
Randomization will be stratified by the presence of cavitation at baseline (time of diagnosis), since 
cavitation is associated with a decreased rate of 2-month culture conversion, and HIV status.  Cavitation 
is defined as a gas-containing lucent space at least 1 cm in diameter within the lung parenchyma 
surrounded by an infiltrate or fibrotic wall greater than 1 mm thick seen on a standard chest radiograph 
(cavitation seen only on chest CT does not satisfy this definition).  
 
This will be an open-label trial in which neither the subjects nor the study staff will be blinded as to 
treatment assignment after randomization.  However, microbiologists performing mycobacterial cultures 
and statisticians will be blinded as to treatment assignment of individual patients. 
 
6 
POPULATION 
 
6.1 General Considerations 
 
Study entry is open to males and females age 18 years or older of any ethnic background who meet study 
eligibility criteria. Historically, approximately 60% of patients with TB at clinical sites are males.  The 
gender, ethnicity, and socioeconomic background of study subjects are expected to mirror that of the 
population served by the study site, and that of the population most affected by TB.  Study subjects will 
be recruited from the hospital and clinics of the University of Cape Town, South Africa.   
  
6.2 Special Populations 
 
6.2.1 
Children, Pregnant Women, and Breast-Feeding Women 
Children and pregnant or breast-feeding women will not be enrolled because of uncertainties about the 
safety of PA-824 in these groups of patients.  Further, dose equivalence studies have not been performed 
in pediatric patients. 
 
6.2.2 
Prisoners 
This study will not enroll prisoners.  However, it is possible that a participant will be incarcerated after 
enrollment.  If an enrolled individual is incarcerated, then study medications will be stopped and the 
participant will be treated for active TB according to the standards of the institution in which s/he is 
incarcerated.  While incarcerated, individuals will not be followed in the study.  When the individual is no 
longer incarcerated, study follow-up may continue, at the discretion of the investigator.  
 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 33 of 56 
 
6.2.3 
HIV-Positive Individuals  
 
HIV-negative individuals and HIV-positive individuals with CD4 > 350 cells/cu mm will be included in 
this study.  HIV-positive individuals with CD4 <350 cells/mm3 will not be included in this study, as these 
patients may be better served by individualized (non-study) TB and HIV therapy.  If one or both of the 
proposed experimental regimens is demonstrated to be effective and safe in this study, then subsequent 
future studies including individuals with advanced AIDS may be warranted.  Since drug-drug interactions 
between rifampin and protease inhibitors or nevirapine can compromise HIV treatment, patients with HIV 
co-infection who are receiving protease inhibitors or nevirapine will not be enrolled in this study. Further, 
patients taking efavirenz require a dose adjustment of rifabutin to 450 mg, and variability in dosing in the 
experimental regimen may compromise study results, so EFV use will not be permitted. Patients who, 
based on study testing, are newly identified to be HIV positive will receive individualized counseling 
about the risks and benefits of study therapy and delay of antiretroviral therapy.  Individuals in whom 
prompt initiation of antiretroviral therapy is clinically indicated and appropriate will not be enrolled in the 
study.  If a participant is already enrolled in the study, they will be taken off of study medicines and 
referred to the clinics for treatment with individualized (non-study) TB and HIV therapy.       
 
6.3 Inclusion Criteria 
 
Subjects must meet all inclusion criteria in order to participate in this study. 
1. Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated sputum 
at Screening.  Patients having extra-pulmonary manifestations of tuberculosis, in addition to 
smear-positive pulmonary disease, are eligible for enrollment.   
 
 
2. Age > 18 years 
 
3. Weight ≥ 40 kg and ≤ 80 kg 
 
4. Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of 
his/her needs; see Appendix B) 
 
5. Signed informed consent 
 
6. HIV negative, or positive with CD4 ≥350 cells/cu mm and not currently taking or planning to 
take combination antiretroviral therapy for HIV during the experimental phase of the treatment. 
 
7. Ability to adhere with study follow-up 
 
8. Contraceptive requirements 
 
Females may participate if they are: 1) of non-childbearing potential (have had a bilateral 
oophorectomy, tubal ligation and/or hysterectomy or have been postmenopausal for at least 12 
consecutive months), 2) if they are using effective birth control methods and are willing to continue 
practicing birth control methods throughout treatment or 3) practice sexual abstinence or have a 
vasectomized male partner (confirmed sterile), or have a female partner. Therefore to be eligible 
for this study women of childbearing potential should either: 1) use a double barrier method to 
prevent pregnancy (i.e. use a condom with either diaphragm or cervical cap) or 2) use hormonal 
based contraceptives in combination with a barrier contraceptive, or 3) use an intrauterine device 
in combination with a barrier contraceptive. They must also be willing to continue these 
contraceptive measures until one week after the last dose of study medication or one week after 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 34 of 56 
 
discontinuation from study medication in case of premature discontinuation. (Note: Hormone-
based contraception alone may not be reliable when taking rifampin-containing TB regimens; 
therefore, hormone-based contraceptives alone cannot be used by female participants to prevent 
pregnancy). 
 
Male participants who are having heterosexual intercourse with females of child-bearing potential 
are required to use one of the following birth control methods during their participation in the trial 
and for 12 weeks after their last dose of study medication to prevent pregnancy:      
 
- a double barrier method which can include a male condom, diaphragm, cervical cap, or female 
condom; or 
-a barrier method combined with hormone-based contraceptives or an intra-uterine device for the 
female partner.   
The use of the above mentioned birth control method does not apply if the male participant has 
been vasectomised or has had a bilateral orchiectomy minimally one month prior to screening, or 
is not heterosexually active, or practices sexual abstinence or if the female sexual partner has had 
a bilateral oophorectomy, tubal ligation and/or hysterectomy or has been postmenopausal for at 
least 12 consecutive months.  
 
 
6.4 Exclusion Criteria 
 
All subjects meeting any of the following exclusion criteria at baseline will be excluded from study 
participation: 
 
1. Pregnant or breast-feeding 
 
2. Known intolerance or allergy to any of the study drugs 
 
3. Concomitant disorders or conditions for which isoniazid, rifampin, rifabutin, pyrazinamide, or 
ethambutol is contraindicated.  These include severe hepatic damage, acute liver disease of any 
cause, allergy to the drug, and acute uncontrolled gouty arthritis. 
 
4. Current or planned therapy, during the intensive phase of TB therapy with cyclosporine or 
tacrolimus, which have unacceptable interactions with rifamycins.   
 
5. Any medical or psychosocial condition, which, in the view of the study investigator, makes study 
participation inadvisable.   
 
6. Pulmonary silicosis 
 
7. Central nervous system TB 
 
8. ECG at screening with QTc (Fridericia correction) interval >450 ms or any clinically-significant, 
in the opinion of the investigator, ECG abnormality 
 
9. History and/or presence (or evidence) of neuropathy or epilepsy.   
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 35 of 56 
 
10. History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic examination with 
a value of 1.0 or higher on AREDS2 Clinical Lens Opacity Classification and Grading System 
scale. 
 
11. Infection with an isolate known to be resistant to a first-line TB drug (for example, patients with 
Gene Xpert screening through the local TB program with results suggesting resistance to 
rifampin) 
 
12. Laboratory parameters done at, or £ 14 days prior to, screening (with results available for review 
by study personnel) demonstrating any of the following: 
• 
Serum alanine aminotransferase (ALT) activity > 3 times the upper limit of normal 
• 
Serum total bilirubin level >  2 times the upper limit of normal 
• 
Serum creatinine greater than the upper limit of normal 
• 
Hemoglobin level less than 7.0 g/dL 
• 
Platelet count less than 100,000/mm3 
• 
Positive pregnancy test (women of childbearing potential) 
 
       13.  More than five days of treatment directed against active tuberculosis in the past 6 months 
 
7 
STUDY SCHEDULE 
 
7.1 Screening Visit 
 
Subjects with a presumptive diagnosis of sputum smear positive pulmonary TB will be invited to 
participate.  Because culture confirmation is rarely available when TB treatment is initiated, patients will 
be recruited based on having a sputum smear that is positive for acid fast bacilli or a sputum specimen 
that is positive for TB by Gene Xpert.   
 
Informed written consent, using IRB-approved consent forms, will be obtained by trained study personnel 
prior to performing any study-specific procedures.  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.  The informed consent process is described in detail in the “Study Procedures” 
section.   
 
The following will be performed after obtaining written informed consent: 
• 
Eligibility criteria will be confirmed 
• 
Participants will be asked questions related to demographics, current and past medical history, 
medications they are taking, alcohol, TB symptoms, and TB risk factors.  They will be advised 
that they can decline to answer any question they consider too personal. 
• 
An expectorated sputum sample will be obtained for smear, culture, and drug susceptibility 
testing at the study laboratory.    
• 
Participants will have heart rate, blood pressure, respiratory rate, temperature, height and weight 
measured 
• 
Blood will be drawn for a CBC and serum creatinine, ALT, total bilirubin, albumin and 
potassium, unless results from these tests within the previous 14 days or less are available. 
• 
All participants will undergo HIV testing and counseling regardless of whether they have had a 
previous HIV test or not. HIV testing will be carried out with two rapid tests (the second test will 
be to confirm the result of the first); only one test need be carried out if the subject is known to 
have HIV, the single test will be confirmatory. Should there be a discrepancy between the two 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 36 of 56 
 
rapid tests, blood will be sent to the laboratory for enzyme-linked immunosorbent assay Elisa and 
Western Blot test in order to confirm the diagnosis. 
• 
For HIV-positive participants, a CD4 count should be performed unless written results are 
available from a test done within the preceding 3 months or less. 
• 
Urine will be collected for pregnancy testing if a woman is of child-bearing potential. 
• 
A posterior anterior chest radiograph will also be taken, unless a posterior anterior chest 
radiograph done within the previous 14 days or less is available for review.  The chest radiograph 
must be read prior to randomization.   
• 
Visual acuity testing and color vision perception testing will be performed. Slit lamp 
ophthalmologic examination will be performed to rule out opacities (cataracts). 
• 
An ECG will be performed 
 
Screening evaluations may be done in the context of one or more visits. For example, ophthalmologic 
examination may be performed after other screening tests indicate that the patient is likely to meet the 
criteria for study inclusion. 
 
7.2 
Baseline Visit 
 
The baseline visit is defined as the visit at which study drug treatment is initiated.  The baseline visit (and 
initiation of study drug treatment) should occur as soon as feasible after randomization. The Baseline visit 
may be done as soon as the Screening results are available, even if this occurs on the same day as a 
Screening test is performed. 
Procedures to be performed at the Baseline Visit 
• 
Review of eligibility criteria 
• 
Review of concomitant medications 
• 
Targeted symptom assessment 
• 
Measurement of weight 
• 
Interval medical history 
• 
Pregnancy evaluation 
• 
Vital signs (heart rate, blood pressure, respiratory rate, temperature) 
• 
Sputum obtained for smear and culture 
• 
Counseling about study procedures and drug toxicity 
 
 
Participants who continue to meet eligibility criteria will be started on study drug treatment.  Instructions 
for administering study drugs are provided in the “Administration of Study Drugs” section.  
Any residual sputum sample may be stored for future testing.    
Participants who no longer meet eligibility criteria may 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.   
 
7.3 Study Visits During Experimental Phase of TB Treatment (Weeks 0-12) 
 
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 this context, 
participants will be queried about signs/symptoms potentially related to drug toxicity at the time of 
medication doses 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.   


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 37 of 56 
 
 
 
Study Visits at Days 7, 14, 21, 28, 42, 56, 70, (all +/- 2 days) and 84 (+5days)  
 
The following will be performed: 
• 
Targeted symptom assessment 
• 
Interval medical history 
• 
Adverse event assessment 
• 
Pregnancy evaluation 
• 
Concomitant medication assessment 
• 
Vital signs (heart rate, blood pressure, respiratory rate, temperature) 
• 
Measurement of weight 
• 
Sputum obtained for smear and culture. Two sputum samples will be obtained at Day 84 visit. 
Drug susceptibility testing will performed on Day 56 and/or Day 84 positive cultures as relevant. 
• 
Counseling about study procedures and drug toxicity 
 
In addition,  
• 
Complete blood count, serum creatinine, alanine aminotransferase (ALT), total bilirubin will be 
performed at days 7, 14, 28, 42, 56, and 84.  ALT and bilirubin will be collected on Day 21 
• 
Single 12-lead ECG will be performed on Days 7 and 28 
• 
Testing of visual acuity and color perception should be performed at the Day 28 study visit 
• 
Semi-intensive PK sampling will be performed on day 14 (+5) days (see Section 8.13) for 
patients in Arms 1 or 2 
• 
Sparse PK samples will be collected on days 28, 56, and 84 for patients in Arms 1 or 2 
 
7.4 
Study Visits During Non-Experimental Continuation Phase TB Treatment (Weeks 13-24) 
and Following Completion of Treatment 
 
Week 16 and Week 24 (+/- 7 days) Study Visits 
The following will be performed: 
• 
Targeted symptom assessment 
• 
Interval medical history 
• 
Review of interval TB treatment 
• 
Concomitant medication assessment at Week 16 in case of Grade 1 or higher AE/SAE 
• 
Measurement of weight 
• 
Sputum will be obtained for smear and culture 
 
Adverse event assessment and counseling about study procedures and drug toxicity will be performed at 
the Week 16 visit. In addition, ophthalmologic examination (including visual acuity and color perception) 
will be performed at the Week 24 visit. Arms 1 and 2 participants will also undergo slit-lamp 
ophthalmologic examination. 
 
Week 48 (+/- 7 days) Study Visit 
The following will be performed. This visit can also be conducted via the phone at the investigator’s 
discretion and participant availability. 
• 
Targeted symptom assessment 
• 
Interval medical history 
  
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 38 of 56 
 
Additional investigations may be conducted at the investigator’s discretion should active TB be 
suspected. 
 
7.5 Early withdrawal 
In case of early withdrawal during the study treatment period of the study (prior to Day 84), all efforts 
shall be made to complete the Early Withdrawal assessments as soon as possible or within 7 days of site 
notification of the participant withdrawal.  At the early withdrawal visit the following information will be 
collected and procedures performed: 
• 
Interval medical history 
• 
Adverse event assessment 
• 
Pregnancy evaluation 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
Targeted symptom assessment 
• 
Complete blood count 
• 
Serum creatinine, alanine aminotransferase (ALT), total bilirubin 
• 
12-lead ECG 
• 
Single sample for PK evaluation (Arms 1 and 2), if study drug has been given within 24 hours of 
the visit 
 
7.6 Unscheduled visit 
In the case of an unscheduled visit, the following should be performed as relevant, based on the 
judgement of the site team. 
 
       ●12 lead ECG 
       ● Targeted symptom assessment 
       ●Vital signs (heart rate, blood pressure, respiratory rate, temperature) 
       ●Measurement of weight 
       ●Counseling about study procedures and drug toxicity 
       ●Sputum obtained for smear and culture 
       ●Pregnancy evaluation 
       ●Poster anterior chest radiograph 
       ●Complete blood count, 
       ●Serum creatinine, alanine aminotransferase (ALT), total bilirubin 
 
 
 
8 
STUDY PROCEDURES 
 
8.1 Informed Consent Process 
 
Informed written consent, using IRB-approved consent forms, will be obtained by trained study personnel 
prior to performing study-specific procedures.  Potential subjects will receive information about risks and 
possible benefits of study participation, study objectives and procedures, potential toxicities, and the 
informed consent process.  Informed consent requires the signature or mark of the subject.  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, and that they may withdraw 
consent at any time.  Individuals who choose not to participate in the study will be referred to local 
sources of TB care.  


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 39 of 56 
 
 
 
8.2 Administration of Study Drugs 
 
Patients should start on assigned study therapy as soon as possible after randomization.  Doses of study 
therapy will be given as directly observed therapy (DOT) by study personnel, or by a health care worker 
or lay treatment supervisor who is aware of the study protocol and trained regarding the study protocol.  
Alternatively, doses of study therapy can be given via DOT by a family member or employer who has 
been trained by the study team.  Adherence will be confirmed by review of the participant’s treatment 
card, and retraining of the DOT provider will be provided if needed. DOT may be administered at the TB 
clinic or other health care facility, or, with the subject’s permission, at the subject’s residence, workplace, 
or other mutually agreed upon location convenient for the subject.  
 
During the first three months of treatment (experimental phase), study treatment will be 7 days per week.  
During the experimental phase, non-study TB treatment, either in addition to or in place of study drugs, 
should not be given.   
 
 
8.3 Obtaining Sputum Specimens 
 
Sputa should be obtained by spontaneous expectoration whenever feasible.  Sputa should be refrigerated 
at approximately 4◌۫ C after collection, and transported to the laboratory as soon as possible but within 2 
working days of collection (i.e. received in the laboratory within 2 working days of collection). 
 
8.4 Laboratory Aspects of Sputum Analysis 
 
Laboratory evaluation of sputa will be performed at a qualified mycobacteriology reference laboratory in 
Cape Town and will be done according to detailed written lab SOPs.  Briefly, sputa will be homogenized 
and decontaminated using the NALC-NaOH method.  Fluorescence smear microscopy will be performed 
on an aliquot of the concentrated processed specimen.  Aliquots will be added to Lowenstein Jensen 
(solid) media and MGIT (liquid) media.  Nucleic acid and/or biochemical methods will be used for 
mycobacterial species determination.  Quality monitoring procedures will be documented, and laboratory 
activities will be subject to regular study monitoring.  
 
8.5 Drug Susceptibility Testing 
 
Pre-treatment isolates of Mycobacterium tuberculosis collected at screening will undergo conventional 
drug susceptibility testing to isoniazid and rifampin.  Susceptibility testing to, pyrazinamide, ethambutol 
and PA-824 may also be performed pending availability of drug susceptibility testing for these drugs. 
Susceptibility testing will performed on Day 56 and/or Day 84 positive cultures as relevant.   
 
8.6 Electrocardiograms (ECG) 
 
Single ECGs will be recorded for 10 seconds. Timing and registration technique for ECGs will be 
standardized for all participants.  Participants should be lying down (recumbent) for at least 5 minutes 
prior to each 12-lead ECG evaluation.  
 
8.7 Ophthalmologic examinations 
 
Visual acuity will be tested using a Snellen chart.  Color vision perception will be tested using the 
Ishihara charts to test for color-blindness. The slit lamp examination will be performed by an 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 40 of 56 
 
ophthalmologist, and results will be documented using the AREDS2 Clinical Lens Opacity Classification 
and Grading System. 
  
8.8 Review of Symptoms Since Last Study Visit 
 
Patients will be asked whether they have experienced any of the following since the last study visit: 
fevers, sweats, cough, rash, itching, jaundice, nausea, vomiting, diarrhea, loss of appetite, vision 
problems, numbness/tingling of extremities, headache, joint pain, eye pain.  In addition, patients will be 
asked whether they have had other symptoms (not listed above); if yes, then these symptoms will be 
recorded and graded. In addition, targeted diagnostic evaluations may be indicated to determine the 
underlying cause of symptoms and their association with study drug use. 
 
8.9 Concomitant Medications 
 
The use of all non-study drugs (including over-the-counter medications) from 14 days before starting 
study therapy through the end of experimental treatment will be monitored and recorded. In addition, if a 
grade 1 or higher AE or SAE occurs within 28 or fewer days after completion of experimental phase 
therapy, then the use of all non-study drugs (including over-the-counter medications) during the interval 
from study drug completion to AE/SAE onset will be recorded.  The use of all non-study drugs (including 
over-the-counter medications) will be recorded at this study visit.  
 
Concomitant antimicrobials with known antituberculous activity (amoxicillin/clavulanic acid, amikacin, 
kanamycin, streptomycin, moxifloxacin, ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin, 
gemifloxacin, linezolid, capreomycin, cycloserine, ethionamide, para-aminosalicylate sodium) should not 
be used during the study phase therapy. Any patient who receives more than 2 doses of any of the 
medications listed above will be classified as being on a non-study regimen.  Antimicrobials with no 
known antituberculous activity may be prescribed for intercurrent infections at the discretion of the 
investigator.   
 
Ethanol can exacerbate the potential hepatotoxicity of isoniazid, rifampin, and pyrazinamide.  Participants 
will be counseled to abstain from alcohol while on TB therapy. 
 
8.10 Management of Subjects Deemed Protocol Ineligible Based on Culture Results 
 
Because of the relatively slow growth of M. tuberculosis in culture, the results of sputum mycobacterial 
cultures and drug susceptibility testing are rarely available at the time of initiation of TB treatment.  
Therefore, for this study we plan to enroll patients on the basis of a positive sputum AFB smear 
microscopy result for TB. We anticipate that approximately 10% of enrollees subsequently will be 
deemed protocol ineligible based on culture results.   
 
Management of individuals having either a) NO baseline sputum culture that is positive for M. 
tuberculosis OR b) a baseline M. tuberculosis isolate that is resistant to any one or more of the following: 
rifampin and/or isoniazid and/or pyrazinamide and/or ethambutol:  these individuals will be taken off of 
their assigned study regimen, and treated with an individualized regimen at the discretion of the treating 
clinician.  All patients receiving experimental phase therapy at the time of discontinuation of the study 
regimen will have a study visit at 2 weeks after discontinuation of the study regimen for assessment of 
delayed toxicity.  
 
8.11 
Management of Subjects that are not Protocol-Correct  
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 41 of 56 
 
Some subjects may have toxicity, adherence problems, or other problems that prevent completion of 
experimental phase therapy in the protocol-correct timeframe.  These patients should continue to be 
followed in the study (unless consent is withdrawn), and continue to have protocol-specified evaluations.   
 
8.12 Compensation of Study Subjects 
 
Study subjects will be compensated for their time and travel to and from study visits and for time spent 
during PK sampling.  The form and amount of compensation will be in accordance with local guidelines. 
 
 
8.13 Steady State Pharmacokinetic Assessments 
 
Semi-intensive PK sampling:  At Day 14(+5) days each subject receiving PA-824 will have a steady state 
PK assessment for PA-824.  An additional aliquot will be saved for possible future PK determination of 
companion drugs, should this become of scientific interest.  Samples will be collected via an indwelling 
catheter or by direct venipuncture.  Approximately 4 cc of blood will be obtained immediately prior to 
administration of study medications and then at 1, 2, 5, 8, and 24 hours post-dose.  The 24 hour specimen 
should be drawn immediately before administration of the next medication dose.  Specimens will be 
obtained, processed, and assayed according to procedures in a detailed procedures manual.  
 
Sparse PK sampling:  On Days 28, 56, and 84, patients receiving PA-824 will have a sparse sampling for 
PA-824 PK analysis. It is preferable that these samples be collected pre-dose (within 2 hours of scheduled 
dosing) and then 2-4 hours after an observed dose, if scheduling allows. 
  
8.14 
Management of HIV-Positive Subjects 
 
All participants will undergo HIV testing and counseling regardless of whether they have had a previous 
HIV test or not. HIV testing will be carried out with two rapid tests (the second test will be to confirm the 
result of the first) for patients who are not known to have HIV. For patients with an existing HIV 
diagnosis, one rapid test will be performed to confirm the diagnosis.  Should there be a discrepancy 
between the two rapid tests, blood will be sent to the laboratory for enzyme-linked immunosorbent assay 
Elisa and Western Blot test in order to confirm the diagnosis. 
 
For HIV-positive participants, a CD4 count should be performed unless written results are available from 
a test done within the preceding 3 months or less. 
 
Patients who, based on study testing, are newly identified to be HIV positive will receive further 
individualized counseling about the risks and benefits of study therapy.  Individuals in whom prompt 
initiation of antiretroviral therapy is clinically indicated will not be enrolled in the study.  If a participant 
is already enrolled in the study, he or she will be taken off of study medicines and referred to the clinics 
for treatment with individualized TB and HIV therapy.  All HIV-positive individuals who screen for, or 
participate in, the trial will be referred to local sources of free HIV care by the study team.  HIV-positive 
individuals who participate in the trial will be referred for HIV treatment following completion of 
experimental TB treatment.  
 
 
 
8.15 
Procedures to maximize compliance with study visits    
   
Several methods will be used to maximize the proportion of participants who routinely keep their study 
visit appointments. First, only individuals with an expressed interest in participating and keeping 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 42 of 56 
 
appointments will be enrolled.  Second, at enrollment, information will be collected including the 
participant’s name, address, phone number, and, with the permission of the participant, names and 
telephone numbers of friends/relatives who would normally know the participant’s whereabouts.  Third, 
participants will be given written appointment cards.  Fourth, participants with telephones may be called 
the day before the scheduled visit to remind them.  Fifth, participants who miss appointments will be 
contacted either by phone or by domiciliary visit or through friends/family whose names were provided 
by the participant.  Finally, study subjects will be compensated for their time and travel to and from study 
visits and for time spent during PK sampling.  The form and amount of compensation will be in 
accordance with local guidelines. 
 
9 
ASSESSMENT OF SAFETY AND TOLERABILITY 
 
9.1 Safety and Tolerability Endpoints 
 
The primary endpoint for analysis of safety and tolerability is Grade 3 or higher adverse events.  
Secondary endpoints include permanent discontinuation of assigned study regimen for any reason (other 
than new recognition of subject ineligibility based on absence of M. tuberculosis growth in baseline 
sputum cultures, or growth of M. tuberculosis resistant to isoniazid and/or rifampin and/or pyrazinamide 
and/or ethambutol). Other aspects of safety and tolerability that will be assessed include mortality and the 
rates and types of toxicity thought related to study drugs by the investigator. 
 
9.2 Safety Evaluation 
 
A Data and Safety Monitoring Board (DSMB) will review the study protocol and oversee progress of the 
trial.  The DSMB will review safety data once 50% of the participants have completed study treatment. 
Since this is an open-label study, the DSMB will have access to treatment group assignment.  The DSMB 
will be comprised of at least the following: an expert in statistics, an expert in clinical trials, and an expert 
in clinical TB.  No early stopping rules will be formally adopted.   
 
9.3 Interim Efficacy and PK Analysis 
 
The study will randomize 183 individuals with smear positive TB to the 3 study arms. In alignment with 
the timing of the Safety Evaluation (Section 9.2), An interim efficacy and PK analysis is planned when 
50% of participants have completed study treatment.  Each experimental arm (Arm 1 and Arm 2) will be 
compared to the control arm (Arm 3). Interim analysis will be done for time to culture conversion on 
liquid media and to assess PK interactions. 
 
Time to culture conversion 
Unadjusted hazard ratio for time to culture conversion will be estimated using Cox-proportional hazards 
model. A hazard ratio of at least 1.20 will ensure enhanced efficacy of each experimental treatment 
arm. The interim analysis is powered at 95% to ensure the end of study power at 90%. An experimental 
arm that does not meet efficacy criteria at the interim analysis may be dropped, following a formal 
review of all data by the study team leadership and the DSMB. 
 
PK analysis 
PK parameters (e.g. area under the concentration-time curve over 24 hours (AUC0-24), minimum 
concentration (Cmin), maximum concentration (Cmax), and oral clearance (Cl/F)), will be estimated for 
PA-824 from semi-intensive sampling data, using a noncompartmental approach using standard PK 
software, like Phoenix WinNonLin.  Using all PK data (sparse and semi-intensive), a PK/PD model will 
be developed to evaluate the PK values for PA-824 when given with rifampicin vs. with rifabutin. 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 43 of 56 
 
Results may be helpful as accessory information that will put interim efficacy results into 
pharmacologic context.  
 
9.4 Early Stopping Rules 
 
No early stopping rules will be formally adopted. 
 
9.5 Study Treatment Discontinuation Criteria 
 
Participants who prematurely discontinue study treatment after having received one or more doses of PA-
824 will not be replaced. The exception to this is in cases of new recognition of subject ineligibility based 
on absence of M. tuberculosis growth in baseline sputum cultures, or growth of M. tuberculosis resistant 
to isoniazid and/or rifampin and/or pyrazinamide and/or ethambutol.  Study treatment must be 
immediately discontinued as a result of the following: 
 
• 
Withdrawal of informed consent. 
• 
Investigator considers it for safety reasons in the best interest of the participant that he/she be 
withdrawn. 
• 
If a participant develops a new onset stage 4 illness after enrollment, they would meet the criteria for 
withdrawal from the study and, if HIV positive, for fast track initiation of ART per the South African 
National Department of Health ART guidelines.  The Interim WHO Clinical Staging of HIV/AIDS and 
HIV/AIDS Case Definitions for Surveillance, African Region (2005) will be used for guidance on 
definitions of stage 4 illnesses (34). 
• 
Resistance to isoniazid, rifampin, pyrazinamide, or ethambutol determined during study. 
• 
Participant experiences specific toxicities as outlined in Section 9.7. 
• 
Participant becomes pregnant. 
• 
Termination of the study by the sponsor. 
 
All participants withdrawn from treatment will be referred to the local community TB clinics for standard 
antituberculosis chemotherapy according to National Guidelines. The participants will be provided with a 
referral letter to take with them to the TB Clinic.  Participants will be transported by the study staff to the 
clinic, or a follow-up call will be made by the study site staff to the clinic to determine if the participant 
attended the clinic on the date as arranged. Every effort will be made to continue to follow participants 
who discontinue study medicine prematurely until the final study visit, if they are agreeable. Any 
participant who received at least one dose of PA-824 and is withdrawn or withdraws early from study 
treatment will undergo an early treatment discontinuation visit and will be requested to return for the 
applicable follow up visits. Evaluations at these visits will not include PK sampling.  
 
9.6 Subject Study Withdrawal Criteria 
Participants who withdraw from the trial after having received one or more doses of PA-824 will not be 
replaced. The exception to this is in cases of new recognition of subject ineligibility based on absence of 
M. tuberculosis growth in baseline sputum cultures, or growth of M. tuberculosis resistant to isoniazid 
and/or rifampin and/or pyrazinamide and/or ethambutol.  A participant may be prematurely withdrawn 
from the trial as a result of the following: 
 
• 
At their own request or at the request of their legally acceptable representative. 
• 
If, in the investigator’s opinion, continuation in the trial would be detrimental to the well-being of 
the participant. 
• 
At the specific request of the sponsor. 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 44 of 56 
 
 
Every effort will be made to reduce loss to follow-up, as described in 8.16.  Subjects will be contacted by 
phone if they do not return for study visits. All participants withdrawn will be referred to the local 
community TB clinics for standard antituberculosis chemotherapy according to National Guidelines. The 
participants will be provided with a referral letter to take with them to the TB Clinic.  The participants 
will either be transported to the clinic by the study staff, or else a follow-up call will be made by the study 
site staff to the clinic to determine if the participant attended the clinic on the date as arranged.  
 
 
9.7 Adverse Events 
 
The Investigators are responsible for eliciting adverse events by observing study participants and 
recording all adverse events observed by him/her or reported by study participants during the trial.   
 
9.7.1 
Definitions 
Adverse event (AE):  Any untoward medical occurrence in a study participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An 
adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not 
related to the medicinal product. 
 
Serious adverse event (SAE): Any untoward medical occurrence that at any dose: 
• 
results in death; 
• 
is life threatening (any event in which the subject was at risk of death at the time of the event; it does 
not refer to an event, which hypothetically might have caused death if it were more severe); 
• 
requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
results in persistent or significant disability/incapacity;  
• 
is a congenital anomaly/birth defect; or 
• 
is a medically important event. 
Note:  
 
Medical and scientific judgment should be exercised in deciding events are “medically important.”  
These events are those that may not be immediately life-threatening or result in death or 
hospitalization, but may jeopardize the study participant or may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or the development of drug dependency or drug 
abuse.   
 
Unexpected Adverse Event (UAE):  An adverse reaction, the nature or severity of which is not consistent 
with the applicable product information (e.g., Investigator’s Brochure for an unapproved investigational 
product or package insert/summary of product characteristics for an approved product). 
 
9.7.2 
Association and Attribution/causality 
 
An adverse event is considered associated with the use of the drug (Adverse Drug Reaction) if the 
attribution is possible, probable or definite. 
 
 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 45 of 56 
 
The following definitions for rating attribution/causality will be: 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Doubtful 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive.  The relationship in time is reasonable; 
therefore the causal relationship cannot be excluded. 
Probable 
An adverse event, which might be due to the use of the drug.  The 
relationship in time is suggestive, e.g., confirmed by dechallenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Definite 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).   
 
 
9.7.3 
Severity 
 
With the exception of QTc interval, all symptoms and laboratory findings will be graded according to 
severity using the Division of AIDS Table for Grading Severity of Adult Adverse Events (Appendix D), 
which, in our view is the most comprehensive grading scale for patients with infectious diseases, 
including TB or HIV. 
 
 
The protocol-specific criteria for grading prolonged QTc are as follows: 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY  LIFE-
THREATENING 
Prolonged QTc 
(using Fridericia 
QT correction 
formula) 
Asymptomatic, 
QTc interval 0.45 
– 0.47 sec  
Asymptomatic, 
QTc interval 
>0.470 – <0.50 
sec  
Asymptomatic, 
QTc interval 
≥0.50 sec OR a 
QTc >0.48 sec 
with  an increase 
in interval ≥ 0.06 
sec above baseline 
Life threatening 
consequence, e.g., 
Torsade de pointes or 
other associated serious 
ventricular dysrhythmia 
 
 
 
 
 
9.7.4 
Reporting 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 46 of 56 
 
AE:  Adverse events will be collected by the investigators from the time a study participant receives 
the first dose of study drug through the Week 16 visit. Any AE (serious or non-serious) observed by 
the investigator or reported by the study participant that meets the AE reporting requirements (see 
below) will be recorded on an Adverse Event Case Report Form.  The Investigator will review each 
AE and assess its relationship to drug treatment based on all available information at the time of the 
completion of the case report form.  The following information will be recorded for each Adverse 
Event reported: 
• 
Diagnosis of the AE, if possible.  In the case where an overall diagnosis cannot be made, each 
specific sign and/or symptom will be recorded as individual AEs; 
• 
Date of onset; 
• 
Stop Date (duration) if applicable; 
• 
Severity;   
• 
Action taken with study drugs; 
• 
Other action taken; 
• 
Outcome; 
• 
Relationship to study drugs; 
• 
Seriousness. 
 
The following adverse events must be reported on an Adverse Event Report Form: 
• 
new medical diagnosis (at the time of enrollment, if the patient already has a medical diagnosis 
whose signs or symptoms worsen during the study to a Grade 3 or 4, this is an adverse event that 
must be reported) 
• 
any grade 1 or higher adverse event 
• 
study drug discontinuation due to an adverse event 
• 
pregnancy   
• 
lab values that are considered clinically significant by the investigator 
 
SAE:  Any SAE must be recorded and reported by the site investigator to the Johns Hopkins 
University study coordinator immediately (within 24 hours), to the relevant drug safety team at TB 
Alliance or Pfizer and to the local IRB and to regulatory authorities in accordance with local 
requirements and ICH guidelines for Good Clinical Practice.  SAEs will be collected from the time a 
study participant receives the first dose of study drug through Week 16. 
 
The study drugs are PA-824, ethambutol, isoniazid, rifampin, rifabutin, and pyrazinamide.  The most 
common adverse effects associated with the study drugs are specified in the "Study Drugs" section. The 
investigator is responsible for monitoring all adverse events that are observed or reported during the 
study, regardless of whether they are related to study drugs.   
In accordance with the FDA’s Code of Federal Regulations, the study sponsor and the participating 
investigators are responsible for reviewing all information relevant to the safety of the study drugs.  
Reporting and monitoring of SAEs is required to alert the FDA, sponsor, institutional review boards, and 
the clinical investigators of real and potential safety issues.  The investigators will carefully review the 
Adverse Event Reports and use this information to monitor the investigational drug's toxicity profile and 
patient safety.  Any adverse experience associated with the use of the drug that is both serious and 
unexpected will be reported to the FDA in the form of a written Safety Report.   
The responsible institutional review boards, FDA and South African Regulatory body (Medicines Control 
Council) will be notified of all SAEs and AEs according to their individual guidelines. 
 
 
9.7.5 
Pregnancy 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 47 of 56 
 
The Investigator will immediately notify the sponsor of any pregnancy that is discovered during study 
drug administration or which started during study drug administration. The Investigator will also report 
pregnancies which occur within one month of the completion of PA-824. Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial. In addition, with the permission of the 
study participant, or female partner of a male participant, the investigator will report follow-up 
information regarding the outcome of the pregnancy, including perinatal and neonatal outcome.  Infants 
will be followed for 6 months.   
 
All women of childbearing potential will be instructed to contact the study team immediately if they 
suspect they might have become pregnant (for example, missed or late menses) during study treatment or 
within one month of receiving their last dose of study medication. 
 
If pregnancy is suspected for a participant in Arm 1 or Arm 2 while the subject is receiving PA-824, the 
PA-824 will be withheld immediately until the result of the pregnancy test is known.  If pregnancy is 
confirmed, the PA-824 will be permanently discontinued in an appropriate manner and the subject 
withdrawn from the trial. Protocol-required procedures for trial discontinuation and follow-up will be 
performed unless contraindicated by the pregnancy. Patients will be referred to prenatal care and to the 
local TB program for continuation of their TB treatment.  Women will be asked questions about 
pregnancy history as well as information about the current pregnancy and birth.  Permission will also be 
requested to follow the infant for six months. 
 
Should the female partner of a male Subject enrolled in Arm 1 or Arm 2 become pregnant during study 
treatment or in the 4 weeks after the completion of PA-824 and the investigator becomes aware that this 
situation has occurred, consent will be requested from the female partner for collection of information on 
her pregnancy history and for information on the current pregnancy and birth.  Permission will also be 
requested to follow the infant for six months. 
 
Pregnancy reporting will follow the same time lines and reporting structures as for a SAE (see above). 
SAE reporting will also occur if the pregnancy outcome is a congenital anomaly.  This will follow the 
reporting procedures described above for SAE reporting plus an additional clinical report. 
 
9.8 Clinical Management of Adverse Events 
 
9.8.1 
Liver toxicity 
 
Study treatment will be stopped if any of the following criteria are met:   
 
• 
ALT > 5x the upper limit of normal (ULN) 
• 
ALT > 3x ULN with signs or symptoms suggestive of clinical hepatitis including one or more of 
the following:  nausea, vomiting, abdominal pain, dark or clay colored stools, unexplained fever, 
jaundice, liver tenderness, or hepatomegaly 
• 
ALT > 3xULN and Total Bilirubin ≥ 2xULN  
 
If a patient develops hepatic toxicity meeting the above stopping criteria, the following evaluation will be 
undertaken: assessment for history of injection or non-injection drug use, alcohol ingestion, use of other 
hepatotoxic drugs, and performance of serologic tests for viral hepatitis (IgM antibody for Hepatitis A, 
Hepatitis B surface antigen, IgM antibody to Hepatitis B core antigen, antibody to Hepatitis C).  In 
addition, an AST and INR should also be checked, if not already done. 
Participants will be followed until resolution (return to baseline) or stabilization of the ALT elevation. 
 
For management of liver toxicities that do not meet these criteria, refer to section 9.7.3.  


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 48 of 56 
 
 
 
 
9.8.2 
Cardiac rhythm disturbances 
 
For Grade 1 (asymptomatic) or Grade 2 (asymptomatic, transient rhythm abnormality not requiring any 
treatment) cardiac rhythm disturbances, participants may continue study treatment and should be carefully 
evaluated and followed closely. For Grade 3 (recurrent, persistent, symptomatic arrhythmia requiring 
treatment) or Grade 4 (unstable dysrhythmia requiring treatment) cardiac rhythm disturbances: 
participants will permanently discontinue study drugs and be withdrawn from the trial. For QTc 
prolongation meeting Grade 3 or 4 criteria as described in Section 9.6.3, subjects should be permanently 
withdrawn from the trial.  
 
 
9.8.3 
Other toxicities 
 
Grade 1 toxicities:  In general, for grade 1 toxicities, the patient will be followed carefully, and the study 
drugs will be continued.   
Grade 2 toxicities:  For grade 2 toxicities, the patient will be followed more carefully, with additional 
laboratory and/or clinic visits as necessary, and the study drugs temporarily held at the investigator's 
discretion.  
Grade 3 toxicities:  For any grade 3 toxicity that, in the principal investigator’s judgment is due to study 
drug(s), the causative study drug(s) should be held.  The clinician should rule out other possible causes of 
the symptoms before discontinuing study medication.  When possible, concomitant medications should be 
held first at the discretion of the principal investigator if he/she suspects they are contributing to the 
toxicity.  Depending on the nature and severity of the toxicity, the degree to which it resolves, and/or the 
emergence of alternative explanations for the toxicity or the subject’s deterioration, the study drugs(s) 
may be restarted at the discretion of the investigator.   
Grade 4 toxicities:  Any patient with grade 4 renal, hepatic, cardiac or hematological toxicity will be 
immediately discontinued from study therapy.  The laboratory test or clinical finding in question will be 
reassessed as soon as possible. The repeat test will guide management of the event as follows: 
• 
If the repeat assessment shows toxicity of grade 3 or lower, and if the patient has continued to 
receive study drugs between the two testing dates, then the patient will be managed according to 
the appropriate toxicity level of the repeat test. 
• 
If the repeat test shows toxicity of grade 3 or lower, and if the patient has not received study 
drugs between the two testing dates, then the patient will be managed at the discretion of the 
investigator with regard to the re-administration of study drugs, and otherwise according to the 
toxicity level of the repeat test. 
• 
If the repeat test shows grade 4 toxicity, then the patient will be permanently discontinued from 
study medications.  Further treatment of TB will be directed by the investigator on an 
individualized basis.  The patient will continue to be followed for study monitoring purposes (as 
are other patients who make a permanent departure). 
 
For other grade 4 toxicities, the study drugs will be temporarily held and may be restarted or permanently 
stopped at the discretion of the investigator.  Toxicities graded 3 or 4 and occurring during study therapy 
will be documented on the Adverse Event Form, according to the criteria described in the following 
sections.  The maximum level of toxicity reached will be clearly indicated.   
For all toxicities that are treatment-emergent and that require the study therapy to be temporarily or 
permanently discontinued, relevant clinical and laboratory tests will be obtained as clinically indicated 
and repeated as needed until final resolution or stabilization of the toxicity. 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 49 of 56 
 
 
Temporary or permanent discontinuation of study drugs:  Certain events or conditions may necessitate 
temporary or permanent discontinuation of the study medication.  Patients who experience such events or 
conditions, however, will still be "on study" and will be followed until study completion.  Any patient for 
whom the study medication is temporarily discontinued will be restarted on study medication as soon as 
possible.  Study regimens will be discontinued and non-study regimens will be used with continued study 
follow-up for patients who fail to respond to study therapy either clinically and/or bacteriologically, for 
patients in whom treatment-emergent drug toxicity warrants discontinuation of study therapy, and for 
patients who become pregnant.  If study drugs are permanently discontinued, further antituberculosis 
therapy may be administered at the investigator's discretion. 
  
Criteria for temporary discontinuation of study therapy 
• 
Development of a toxicity that, depending on its nature and severity, requires temporary 
discontinuation of the study medication until the toxicity resolves as indicated in the preceding 
toxicity management section. 
• 
Development of another medical condition that makes the administration of the study drug 
inadvisable.  The decision to discontinue temporarily the study medication in this situation will be 
at the investigator's discretion.  The period during which the patient is off study medication will 
be as short as clinically possible. 
 
 
10 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
 
Details of the analyses specified in this section will be contained in a statistical analysis plan. 
 
10.1 
Hypotheses 
• 
Among patients with pulmonary TB, the addition of PA-824 to first-line TB treatment that 
includes isoniazid, a rifamycin antibiotic, and pyrazinamide for 12 weeks will reduce the time to 
sputum culture conversion compared to standard treatment with isoniazid, rifampin, pyrazinamide 
and ethambutol, measured over 12 weeks 
 
• 
PA-824 at a dose of 200 mg daily given for 12 weeks with first-line drugs will be safe and well-
tolerated 
 
 
10.2 
Data Analysis 
 
This is a three arm randomized controlled trial to estimate the rate of, and time to sputum culture 
conversion among pulmonary TB patients receiving either PA-824 or control. The two treatment arms 
will be independently compared with the control arm. The statistician performing the analysis will be 
blinded to the random treatment assignment until database lock.  
 
Baseline data, demographic, clinical and laboratory data will be summarized by the three treatment arms. 
Continuous variables will be summarized using medians and inter-quartile range and compared using a 
Wilcoxon rank-sum test. Categorical variables will be summarized by frequencies and compared across 
treatment arms using a Fisher’s exact test.   
 
Time to culture conversion to negative is the measure of the sterilizing activity of the study regimens in 
this trial. Results on solid and liquid media will be analyzed separately.  Analysis of sputum culture 
conversion will be per protocol, and also separately by modified intention-to-treat (MITT).  The per 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 50 of 56 
 
protocol analysis will be the primary analysis, although both analyses will be reported. For the per-
protocol analysis, patients meeting all of the following criteria will be included: had at least one evaluable 
culture obtained at the end of intensive phase, had M. tuberculosis on baseline culture, were not excluded 
based on drug-resistance of the baseline culture, and completed the assigned study phase treatment.  For 
the MITT analysis, patients meeting all of the following criteria will be included: had M. tuberculosis on 
baseline culture and were not excluded based on drug-resistance of the baseline culture.   
 
Rate of sputum culture negativity (95% CI) and median time to conversion of sputum cultures to negative 
after initiation of treatment will first be estimated by the Kaplan-Meier method, and the difference in 
Kaplan-Meier curves will be compared by the log-rank test at 5% level of significance.  An univariable 
and multivariable analysis using Cox proportional hazard model will be used to determine whether or not 
treatment arm is independently associated with the time to sputum culture conversion, after adjusting for 
other variables known to affect time to culture conversion (baseline burden of disease, as measured by 
smear grade; cavitary disease; HIV; etc.)  All adverse events, grade 3 or higher, will be summarized using 
rates, defined as a ratio of number of events to total person-years of follow-up, and Poisson exact 95% 
confidence intervals. Unadjusted and adjusted incidence rate ratios of serious adverse events by treatment 
arms will be estimated using univariable and multivariable Poisson regression models respectively.  
PK parameters (e.g. AUC0-24, Cmin, Cmax, and Cl/F), will be estimated for PA-824 from semi-intensive 
sampling data, using a noncompartmental approach using standard PK software, like Phoenix 
WinNonLin.  Using all PK data (sparse and semi-intensive), a PK/PD model will be developed to 
evaluate the relationship between drug exposures (e.g. Cmax, T>MIC or AUC0-24) and outcomes (e.g. 
time to culture conversion). 
 
10.3 
Sample size 
 
Sample size will be 183 participants based on the following assumptions: a two-sided type 1 error of 5%, 
power of 90%, target hazard ratio of >1.9, and 15% inevaluable or lost to follow-up. The target hazard 
ratio of 1.9 is based on the OFLOTUB Phase 2 trial in which replacement of ethambutol with 
moxifloxacin resulted in a hazard ratio of 1.7, comparing time to culture conversion in the experimental 
arm with the control (33).  This was considered to be sufficient evidence (alongside other trials) (24) for 
evaluating this regimen in a Phase 3 treatment-shortening trial.  A treatment effect at least this large is 
expected to be necessary to shorten treatment duration to <4 months from the current duration of 6 
months (25).  
 
 
11 HUMAN SUBJECTS PROTECTION 
 
11.1 
Institutional Review Board Involvement 
 
This research will be conducted in compliance with the requirements of the US DHHS regulations to protect 
human subjects from research risk (45 CFR Part 46), in compliance with South African regulations 
protecting human subjects, and with oversight by the IRBs of Johns Hopkins University School of Medicine 
(FWA #00005752) and the University of Cape Town (FWA #00001637).  All study personnel will complete 
a course in protection of human subjects prior to participating in the study.   
 
The investigator will ensure that the purpose of the study is explained to the patient and that written consent 
is obtained prior to participation in the study.  The patient, investigator or designee, and others as required 
by local regulatory guidelines will sign the consent prior to entry into the study.  The patient will receive a 
copy of his/her signed consent form.  The investigator will retain a copy of the signed consent forms, which 
may be inspected at the monitor’s or auditor’s request.  
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 51 of 56 
 
The investigator will promptly report to the Ethics Committee/IRB and regulatory body of all changes in 
the research activity and all unanticipated problems involving risks to human subjects or others, and will 
not make changes in the research without Ethics Committee/IRB and regulatory body approval, except 
where necessary to eliminate apparent immediate hazards to human subjects. 
 
11.2 
Informed Consent 
 
Written informed consent will be obtained by trained study personnel prior to screening for inclusion and 
exclusion criteria.  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.  The informed 
consent process is described in detail in the “Informed Consent Process” section of “Study Procedures” 
(Section 8).  
 
11.3 
Confidentiality 
 
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 study team members.  The study monitor(s) or other authorized representatives of the 
sponsor may inspect all documents and records required to be maintained by the investigator.   
 
11.4 
Special Populations 
 
There will be no exclusion based on gender or ethnicity.  Children and pregnant or breast-feeding women 
will be excluded from this study because of uncertainties about the safety of PA-824 in these groups.  It is 
anticipated that approximately 40% of study subjects will be women, since, historically, approximately 
60% of patients with tuberculosis at clinical sites are males.  The gender, ethnicity, and socioeconomic 
background of study subjects are expected to mirror that of the population of the hospital and clinics served, 
and that of the population most affected by tuberculosis. 
 
This trial will not enroll persons who are incarcerated.  Section 6 “Population” details issues related to 
follow-up of study subjects who become incarcerated after study enrollment.  
 
11.5 
Ethical Issues in Doing This Trial in South Africa 
The vast majority of the global TB burden occurs in developing countries.  South Africa has an exceedingly 
high TB case rate of approximately 600/100,000 population/year, and ranks #7 in the world based on 
number of incident cases.  New treatment regimens that substantially improve tuberculosis treatment 
(shorten and/or simplify therapy) are critically needed in this setting.  Therefore, it is appropriate to evaluate 
a new drug for TB treatment in South Africa.  
 
11.6 
Future Use of Stored Specimens 
 
Two types of specimens will be stored:  M. tuberculosis isolates and plasma.  Specimens stored for study 
purposes will be labeled with study identification number and collection date, and will not be labeled with 
participant name. 
 
M. tuberculosis isolates:  The pretreatment M. tuberculosis isolates will be stored frozen, and may be used 
for confirmation of drug susceptibility testing during the course of the study.   
 
Susceptibility testing will performed on Day 56 and/or Day 84 positive cultures as relevant.   
 
Plasma specimens will be obtained for pharmacokinetic analyses.  Plasma specimens will be stored at  


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 52 of 56 
 
-70˚C and may be assayed for concentrations of tuberculosis drugs other than PA-824 during the course of 
the study. 
 
No samples will be stored for future use or research beyond the study and we confirm that no genetic testing 
will be conducted on participant DNA. 
 
12 MONITORING AND DATA HANDLING 
 
Site Monitoring will be conducted 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.  Site monitoring will performed according to details in a written monitoring 
plan. 
 
Data handling and record keeping will be performed according to procedures that will be developed in a 
detailed Data Management Operations Manual.    Each participant will be assigned a unique study ID 
number.  This number will be recorded on each data collection form and clinical specimen.  Names and 
other obvious identifiers will not be used on data collection forms.  All study records will be stored in 
locked files in a secure area and access will be limited to study personnel and designated regulatory 
personnel.  All forms will be reviewed prior to data entry for accuracy, consistency, and completeness by 
designated study staff.   
 
Source Documents and Access to Source Documents   Appropriate 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 will have access to study records: members of the 
study team; IRBs that review the study, the Office of Human Research Protections, the FDA, and the MCC.  
Authorized representatives of the sponsor and regulatory agencies will be permitted to examine study 
records for QA reviews, audits, and evaluation of the study safety and progress. 
  
Data Management Responsibilities    The on-site principal investigator and data manager will be responsible 
for accuracy, completeness, and storage of source records and data collection forms. The study team and 
data entry staff will review source documents to ensure accuracy and completeness.  The site administrator 
will maintain logbooks to record dates of completed and upcoming clinic visits and specimen collections.   
 
Data Capture Methods    Data will be manually entered from the source documents directly into the eCRF. 
 
Reports   The timing of reports will be detailed in the Data Management Operations Manual.  Briefly, safety 
data will be reviewed by the DSMB after 50% of the participants have been enrolled and annually thereafter; 
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. 
 
Study Records Retention    Within 2 years of study completion, identifiers excluding study ID number will 
be deleted from data files.  Study records will be maintained by the investigator following study 
discontinuation in accordance with all applicable FDA and local South African regulatory requirements.  
The FDA will be notified prior to destruction of study records. 
 
Protocol Deviations   A protocol deviation is any noncompliance with the clinical trial protocol or Manual 
of Procedures. As a result of deviations, corrective actions are to be developed and implemented promptly.  
The site will identify and report deviations according to the guidelines of the IND sponsor and IRBs. 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 53 of 56 
 
Quality Management Procedures for quality management will be detailed in a separate Quality Management 
Plan.  The study site will provide direct access to all trial related facilities, source documents, and reports 
for the purpose of monitoring and auditing by the sponsor, and inspection by regulatory authorities. 
Following written procedures, study monitors will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol and the applicable 
regulatory requirements. 
 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 54 of 56 
 
13 REFERENCES 
 
(1) World Health Organization. Tuberculosis. Fact sheet 104. March 2012. 
http://www.who.int/mediacentre/factsheets/fs104/en/. Retrieved September 11, 2012. 2012. 
 
(2) World Health Organization. Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global 
report on surveillance and response.<br />WHO/HTM/TB/2010.3. 2010. 
 
(3) Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 
2000 Sep;4(9):796-806. 
 
(4) Lin PL, Dartois V, Johnston PJ, Janssen C, Via L, Goodwin MB, et al. Metronidazole prevents 
reactivation of latent Mycobacterium tuberculosis infection in macaques. Proc Natl Acad Sci U S A 2012 
Aug 28;109(35):14188-14193. 
 
(5) Brooks JV, Furney SK, Orme IM. Metronidazole therapy in mice infected with tuberculosis. 
Antimicrob Agents Chemother 1999 May;43(5):1285-1288. 
 
(6) Via LE, Lin PL, Ray SM, Carrillo J, Allen SS, Eum SY, et al. Tuberculous granulomas are hypoxic in 
guinea pigs, rabbits, and nonhuman primates. Infect Immun 2008 Jun;76(6):2333-2340. 
 
(7) Carroll MW, Jeon D, Mountz JM, Lee JD, Jeong YJ, Zia N, et al. Efficacy and safety of 
metronidazole for pulmonary multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2013 
Aug;57(8):3903-3909. 
 
(8) Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. 
Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med 2012 Jun 7;366(23):2151-2160. 
 
(9) Skripconoka V, Danilovits M, Pehme L, Tomson T, Skenders G, Kummik T, et al. Delamanid 
Improves Outcomes and Reduces Mortality for Multidrug-Resistant Tuberculosis. Eur Respir J 2012 Sep 
27. 
 
(10) Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. A small-
molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000 Jun 
22;405(6789):962-966. 
 
(11) Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. Preclinical 
testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in 
vitro and in vivo models. Antimicrob Agents Chemother 2005 Jun;49(6):2294-2301. 
 
(12) Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 kills 
nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 2008 Nov 
28;322(5906):1392-1395. 
 
(13) Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in patients 
with pulmonary tuberculosis. Am Rev Respir Dis 1980 Jun;121(6):939-949. 
 
(14) Jindani A, Dore CJ, Mitchison DA. Bactericidal and sterilizing activities of antituberculosis drugs 
during the first 14 days. Am J Respir Crit Care Med 2003 May 15;167(10):1348-1354. 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 55 of 56 
 
(15) Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, et al. Early bactericidal 
activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob Agents 
Chemother 2010 Aug;54(8):3402-3407. 
 
(16) Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II dose-ranging 
trial of the early bactericidal activity of PA-824. Antimicrob Agents Chemother 2012 Jun;56(6):3027-
3031. 
 
(17) Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, et al. Early bactericidal 
activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob Agents 
Chemother 2010 Aug;54(8):3402-3407. 
 
(18) Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, et al. 14-day 
bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised 
trial. Lancet 2012 Jul 20. 
 
(19) Williams KN, Brickner SJ, Stover CK, Zhu T, Ogden A, Tasneen R, et al. Addition of PNU-100480 
to first-line drugs shortens the time needed to cure murine tuberculosis. Am J Respir Crit Care Med 2009 
Aug 15;180(4):371-376. 
 
(20) Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. Bactericidal 
activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents 
Chemother 2005 Jun;49(6):2289-2293. 
 
(21) Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. Combination 
chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis. 
Antimicrob Agents Chemother 2006 Aug;50(8):2621-2625. 
 
(22) Tasneen R, Tyagi S, Williams K, Grosset J, Nuermberger E. Enhanced bactericidal activity of 
rifampin and/or pyrazinamide when combined with PA-824 in a murine model of tuberculosis. 
Antimicrob Agents Chemother 2008 Oct;52(10):3664-3668. 
 
(23) Harper J, Skerry C, Davis SL, Tasneen R, Weir M, Kramnik I, et al. Mouse model of necrotic 
tuberculosis granulomas develops hypoxic lesions. J Infect Dis 2012 Feb 15;205(4):595-602. 
 
(24) Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, et al. Moxifloxacin versus 
ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. 
Lancet 2009 Apr 4;373(9670):1183-1189. 
 
(25) Phillips PP, Gillespie SH, Boeree M, Heinrich N, Aarnoutse R, McHugh T, et al. Innovative trial 
designs are practical solutions for improving the treatment of tuberculosis. J Infect Dis 2012 May 15;205 
Suppl 2:S250-7. 
 
(26) Radenbach KL. Minimum daily efficient dose of ethambutol: general review]. Bull Int Union Tuberc 
1973 Jun;48(0):106-111. 
 
(27) Donald PR, Sirgel FA, Botha FJ, Seifart HI, Parkin DP, Vandenplas ML, et al. The early bactericidal 
activity of isoniazid related to its dose size in pulmonary tuberculosis. Am J Respir Crit Care Med 1997 
Sep;156(3 Pt 1):895-900. 
 


PIs: KE Dooley and R. Dawson 
Phase 2B trial of PA-824 for drug-sensitive pulmonary TB 
Protocol No.:  NA_00093014                                                 Version 6.0 7 February 2018 
Page 56 of 56 
 
(28) Ahmad Z, Peloquin CA, Singh RP, Derendorf H, Tyagi S, Ginsberg A, et al. PA-824 exhibits time-
dependent activity in a murine model of tuberculosis. Antimicrob Agents Chemother 2010 Oct 11. 
 
(29) Davies G, Cerri S, Richeldi L. Rifabutin for treating pulmonary tuberculosis. Cochrane Database 
Syst Rev 2007 Oct 17;(4)(4):CD005159. 
 
(30) Burman W, Dooley KE, Nuermberger E editors. The rifamycins: renewed interest in an old drug 
class.  Volume 40, Chapter title: "Antituberculosis Chemotherapy", edited by Peter Donald and Paul van 
Helden. : Karger AG -- Medical and Scientific Publishers; 2011. 
 
(31) Investigator's Brochure: PA-824, Version 13, 23 July 2010.  
 
(32) Dooley KE, Luetkemeyer AF, Park J, Cramer Y, Allen R, Sutherland D, et al. ACTG Study  
5306:  Phase I, three-arm safety and PK study of PA-824, an investigational nitroimidazole for treatment 
of TB, together with efavirenz, ritonavir-boosted lopinavir, or rifampin.  9 September 2013, Denver, CO. 
Clinical Pharmacology of TB Drugs 2013. 
 
(33) Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A Phase II study of the 
sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc 
Lung Dis 2008 Feb;12(2):128-138. 
 
(34) Interim WHO Clinical Staging of HIV/AIDS and HIV/AIDS Case Definitions for Surveillance, 
African Region. 2005. 
 

ICF_001.pdf: 
 
 
CONFIDENTIAL 
Page 1 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
 
 
A Phase 2 Randomized, Open-Label Trial of PA-824-Containing Regimens 
versus Standard Treatment for Drug-Sensitive Sputum Smear-Positive 
Pulmonary Tuberculosis  
 
NCT02256696 
 
Informed Consent Form  
 
28 May 2020 
 


 
 
 
 Page 2 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
 
 
 
 
 
 
 
PATIENT INFORMATION AND INFORMED CONSENT FORM 
 
Site of Research: 
University of Cape Town Lung Institute (UCTLI), 
South Africa 
 
Protocol Title:  
 
A Phase 2 Randomized, Open-Label Trial of PA-824-
Containing Regimens versus Standard Treatment 
for Drug-Sensitive Sputum Smear-Positive 
Pulmonary Tuberculosis 
 
Johns Hopkins University IRB No.: 
NA_00093014 
 
UCT Lung Institute Protocol No.:  
NA_00093014 
 
Sponsor: 
Food and Drug Administration, Office of Orphan Drug 
Products Development Grant Program, United States of 
America 
 
Date:      
 
 
Version No. 9.0 
28 May 2020 
 
International Principal Investigator: 
Dr. Kelly Dooley, MD, PhD 
 
UCTLI  Principal Investigator: 
Dr. Rodney Dawson  MBChB, FCP(SA), Cert. 
Pulm.(SA) 
 
 
This consent form tells you about the study and the reason for doing this study. It tells you what you will 
be asked to do if you are in the study, and explains the things that may cause you discomfort. We may 
have used words that you don’t understand, so please ask your study nurse or doctor if there is anything 
you do not understand in the consent form.  You may take this consent form home to read or talk about 
it with your family or friends before deciding if you want to be part of this study or not.  
 
1. 
What should you know about this study?   
• You are being invited to join a research study. This research is sponsored by the Food and 
Drug Administration (FDA) in the United States of America (USA). 
• The study is being carried out by University of Cape Town Lung Institute (UCTLI) in 
association with the Johns Hopkins University in the USA. 
• This consent form explains the research study and your part in the study.   
• Please read it carefully and take as much time as you need.  
 
 
 
 
 
Participant I.D. Plate 


 
 
 
 Page 3 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
• Please ask questions at any time about anything you do not understand  
 
• The word biospecimen may be used in this consent form.  Biospecimen may include any of 
the following: blood, tissue, saliva, urine, bone marrow, cells, etc. Most biospecimens 
contain DNA, which is the genetic code for each person. 
• A description of this clinical trial will be available on www.sanctr.gov.za as required by 
South African law.   
• For clinical trials: A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law.  This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.  
• All your health information collected during the study will be confidentially stored and only 
those persons working on the study will have access.  We are asking you to allow us to use 
and give out details about your health, including medical notes and lab results as allowed by 
this U.S. law (and local South African law). Your name or information that directly identifies 
you will not be included with your sample or with your medical information.  You do not 
have to agree to allow us to use and give out the details.  If you do not agree, you may not 
join this research study. 
• For clinical trials: If you would like to review the information for this study, or a summary of 
the results, ask the study team doctor for the ClinicalTrials.gov study registration number. 
 
This study is being run by the University of Cape Town Lung Institute.  
 
2. 
Why is this research being done? 
This research is being done to see if a new drug called PA-824 can improve the treatment of 
tuberculosis (TB).   
 
If a drug is new, it means that it has not been approved by the United States Food and Drug 
Administration (FDA).  The FDA is an agency of the United States Department of Health and 
Human Services which controls the use of medicines in the USA.  PA-824 is also not registered 
for use in South Africa.  The FDA is allowing the use of PA-824 in this study. 
 
People joining the study will receive either PA-824 for 12 weeks with Rifampin, PA-824 for 12 
weeks with Rifabutin, or standard TB treatment including ethambutol and Rifampin for 8 weeks. 
Everyone joining the study will also get two standard TB medicines called isoniazid (INH) for 
12 weeks, and pyrazinamide (PZA) for 8 weeks.  After you have been in the study for 3 months, 
you will receive standard TB treatment medicines from your TB clinic for 3 more months to 
finish your TB treatment.  
 
In this study, PA-824 will be given at a dose of 200 mg per day.  
 
3. 
Who can join this study? 
• To join this study you must have TB in your lungs and your sputum test must show that you 
have TB. You must not have had more than five days of treatment for active TB in the past 
six months. 
• It is important that you tell your study doctor or nurse what other medicines you are taking 
and have taken in the past 2 months as some medicines cannot be taken with the study 


 
 
 
 Page 4 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
medicines. We will also need to know what other diseases you have had as some other lung 
diseases will prevent you from taking part in the study.  
• Only participants 18 years or older can join this study.  
• You must weigh between 40Kg and 80Kg. 
• You must be able to care for most of your needs and understand what you need to do for this 
study and be able to attend the Lung Institute clinic for study visits.  
• You can be HIV positive or negative, but your CD4 count must be greater than or equal to 
350 cells/cu mm. You cannot be currently taking or plan to take combination antiretroviral 
therapy for HIV for the next three months. 
• The TB medicines called Rifampicin and Rifabutin may stop birth control pills, hormone 
injections, and hormonal implants from working to prevent pregnancy. Therefore, while you 
are on this study, you must use some other kind of birth control. Not having sex is also a way 
to avoid pregnancy while in the study. Women who are able to have children must have a 
urine test for pregnancy and the test must be negative for her to join the study.  
• Women who are pregnant or breastfeeding may not join the study.  Women who plan to 
become pregnant may not join the study.  
• The blood tests for this study must show the study doctor that it will be safe for you to be in 
the study.  
• Patients who are allergic to the study TB medication may not join the study.  Patients who 
have a disease which will be affected by the study TB medication may not take part in this 
study.  
• Your study doctor or nurse will check to see if it is safe for you to take part in the study.  
Your study doctor will make sure that you are able to come to the clinic for your study visits.  
They will also make sure that you are able take your study TB medicine properly.  
• Before you have any study visits it is important that you understand this information, and that 
you sign this form. 
 
4. 
What happens if you do not join this study or if you decide to leave the study 
early? 
You are a volunteer in this study. If you decide to join the study you can leave the study at any 
time. It is up to you to decide to join this study or not. If you decide not to be part of this study or 
if you leave the study early, your care at the TB clinic will not be affected in any way.  If you 
leave the study early you will be treated for TB at your local clinic with the routine TB 
medicines. 
 
If the study doctor decides it is not safe for you to join this study or you cannot join the study, 
your study doctor will talk to you about the best and safest treatment for your TB at this time.  
 
If your study doctor finds that your TB can’t be treated with the medicine (is resistant), the study 
regimen will be stopped and we will ask you to return in 7-14 days for a safety visit. You will 
still need to continue TB treatment with different medicines. We will advise you as to how and 
where you should continue with your TB treatment. 
 
If you decide not to participate you will still need to receive routine treatment for your TB for six 
months.  If you leave the study early you will need to receive routine medications for TB until 
you complete six months. We will help you with how and where you should continue with your 
TB medicines.  


 
 
 
 Page 5 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
 
If you decide to leave the study, with your permission, we will ask you to continue your study 
visits. If you decided to leave the study early, we will request that you return for a final safety 
visit within one week. 
 
We may learn things during the study that might make you want to stop being in the study. If this 
happens, we will tell you about it. You can then decide if you want to stay in the study or whether 
you want to take the routine TB medicines only. 
 
5. 
How many participants will be in this study? 
About 183 participants will be in this study. 
 
6. 
What will happen if you join this study? 
If you agree to be in this study and you have signed this Informed Consent Form, you will need 
to visit the Lung Institute clinic about 13 times over the next 12 months.  You will have the 
following tests to make sure that you can take part in the study safely and to check that you have 
TB: 
 
Screening Visit (First visit) 
The following tests will be carried out to make sure you have TB and that you can take part in 
this study safely: 
• Your medical history will be collected from your medical records and by talking to you. 
• You will be asked questions about your health.  These questions will include: 
-Questions about your TB and how it makes you feel, 
-Whether you have had past treatment for TB 
-Any other illnesses you have had  
-And if you drink alcohol or take drugs. 
 
Some of these questions are personal and you do not have to answer them if you do not want 
to. 
• We will also ask you your age and whether you are male or female. Your heart rate, blood 
pressure, breathing rate and temperature will be measured. We will also measure your height 
and weight.   
• We will ask you about any medicines you are taking now and any medications you have used 
during the last 14 days. 
• If you are a woman, you must not be pregnant or breast-feeding.  You must not become 
pregnant during the six months you are on treatment for your TB. This is because the study 
TB medication may harm an unborn child.  It may harm your baby if you are breastfeeding. 
Women who are capable of having children will be asked to give a urine sample.  This 
sample will be checked for pregnancy. 
• Women who are able to have children will be asked about what type of birth control they are 
using. Rifampicin may stop birth control pills, hormone injections, and hormonal implants 
from working to prevent pregnancy. So, while you are on this study you must use some other 
kind of birth control.  This could include a diaphragm or cervical cap, condom, birth control 
sponge, or IUD.  You need to use one of these kinds of birth control instead of, or along with, 
birth control pills, hormone injections, or hormonal implants.  Not having sex is also a way to 
avoid pregnancy while in the study. 


 
 
 
 Page 6 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
• 
If you are a male participant who is having intercourse with women who are able to have 
children, there are some requirements. These must be used while you are taking part in the 
trial and for 12 weeks after your last dose of study medicine. These include the following:      
o Use of a male condom, diaphragm, cervical cap, or female condom; or 
o Use of one of the above with hormonal contraceptives or an intra-uterine device for the 
female partner.   
• You will have your eyes tested to check how well you can see, including seeing colors.  Your 
eyes will also be checked to make sure you don’t have any cataracts. 
• We need to know whether or not you are HIV positive.  This is a recommended test for 
everyone with TB and is needed for this study. All participants will have an HIV test and 
counseling (even if you have had an HIV test before) and you will need to sign a separate 
consent form to confirm that you give permission to have an HIV test. This will be done at 
the Lung Institute Clinic with a finger prick test.  Sometimes more than one test is needed. 
Please note the results of these tests will be kept confidential at all times. 
• If you are HIV positive, you will have about another 2 teaspoons (10 ml) of blood taken from 
a vein for a CD4 (T-cell) count. We will give you the result of this test. We will not do the 
CD4 count test if we can get a written copy of this test result from anytime in the 3 months 
before you start the study medicines. 
• We will take about another 4 teaspoons (20 ml) of blood from a vein to check your liver, 
kidneys, and blood count. We will also check the protein in your blood (albumin) and a salt 
called potassium. These tests are to make sure it is safe for you to take part in the study. You 
will have these blood tests before starting the study, unless we can get the results of the same 
tests done within the past 14 days.  
• A sputum (material coughed up from the lungs and windpipe) test will be done to check if 
you have TB or not. Only participants who have TB can take part in this study.  This sputum 
will be tested to make sure that the study drugs will work on your TB. 
• We will also check if you have TB by doing a chest x-ray (a photograph of your lungs). If 
you have had an x-ray of your lungs within 14 days before your screening visit (first study 
visit), and we can get your results we won’t need to do another x-ray. 
• We will also perform an ECG. This is a simple and fast procedure to record the electrical 
activity of the heart. An electrode is attached to your chest, arm, and leg. The procedure does 
not cause pain or discomfort. 
 
After your screening visit your study doctor will decide whether you are able to continue in the 
study or not. If you are not able to continue in the study we will explain why and we will help 
you to get the right care for your TB at a place convenient for you. If you are able to continue in 
the study you will need to return to the Lung Institute clinic for another study visit called the 
baseline visit. This visit will take place as soon as possible after the screening visit (first study 
visit).  
 
Baseline Visit  
At the baseline visit we will check again to make sure you can take part in this study safely. The 
following tests and procedures will also be carried out: 
• Your heart rate, blood pressure, breathing rate and temperature will be measured. We will 
also measure your weight.  
• We will ask you about any medications you have started taking since your screening visit. 


 
 
 
 Page 7 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
• We will give you information on the study drug (PA-824) and the standard TB treatment 
drugs to make sure that you know what the side effects of these drugs can be and what to do 
if you have these side effects. 
• We will ask you questions about your health and about your TB. 
• A sputum (material coughed up from the lungs and windpipe) test will be collected.  
• Women who are capable of having children will be asked if they could be pregnant and the 
date of the first day of their last menstrual period (monthly bleeding). If there is a chance you 
could be pregnant you must tell the study doctor or nurse. You may be asked to give a urine 
sample which will be used to check if you are pregnant or not.  
 
Study Regimen 
At your Baseline Visit, if you are able and still want to participate in the study, you will be 
randomly assigned (by chance, like pulling numbers from a hat) to one of 3 study groups:  
 
1. One group will have 8 weeks of daily standard TB medicines given once a day for 7 days 
per week, then 4 weeks of isoniazid and rifampin.  
2. One group will have 8 weeks of PA-824 at a dose of 200 mg per day plus 3 standard TB 
medicines given once a day for 7 days per week, then 4 weeks of PA-824, isoniazid and 
rifampin. 
3. One group will have 8 weeks of PA-824 at the dose of 200mg per day and Rifabutin plus 
2 standard TB medicines, then for the next 4 weeks PA-824, isoniazid, and Rifabutin. 
 
The same number of people will be put onto each of the three groups.  
 
Everyone will also take a 50mg Vitamin B6 tablet with each dose of TB medicines.  This 
decreases the chance of a numb feeling in the arms and legs when taking TB medicines.   
 
All of these medicines are tablets which you will need to swallow.  
 
Taking the Study Medicines: 
Your TB medication will be given to you each day by study team member or a health care 
worker.  Your treatment might also be given to you by a lay treatment supervisor, family 
member or employer.  Anyone who gives you medicine will have received training about the 
study. This way of giving you your TB treatment is called ‘Directly Observed Therapy’ (DOT) 
and this will happen for the first 12 weeks of you taking TB medication. You may take your TB 
medication at the TB clinic or other health care facility.  If you prefer, you may take the 
medication at your home or work.   The reason for this is because we have to make sure that each 
participant on this study takes their medication properly.  
 
Depending on which group you are in, you will be told whether or not your study medicines 
should be taken with food.  
 
In this study, you cannot take certain medicines during the first 3 months of taking the TB 
medicines.  This includes medicines to treat HIV infection.  The study team will discuss all 
medicines that you are taking to make sure that there are no problems. 
 
 
 


 
 
 
 Page 8 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
How long will you be in the study? 
• You will be in the study for 12 months in total.  You will take TB study medicines for the 
first 3 months (12 weeks) and then standard TB treatment for the next 3 months (12 weeks). 
You will have to return to the Lung Institute clinic weekly for the first 8 weeks and then 
weeks 10 and 12.  You will also be asked to return to the Lung Institute for follow-up visits 
at month 4, month 6 and month 12. 
 
Weekly Study Visits (Weeks 1, 2, 3, 4, 6, 8, 10, 12)  
You will have frequent study visits to the Lung Institute clinic for the first eight weeks of the 
study. Your first visit will be Day 7, the day of your 7th dose.  
 
The following tests and procedures will be done during these weekly visits: 
• You will meet with a study doctor or nurse every week after you start the study for 8 weeks. 
These study visits will take about 30 minutes.  
• You will be asked questions about your TB, how you are feeling and if you have taken any 
medicines or had any illnesses since your last Lung Institute clinic visit. We will also ask you 
if you have taken any new medicines (over the counter and prescription medicines) since 
your last visit.  
• We will measure your heart rate, blood pressure respiratory rate, temperature and weight. 
• We will also perform an ECG at weeks 1 and weeks 4.  If you are withdrawn early from the 
study you will also need an ECG. This is a simple and fast procedure to record the electrical 
activity of the heart. An electrode is attached to your chest, arm, and leg. The procedure does 
not cause pain or discomfort 
• You will have blood taken from a vein at your Lung Institute clinic visit at weeks 1, 2, 4, 6, 8 
and 12, to check your liver, kidneys, and blood count. At week 3, blood will be taken to 
check your liver.  If you are withdrawn early from the study you will also need to have blood 
taken at that visit. We will take about 2 teaspoons (10 ml) of blood for these tests. These tests 
will help us to decide if it is still safe for you to be in this study. 
• We will give you information on the study drug (PA-824) and the standard TB treatment 
drugs to make sure that you know what the side effects of these drugs can be and what to do 
if you have these side effects. 
• A sputum (material coughed up from the lungs and windpipe) test will be done at each of the 
weekly study visits. This test is important in this study as it will tell us how well the study 
drugs are working. 
• At your 4 week Lung Institute clinic visit you will have your eyes tested again to check how 
well you can see and how well you can see different colours. 
• Women who are capable of having children will be asked if they could be pregnant and the 
date of the first day of their last menstrual period (monthly bleeding). If there is a chance you 
could be pregnant you must tell the study doctor or nurse. You may be asked to give a urine 
sample which will be used to check if you are pregnant or not.  
• Two weeks after you start the study, we will measure the level of the study drug in your 
blood. You will need to stay at the clinic until 8 hours after you have taken your study TB 
medicines.  You will have a needle put into a vein. We will take less than 1 teaspoon (4 ml) 
of blood 5 times on this day for a total of 5 teaspoons. The next morning you will need to 
come to the clinic before you have taken your study TB medication so that we can take 
another 1 teaspoon (4 ml) of blood for the PK test. 
• Three other times in the study (at Weeks 4, 8 and 12), we will ask for two blood samples to 


 
 
 
 Page 9 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
test the level of the study drug in your blood.  If you are withdrawn early from the study you 
will need to come to the clinic so that we can take another 1 teaspoon (4 ml) of blood for this 
test. 
 
If you are taking the regular TB medicines, you will not have the extra blood samples (PK 
testing) taken. 
 
Follow-up Study Visits:  
This part of the study starts when you finish taking the study TB medicines (after the first 3 
months on the study). Your TB treatment will continue until you have had a total of 6 months of 
TB treatment.  You will collect this medication at your TB clinic to which we will refer you 
when you have completed study medication. During this part of follow-up, you will receive 
standard, routinely used TB medicines.  In most cases this will be isoniazid and rifampicin, 
which are the usual medicines used to finish TB treatment.  To be cured, it is essential that you 
complete your full course of TB treatment. 
 
In some instances, the TB doctors may want to treat you for longer than 6 months.  They will 
discuss this with you if this needs to happen. 
 
 
Month 4 Follow-up Visit 
You will also have a study visit at month 4.  This visit will take about 15 minutes and will 
include: 
• You will be asked questions about your TB and how you are feeling and if you have taken 
any medicines or had any illnesses since your last Lung Institute clinic visit. 
• You will be weighed. 
• We will give you information on the standard TB treatment drugs to make sure that you know 
what the side effects of these drugs can be and what to do if you have these side effects. We 
will also check to see how you are taking your TB medication. 
• A sputum (material coughed up from the lungs and windpipe) test will be done to see if the 
TB is responding to treatment. 
 
Month 6 Follow-up Visit  
After 6 months you will meet with a study doctor to discuss your TB and how you are feeling.  
The doctor will also ask you about medicines you have taken and if you have been sick. 
• You will be weighed. 
• We will check to see how you were taking your TB medication. 
• You will have your eyes tested to check how well you can see and how well you can see 
different colours and to make sure you don’t have any cataracts. 
• A sputum (material coughed up from the lungs and windpipe) test will be done to see if the 
TB is responding to treatment. 
 
Months 12 Follow-up Visit  
At month 12 you will meet with a study doctor or nurse, or be contacted on the phone. This will 
take about 15 minutes and will include: 
• You will be asked questions about your TB and how you are feeling and if you have taken 
any medicines or had any illnesses since your last Lung Institute clinic visit. 
 


 
 
 
 Page 10 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
7. 
What are the risks or discomforts of the study? 
All medicines have possible side effects. Some medicines should not be taken with TB 
medicines. You should tell the study nurse or doctor about all the medicine you are taking. You 
should talk with them before you start any new medicine during your TB treatment. It is possible 
that the study TB medicine which we are studying may not be as effective as the standard TB 
medicines. 
    
Some of the medicines used in this study have been linked with liver problems and could be 
harmful to it. These medicines are: 
 
pyrazinamide, 
 
isoniazid,  
 
PA-824, 
 
Rifabutin, and 
 
rifampicin. 
 
A few people in another study got liver problems and they died.  Liver problems are common in 
patients taking TB medicines.  In patients taking normal TB treatment about 5 out of 100 patients 
may develop liver problems.  In this study, we combine a new drug with routine TB medication.  
This may put you at a higher risk for liver problems.  Liver problems cause nausea or vomiting, 
stomach pain, fever, weakness, itching, unusual tiredness, loss of appetite, light coloured bowel 
movements, dark coloured urine, yellowing of your skin or the white of your eyes.  Liver 
problems may show up in your blood. In rare cases liver problems may be serious and even lead 
to death.  Extra laboratory tests have been added to watch your liver health more closely. Please 
talk to your study doctor about any worries you have about this.  Talking to your doctor is 
important if you have had liver problems before. It is also important if you drink alcohol or use 
herbal medicines. 
 
The study drug may hurt your liver. Liver harm can be seen in the blood. Liver harm in your 
blood is possible if you are taking other medicines that affect your liver.  We will check your 
blood frequently to check for liver harm. 
 
 
Side Effects of PA-824: 
Common side effects (1-10%) 
• Headache 
• Skin rashes 
• Stomach cramping 
• 
Swelling of the liver, called hepatitis.  If you have this swelling, you might notice yellow 
eyes, very poor appetite, nausea, vomiting, or pain in the right side of your abdomen.   
• Some people in other studies have had a high kidney level in their blood. 
• Some people in other studies had a mild change in their heart rhythm. 
 
Rare, but serious side effects (less than 1%) 
• It is possible that the study drug may affect male reproductive organs.  It is also possible that 
both men and women could get cloudy eyes.  Also, this drug has caused one person to fit. 
You will be checked for fitting during the study. 
 
Side Effects of Standard TB medicines: 
 
Common side effects (5-10%) 


 
 
 
 Page 11 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
• Upset stomach, poor appetite, nausea, vomiting, diarrhea, headache 
• Joint pains 
• Mild, itchy skin rash 
• One of the TB medicines can make your tears, sweat, saliva, faeces, and urine turn orange. 
Contact lenses may be stained permanently due to the orange colour of your tears. 
 
 
Rare, but serious side effects (less than 1%) 
• Loss of vision. Loss of vision may last for a short time or be permanent. We will check your 
vision before you start the study and again at your week 4 visit. 
• Uveitis or inflammation of the uvea in the eye is, you might notice redness of the eye or 
blurred vision. 
• Liver swelling called “hepatitis”. You might notice yellow eyes, very poor appetite, nausea, 
vomiting, or pain in the right side of your abdomen.   
• One of the routine TB medicines can cause seizures or trouble thinking.  
• Allergic reaction (rash and fever) to any of the standard TB medicines is possible. Rarely, an 
allergic reaction can cause low blood cell counts or kidney damage. 
 
There may be other side effects from these medicines that we don’t know about yet. If you have 
side effects, you must tell your study doctor or nurse right away. If you do have side effects your 
study doctor or nurse will explain to you how to carry on taking your TB medicines.  For serious 
side effects, you might have some blood tests. You may be taken off the study medicine for 
safety reasons. Your study doctor will then decide what treatment is best for you. 
 
Blood Taking: There are a few small risks from having blood taken from a vein or from having 
your finger pricked. These include brief pain from the needle stick or finger prick, bruising, 
bleeding, dizziness, and only in very few patients, infection where the needle enters the vein or 
where your finger is pricked.  These same risks are true for the “butterfly” or “cannula” used for 
the frequent blood draws for the pharmacokinetic (PK) testing. 
 
Sputum Test: Some people find this test uncomfortable. 
 
Urine Test: There is no risk from urinating. You will be asked to do this privately. 
 
ECG Test: There is no pain or discomfort from this test. An electrode is attached to your chest, 
arm, and leg.  
 
Eye Test: The slit-lamp is a low-power microscope combined with a high-intensity light source.  
The health care provider will examine your eyes. Often a yellow dye (fluorescein) is used to help 
examine the cornea and tear layer. The dye rinses out of the eye with tears as you blink. Your 
eyes will be sensitive to light for a few hours after the exam if dilating drops are used. 
 
Risks of Radiation from X-ray: X-rays are routinely used to diagnosis TB.  You will have an x-
ray when you start the study unless you had one in the previous 14 days. X-rays include exposure 
to radiation from x-rays or gamma rays.  X-rays and gamma rays can damage cells, but at low 
doses, the body is usually able to repair these cells.   
 
The radiation exposure that you will get in this research study is 0.01 rem (a rem is a unit of 
absorbed radiation). This is less than the 0.3 rem that the average person in the United States gets 


 
 
 
 Page 12 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
each year from natural sources like the sun, outer space, air, food, and soil. The risk from the 
radiation exposure in this research study is very small. 
 
HIV test: HIV testing includes counseling before and after the test. You will be told the test 
result. You will be told the meaning of the test result, whether it is positive or negative. Some 
people who have an HIV test might feel anxious. If you feel this way, you can talk about it with 
Dr. Rod Dawson, Tel: 021 406 6856, Cell: 083 2907322.  We will keep your HIV test results 
private as much as the law allows, but there is a small risk of loss of confidentiality about HIV 
test results. 
 
8. 
Are there risks related to pregnancy? 
We do not know enough about the safety of the study medicine, PA-824 when taken by pregnant 
women or women who are breastfeeding. Therefore, you will not be allowed to take part in this 
study if you are pregnant, plan to become pregnant during TB treatment, or if you are 
breastfeeding.  
 
If you can get pregnant, you will have a pregnancy test (a urine test) before starting this study. 
The test must be negative before you can start this study.  
 
Two of the medicines for TB may stop birth control pills, hormone injections, and hormonal 
implants from working for the prevention of pregnancy. Therefore, while you are in the study, 
you must use some other kind of birth control. Not having sex is also a way to avoid pregnancy 
while in the study. 
 
If you become pregnant during the study, you must tell the study doctor or nurse right away. The 
study medication will then be stopped. We would like to ask you questions about your pregnancy 
history as well as information about the current pregnancy and birth.  We would also like to 
follow the health of your infant for six months.  If you do become pregnant, your doctor will 
decide what TB treatment is best for you.  
 
If you are a male and your female partner becomes pregnant, we would like to ask permission of 
your partner to collect information about her pregnancy history as well as information about the 
current pregnancy and birth.  We would also like to follow the health of the infant for six 
months. 
 
9. 
Are there benefits to being in the study? 
There may or may not be a benefit to you from taking part in this study. By taking part in this 
research you may help us find out if PA-824 can improve TB treatment for other patients with 
TB in the future. 
 
10. 
Will it cost you anything to be in this study? 
There is no cost to you for being in the study. You will not have to pay for any medicine or tests 
that are part of this study. 
 
11. 
Will you be paid if you join this study? 
You will not be paid for taking part in this study. However, you will be reimbursed for your time 
and the cost of coming to the Lung Institute clinic visit. For each scheduled study visit at the 
clinic, you will receive R300.  If you need to have the PK blood testing about 14 days after 


 
 
 
 Page 13 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
starting the study, you will need to stay at the Lung Institute Clinic until 8 hours after you have 
taken your study TB medicines and you will receive R450 for your time and inconvenience.  If 
you are asked by the site team to come for an unscheduled study visit at the clinic, you will 
receive R150. 
 
12. 
Leaving the study early 
The study doctor may take you out of the study early if they think you are not getting better on 
the study or if you have a bad reaction to the study medicines.  They may also take you out early 
if you need other medicine that is not allowed on the study.  If you do not come to the clinic or 
take the study medicines the doctor will take you out of the study.  The study might be cancelled 
and end early. Also, you may leave the study early if you wish.  
 
Even if the study medicines are stopped, we may still follow you in the study for a total time of 
12 months. 
 
13. 
How will your privacy be protected? 
This study is being done by the FDA (Food and Drug Administration) in the United States.. 
There is a privacy law in the United States that protects the health information that you give us.  
There is also a privacy law in South Africa that protects this information.  These laws says that 
health information may only be used under strict rules.  We will ask you to give us details about 
your health as part of this study.  These details have been listed on this form. 
 
The study team may see the details about your health.  Also, some United States government 
officials and groups (such as the Food and Drug Administration), members of the Ethics 
Committee/s who have approved this study and members of the South African Health Products 
Regulatory Authority (previously known as the Medicines Control Council), or other companies 
that have given money to do the study may see details about your health. 
 
We are asking you to allow us to use and give out details about your health. All of your health 
information collected during the study will be confidentially stored and only those persons 
working on the study will have access.  Also, your name and information that identifies you, will 
not be included with your medical information.  Your information and tests will be stored to 
keep your identity from being known.  You do not have to agree to allow us to use and give out 
the details.  If you do not agree, you may not join this research study. 
 
If you agree to allow us to use and give out the details about your health, you can decide later to 
change your mind.  If you change your mind, please tell us in writing or ask the study team to 
write down for you this decision to change your mind.  From that date on, we will not collect 
new details about your health and will only use the information or samples collected up to that 
date. 
 
The study findings may be published in a report so that others can know the study results.  The 
report will not contain your name or other information that could be used to identify you.     
 
14. 
Will the study require any of your other health care providers to share your 
health information with your study doctor or nurse? 
Your study doctor may ask to see your health information from your other doctors. 


 
 
 
 Page 14 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
 
With your permission, we will ask these other doctors to give us information about your health 
or your health care involving tuberculosis. We may also ask for your CD4 count if you have 
already had this test.  
 
In South Africa it is the law that we must report your TB to the TB clinic. 
 
15. 
What happens if I am injured because of taking part in this study? 
If you are injured as a result of being in this study, you will be given immediate treatment for       
your injuries. They will also refer you to another healthcare provider for further care if you need 
it. 
 
There is no programme for compensation through the study sponsor (Johns Hopkins), however, 
this research study is covered by an insurance policy taken out by the University of Cape Town if 
you suffer a bodily injury because you are taking part in the study. 
The insurer will pay for all reasonable medical costs required to treat your bodily injury, 
according to the SA Good Clinical Practice Guidelines 2006 (or latest version), which are based 
on the Association of the British Pharmaceutical Industry Guidelines. The insurer will pay 
without you having to prove that the research was responsible for your bodily injury. You may 
ask the study doctor for a copy of these guidelines. 
 
The insurer will not pay for harm if, during the study, you:  
• 
Use medicines or other substances that are not allowed 
• 
Do not follow the study doctor’s instructions 
• 
Do not tell the study doctor that you have a bad side effect from the study medicine 
• 
Do not take reasonable care of yourself and your study medicine 
 
If you are harmed and the insurer pays for the necessary medical costs, usually you will be asked 
to accept that insurance payment as full settlement of the claim for medical costs. However, 
accepting this offer of insurance cover does not mean you give up your right to make a separate 
claim for other losses based on negligence, in a South African court.  
 
It is important to follow the study doctor’s instructions and to report straightaway if you have a 
side effect from the study medicine. 
 
16. 
What other things should you know about this research study? 
 
What is the Institutional Review Board (IRB) and how does it protect you? 
This research study has been approved by both the Johns Hopkins Medicine IRB in the United 
States of America.  It has also been approved by the University of Cape Town Faculty of Health 
Sciences Human Research Ethics Committee (UCTHREC) in South Africa. 
 
The Johns Hopkins Medicine IRB reviews human research studies. It protects the rights and 
welfare of the people taking part in those studies.  You may contact the IRB if you have 
questions about your rights as a participant.  You may also contact them if you think you have 
not been treated fairly.  The IRB office number is +1 410-955-3008. You may also call this 
number for other questions, concerns or complaints about the research.  The Johns Hopkins 
Medicine IRB is made up of: 


 
 
 
 Page 15 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
• Doctors 
• Nurses 
• Ethicists 
• Non-scientists 
• and people from the local community.  
 
The University of Cape Town Faculty of Health Sciences Human Research Ethics Committee’s 
purpose is to review human research studies.  It also protects the rights and welfare of the people 
participating in those studies.  You may contact the UCTHREC if you have questions about your 
rights as a participant in this study or if you think you have not been treated fairly.  The 
UCTHREC’s telephone number (Professor Marc Blockman) is (021) 406 6338.  
 
The study doctor has no conflict of interest enrolling you as a participant in the study.  
 
What do you do if you have questions about the study? 
You can phone the International Principal Investigator for this study, Dr. Kelly Dooley (+1 443-
287-0517), at Johns Hopkins in Baltimore, Maryland USA, or you can call the Principal 
Investigator at the Lung Institute, Dr. Rod Dawson (Tel: 021 406 6856, Cell: 083 290 7322).   
 
 
If you cannot reach the Principal Investigator or you want to talk to someone else, you can phone 
the Human Research Ethics Committee (UCTHREC) Tel: 021 406 6338. An Ethics Committee 
is an independent committee to help protect the rights of research participants. 
 
After you have spoken with your doctor or the Ethics Committee and if they have not provided 
you with answers you need, you should write to the South African Health Products Regulatory 
Authority (SAHPRA) at: 
The Chief Executive Officer 
South African Health Products Regulatory Authority (SAHPRA) 
Department of Health 
Private Bag X828 
Pretoria 
0001 
E-mail: 
enquiries@sahpra.org.za  
Website: 
https://www.sahpra.org.za 
 
What should you do if you are injured or ill as a result of being in this study? 
Phone Dr. Rod Dawson, Tel: 021 406 6856, Cell: 083 290 7322, if you have an urgent medical 
problem related to your taking part in this study.   
 
What happens to Data and Biospecimens that are collected in the study? 
Johns Hopkins and our research partners work to understand and cure diseases. The 
biospecimens and/or data you provide are important to this effort. 
 
If you join this study, you should understand that you will not own your biospecimens or data, 
and should researchers use them to create a new product or idea, you will not benefit financially.  
 
None of your biospecimens will be stored for future use or research beyond the study. 
 


 
 
 
 Page 16 of 16 
UCT Lung Institute English Participant Information and Informed Consent  
Version 9.0 28 May 2020 
 
17. 
What does your signature on this consent form mean? 
 
Your signature on this form means that: 
• you understand the information given to you in this form  
• you accept what is written in this form 
• you agree to join the study 
• You will not give up any legal rights by signing this consent form.  
 
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
_______________________________  
 
_______________________________   
      __________________ 
Printed name of subject                                                 Signature of subject 
 
 
      Date/Time 
 
 
 
 
_______________________________  
 
_______________________________   
      __________________ 
Printed name of person conducting                              Signature of person conducting 
 
      Date/Time 
Informed consent discussion                                        Informed consent discussion 
 
 
 
_______________________________  
 
_______________________________   
       __________________ 
Printed name of Investigator                                         Signature of Investigator 
 
 
       Date/Time 
 
 
 
_______________________________  
 
_______________________________   
       __________________ 
Printed name of witness (if required)                            Signature of witness (if required)  
       Date/Time 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL 
INVESTIGATOR; A COPY MUST BE GIVEN TO THE PARTICIPANT; AND, IF APPROPRIATE A COPY 
OF THE CONSENT FORM MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD.