Clinical trial NCT02114684
Conditions: Recurrent Tuberculosis
Sponsor: Centre for the AIDS Programme of Research in South Africa
Start date: 2013-11-01; Completion date: 2017-07-17
Enrollment: 197 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open label randomized controlled clinical trial comparing two regimens for treatment of smear-positive pulmonary TB, among patients previously treated for TB. The primary objective is to determine if a moxifloxacin-containing regimen, substituting moxifloxacin for ethambutol, of 24 weeks duration is superior to a control regimen of 24 weeks duration in improving treatment outcomes in patients with recurrent TB and shortens the duration of TB treatment.

Detailed description:
Intervention Arm :12 months (6 months treatment + 12 months post treatment follow up) Control Arm :12 months (6 months treatment + 12 months post treatment follow up) Total sample size is 330.

Arms: arm 1: A Moxifloxacin-containing oral regimen of Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Moxifloxacin (M), substituting Moxifloxacin for Ethambutol, daily for 24 weeks, see information below.

Intensive phase 7 days a week for 8 weeks Continuation phase - 7 days a week for 16 weeks

RH(150,75mg), Z (500mg), M (400mg) Dosage and number of tablets dispensed is dependent on participants weight band. arm 2: An Ethambutol oral regimen of Isoniazid (H), Rifampicin(R), Pyrazinamide (Z), Ethambutol(E), daily for 24 weeks duration, substituting Ethambutol for Moxifloxacin.

Intensive phase 7 days a week for 8 weeks Continuation phase - 7 days a week for 16 weeks.See details below.

(150,75,400,275 mg) RHZE Dosage and number of tablets dispensed is dependent on participants weight band.
Interventions: intervention 1: moxifloxacin
Intervention descriptions: intervention 1: \[isoniazid (H), rifampicin (R), pyrazinamide (Z), moxifloxacin (M)\]

Protocol documents:
Prot_000.pdf: 
PI: Dr N Padayatchi 
Site: CAPRISA   
Page 1 of 58 
Study No: CAP 011 
 
Version 4  
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CAP 011 
 
IMPROVING RETREATMENT SUCCESS  
(IMPRESS):  An open label randomized controlled clinical trial comparing a 24 week 
oral regimen containing Moxifloxacin with a 24 week standard tuberculosis (TB) drug 
regimen for the treatment of smear-positive pulmonary TB in patients previously 
treated for TB 
 
 
 
A research protocol prepared by: 
 
 
Centre for the AIDS Programme of Research in South Africa  
CAPRISA 
 
 
 
Funded by: European and Developing Countries Clinical Trials Partnership (EDCTP) 
 
 
 
 
 
 
 
 
 
Principal Investigator/Project Coordinator 
Dr Nesri Padayatchi 
Principal Investigator 
CAPRISA – Doris Duke Medical Research Institute (2nd Floor) 
Nelson R. Mandela School of Medicine 
University of KwaZulu Natal 
719 Umbilo Road 
Congella 
4013, Durban 
 
 
 
 


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CONTENTS 
Acronyms ................................................................................................................................................. 10 
SCHEMA ................................................................................................................................................. 11 
1.0 
Introduction ................................................................................................................................ 12 
1.1  
Background ................................................................................................................................. 12 
1.2  
Streptomycin ............................................................................................................................... 12 
1.3  
Rationale for Moxifloxacin ......................................................................................................... 13 
1.4 
Lipoarabinomannan ..................................................................................................................... 14 
1.5. 
Pharmacokinetic Study: .............................................................................................................. 14 
1.6. Use of Computerized dispensing and cellphone technology: innovative tools to enhance patient 
adherence, tracking and retention ............................................................................................... 16 
1.7 SHIP Project .................................................................................................................................... 16 
2.0    
Study AIMS and Objectives ....................................................................................................... 17 
2.1  
Primary objective ........................................................................................................................ 17 
2.2 
 Secondary Objectives ................................................................................................................. 17 
2.3 
Ancillary Objectives .................................................................................................................... 17 
3.0 
 Study Design and Setting .......................................................................................................... 18 
3.1 
 Study setting: study site and populations ................................................................................... 18 
4.0  
inclusion and exclusion criteria .................................................................................................. 19 
4.1 
Inclusion ...................................................................................................................................... 19 
4.2 
 Exclusion .................................................................................................................................... 19 
5.0  
Randomization Procedures ......................................................................................................... 20 
6.0  
Study Treatment ......................................................................................................................... 20 
6.1  
Regimens, Administration and Duration ..................................................................................... 20 
6.2  
Study product adverse effect information ................................................................................... 21 
6.3  
Pharmacy: Product Supply, Distribution, Accountability and Storage ....................................... 22 
6.4  
Adherence to study product ........................................................................................................ 23 
6.5  
Antiretroviral treatment and PCP prophylaxis ............................................................................ 23 
6.6 
Procedure for Urine LAM testing: .............................................................................................. 23 
7. Clinical and Laboratory Evaluations .................................................................................................... 24 
7.1 
Schedule of Events (SoE) ............................................................................................................ 24 
7.2  
Timing of Evaluations ................................................................................................................. 26 
7.2.1  
Screening Evaluations ........................................................................................................ 26 
7.2.2  
Baseline, Randomization and On Study Evaluations ......................................................... 26 
7.2.3  
Post Entry Evaluations ....................................................................................................... 26 
7.2.4  
Study Visit Window and Unscheduled Visits .................................................................... 27 
7.3  
Instructions for Evaluations ........................................................................................................ 28 
7.3.1 Sputum smear, culture and susceptibility ............................................................................. 28 
7.3.2 Specimen Storage ................................................................................................................. 28 


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7.3.3 Complete Physical Exam ......................................................................................................... 28 
7.3.4   Targeted Physical Exam ........................................................................................................ 28 
7.3.5  
Pregnancy Testing .............................................................................................................. 28 
7.3.6 PK sample collection ............................................................................................................... 28 
7.3.7 Urine samples for testing and storage will be drawn at the following time points in the visit 
schedule: ........................................................................................................................................... 29 
7.3.8 Procedures for computerized dispensing and cellphone technology: innovative tools to enhance 
patient adherence, tracking and retention: ........................................................................................ 29 
8.0  
Clinical Management Issues ...................................................................................................... 29 
8.1  
Clinical Management Issues ....................................................................................................... 29 
8.2 
Specific Clinical Management Scenarios .................................................................................... 30 
8.2.1 Missed TB doses .................................................................................................................. 30 
8.2.2  
Positive smear at M4, M6 ................................................................................................... 30 
8.2.3 MDR TB ............................................................................................................................... 30 
8.2.4 Withdrawal of study drug ..................................................................................................... 30 
8.2.5  
Reporting AE’s ................................................................................................................... 30 
8.3  
Guiding Principles of Adverse Event Management .................................................................... 30 
8.3.1  
Grade 1 Adverse Events ..................................................................................................... 30 
8.3.2 Grade 2 Adverse Events ....................................................................................................... 31 
8.3.3  
Grade 3 and 4 Adverse Events ........................................................................................... 31 
8.4  
 Reporting Serious Adverse Events (SAEs) ................................................................................ 31 
8.5 
 Safety Monitoring ...................................................................................................................... 31 
9.0 
 Statistical Considerations .......................................................................................................... 33 
9.1  
Sample size determination: ......................................................................................................... 33 
9.2 
 Analysis including statistical methods ....................................................................................... 34 
9.3 
Explanation on how the results of this study will be used .......................................................... 34 
10.0 
 Human Participants ................................................................................................................... 34 
10.1  Patient Recruitment ..................................................................................................................... 34 
10.2 Ethics ........................................................................................................................................... 35 
10.3  Regulatory and ethical review .................................................................................................... 35 
10.4  Informed consent process ............................................................................................................ 35 
10.5  Participant Confidentiality .......................................................................................................... 35 
10.6  Good Clinical Practice ................................................................................................................ 36 
11.0  
Data Management ...................................................................................................................... 36 
11.1  Data Collection and Methods ...................................................................................................... 36 
11.2  Information management and analysis software ........................................................................ 36 
11.3  Data entry, editing and management, including handling of data collection forms, different versions 
of data .......................................................................................................................................... 36 
11.4  Data Storage ................................................................................................................................ 37 


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11.5  Quality control/assurance ............................................................................................................ 37 
12.0    
Biohazard Containment .............................................................................................................. 38 
13.0  
 References ................................................................................................................................. 39 
Appendix I: IMPRESS Patient Informed Consent ................................................................................... 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Sites and laboratories participating in the study 
 
 
Clincial Research Site  
Contact person  
Contact Details 
The CAPRISA eThekwini Clinical 
Research Site 
3 Richards Road 
Berea 
Durban 
4001  
South Africa 
Dr Kogieleum Naidoo 
(Project Director) 
Tel : +27 31 260 4687/1922 
Fax : +27 31 307 3936 
E-mail : 
Kogie.Naidoo@caprisa.org  
Laboratories  
Contact person 
Contact Details 
Storage/PBMC Laboratory 
CAPRISA Research Laboratory NPC 
11 Dan Pienaar Road  
Amanzimtoti  
Durban 
4013 
South Africa  
Ms Natasha 
Samsunder  
(Head of CAPRISA 
Laboratories) 
Tel : +27 31 260 4454 
Fax : +27 31 260 4566 
E-mail : 
Natasha.Samsunder@caprisa.org 
 
Safety Bloods 
Global Clinical and Viral Laboratory 
11 Dan Pienaar Road  
Amanzimtoti  
Durban 
4013 
South Africa 
Mr Collin Pillay  
Clinical Trials 
Manager 
Tel : +27 31 9040510 
Fax: +27 31 9040553 
E-mail : 
Collin.Pillay@gcvlabs.co.za  
 
 
 
 


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PROTOCOL TEAM ROSTER 
 
NAME  
QUALIFICATION
S   
ROLE IN THE 
PROJECT 
CONTACT DETAILS 
Nesri 
Padayatchi 
MBChB, MSc 
(Epidemiology) 
 
Principal 
Investigator 
/Project 
Coordinator 
  
CAPRISA  Offices 
Doris Duke Medical Research Institute (2nd Floor) 
Nelson R Mandela School of Medicine 
University of KwaZulu Natal 
719 Umbilo Road  
Congella 
Durban 
4013 
South Africa 
Tel: +27 31 260 4574/4555 
Fax:+27 31 260 4566 
E-mail:Nesri.Padayatchi@caprisa.org  
Kogieleum 
Naidoo 
MBChB 
Project Director  
CAPRISA Offices 
Doris Duke Medical Research Institute (2nd Floor) 
Nelson R Mandela School of Medicine 
University of KwaZulu Natal 
719 Umbilo Road  
Congella 
Durban 
4013 
South Africa 
Tel:+27 31 260 4687/1922 
Fax: +27 31 260 4566 
E-mail: Kogie.Naidoo@caprisa.org 
Tanuja N. 
Gengiah 
B.Pharm, MSc 
(Epi), PHD 
(Therapeutics and 
Medicines 
management) 
Head of 
Pharmacy/ 
Study 
Pharmacist 
CAPRISA Offices 
Doris Duke Medical Research Institute (2nd Floor) 
Nelson R Mandela School of Medicine 
University of KwaZulu Natal 
719 Umbilo Road  
Congella 
Durban 
4013 
South Africa 
Tel:+27 31 260 4262 
Fax: +27 31 260 4566 
E-mail: Tanuja.Gengiah@caprisa.org 
 
Anushka 
Naidoo 
B.Pharm , MSc 
(MedSci, Clin 
Pharm) 
Co-Investigator 
/Study 
pharmacist 
CAPRISA eThekwini Clinical Research Site 
3 Richards Road 
Warwick Avenue 
Berea 
Durban 
4001 
South Africa 
Tel:+27 31 260 1963 
Fax: +27 31 307 3936 
E-mail:Anushka.Naidoo@caprisa.org 


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Study No: CAP 011 
 
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Anneke 
Grobler 
MSc 
(Biostatistician) 
PHD 
(Biostatistician) 
Statistician 
CAPRISA Offices 
Doris Duke Medical Research Institute (2nd Floor) 
Nelson R Mandela School of Medicine 
University of KwaZulu Natal 
719 Umbilo Road  
Congella 
Durban 
4013 
South Africa 
Tel:+27 31 260 4555 
Fax: +27 31 260 4566 
E-mail: Anneke.Grobler@caprisa.org 
Day 
Munatsi 
BSc  
(Computer Science 
and Statistics) 
Data Manager  
CAPRISA Offices 
Doris Duke Medical Research Institute (1st Floor) 
Nelson R Mandela School of Medicine 
University of KwaZulu Natal 
719 Umbilo Road  
Congella 
Durban 
4013 
South Africa 
Tel: +27 31 260 4825 
Fax: +27 31 260 4566 
E-mail: Day.Munatsi@caprisa.org 
Dhineshree 
Govender 
MSc  
(Biochemistry) 
Study 
Coordinator 
CAPRISA eThekwini Clinical Research Site 
3 Richards Road 
Warwick Avenue 
Berea 
Durban 
4001 
Tel : +27 31 260 1905 
Fax : +27 31 307 3936 
E-mail :  
Dhineshree.Govender@caprisa.org 
Charlene 
Harichund 
MSc (Microbiology) CTU 
Coordinator/ 
Head of Quality 
Assurance/ 
CAPRISA  
ExternalMonitor 
Doris Duke Medical Research Institute (2nd Floor) 
Nelson R Mandela School of Medicine 
University of KwaZulu Natal 
719 Umbilo Road  
Congella 
Durban 
4013 
South Africa 
Tel: +27 31 260 4304 
Fax:+27 31 260 4549 
E-mail:  
Charlene.Harichund@caprisa.org 
Rochelle 
Nicola 
Adams 
MBBCh 
Site Research 
Clinician 
CAPRISA eThekwini Clinical Research Site 
3 Richards Road 
Warwick Avenue 
Berea 
Durban 
4001 


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Study No: CAP 011 
 
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South Africa 
Tel: +27 31 260 1962 
Fax: +27 31 307 3936 
E-mail :   
Rochelle.Adams@caprisa.org 
Shanisa 
Naidoo  
MBChB 
Site Research 
Clinician  
CAPRISA eThekwini Clinical Research Site 
3 Richards Road 
Warwick Avenue 
Berea 
Durban 
4001 
South Africa 
Tel: +27 31 260 1962 
Fax: +27 31 307 3936 
E-mail :  Shanisa.Naidoo@caprisa.org 
Tilagavathy 
Chinappa 
MBChB 
Site Research 
Clinician  
CAPRISA eThekwini Clinical Research Site 
3 Richards Road 
Warwick Avenue 
Berea 
Durban 
4001 
South Africa 
Tel: +27 31 260 1962 
Fax: +27 31 307 3936 
E-mail :  Surie.Chinappa@caprisa.org 
Aveshen 
Govender  
 
MBChB 
Site Research 
Clinician  
CAPRISA eThekwini Clinical Research Site 
3 Richards Road 
Warwick Avenue 
Berea 
Durban 
4001 
South Africa 
Tel: +27 31 260 1962 
Fax: +27 31 307 3936 
E-mail :  Aveshen.govender@caprisa.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Site: CAPRISA   
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Study No: CAP 011 
 
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CAP 011 
 
IMPROVING RETREATMENT SUCCESS 
(IMPRESS):  An open label randomized controlled clinical trial comparing a 24 week oral regimen 
containing Moxifloxacin with a 24 week standard tuberculosis (TB) drug regimen for the treatment of 
smear-positive pulmonary TB in patients previously treated for TB 
 
 
INVESTIGATOR SIGNATURE FORM 
Version 4  
11 May 2015  
 
A research protocol prepared by: 
Centre for the AIDS Programme of Research in South Africa  
CAPRISA 
 
 
Funded by:  
European and Developing Countries Clinical Trials Partnership (EDCTP) 
 
 
I, the Investigator of Record, agree to conduct this study in full accordance with the provisions of this protocol. 
I have read and understand the information in the Investigator's Brochure(s), including the potential risks and 
side effects of the products under investigation, and will ensure that all associates, colleagues, and employees 
assisting in the conduct of the study are informed about the obligations incurred by their contribution to the 
study. 
 
 
 
____________________________                                       _______________________ 
Name of Investigator of Record  
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study No: CAP 011 
 
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ACRONYMS  
 
AE 
Adverse Event 
AFB  
Acid Fast Bacilli 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BREC 
Biomedical Research Council 
ICH- GCP 
International Conference on Harmonisation 
CrCl 
Creatinine clearance 
CRF 
Case Report Form 
EMB / E 
Ethambutol 
EAE 
Expedited Adverse Event 
EBA 
Early bactericidal activity 
ECG 
Electrocardiogram 
eCRS 
eThekwini Clinical Research Site 
GCP 
Good Clinical Practice 
INH or H 
Isoniazid 
IATA 
International Air Transport Association 
IUD 
Intrauterine Device 
M.TB 
Mycobacterium  tuberculosis 
MCC 
Medicines Control Council 
MDR 
Multi Drug Resistance 
NTP 
National TB Programme 
NVP 
Nevirapine 
PCZCDC 
Prince Cyril Zulu Communicable Disease Centre 
PID 
Patient Identifier 
RIF or  R 
Rifampicin 
SA GCP 
South African Good Clinical Practice Guidelines 
SAE 
Serious Adverse Event 
SANCTR 
South African National Clinical Trials Register 
SAS 
Statistical Analysis Software 
SID 
Screening Identification number 
SMC 
Safety Monitoring Committee 
SoE 
Schedule of Events 
SOPs 
Study Operating Procedures 
TB 
Tuberculosis 
UKZN 
University of KwaZulu-Natal 
ULN 
Upper limit of Normal 
WHO 
World Health Organization 
WSRR 
World Health Organization Standardized Category II 
Retreatment Regimen 
PZA or  Z 
Pyrazinamide 
 


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Study No: CAP 011 
 
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SCHEMA 
 
Design:            This is an open label randomized controlled clinical trial comparing two regimens for 
treatment of smear-positive pulmonary TB, among patients previously treated for TB. The 
primary objective is to determine if a Moxifloxacin-containing regimen, substituting 
Moxifloxacin for Ethambutol, of 24 weeks duration is superior to a control regimen of 24 
weeks duration in improving treatment outcomes in patients with recurrent TB. 
 
 
Duration : 
 
Intervention Arm : Approximately 6 months treatment + 12 months post treatment follow 
up 
Control Arm : Approximately 6  months treatment + 12 months post treatment follow up 
 
 
Sample Size:  
 
330 
 
 
Population : 
 
This study will include adults 18 years and over with a previous history of TB. HIV 
infected and uninfected patients will be included in the study as well as patients on ARVs 
provided that these are not contra-indicated with any of the study drugs. Patients with M 
tuberculosis resistance to Rifampicin will be excluded at screening using Gene Xpert 
technology.  
 
 
Randomizati
on:  
 
Patients will be randomized to receive 1 of 2 TB retreatment regimens 
 
Figure 1 : IMPRESS patient screening and randomization arms  
STEP 3: RANDOMIZATION 
STEP 4: SCHEDULE OF EVALUATION MONTHLY 
After treatment completion 2 monthly follow up for 
12months 
STEP 1: PATIENT POPULATION  
Patients with smear positive pulmonary Tuberculosis with a past history of TB 
STEP 2: SCREENING 
Gene Xpert to detect M.TB and to exclude Rifampicin Resistance 
 Control Arm 
 Intensive Phase: 2HRZE 
Continuation Phase:  4HR 
Intervention Arm 
Intensive Phase: 2HRZM  
Continuation Phase: 4HRM 


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Study No: CAP 011 
 
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1.0 
INTRODUCTION  
 
1.1  
Background  
 
South Africa has the worst co-epidemic of tuberculosis (TB) and Human Immunodeficiency Virus (HIV) in 
the world where an estimated 70% of TB patients are co-infected with HIV.  The dual epidemics have led to 
unacceptably high TB recurrence rates and previous TB treatment is a strong determinant of drug resistance1.  
In 2010, patients with previously treated tuberculosis comprised 15% of global TB notifications2. South Africa 
has the fourth highest number of multi-drug resistant TB (MDR TB) cases and the proportion of MDR TB was 
five times higher in those with previously treated TB3. According to the World Health Organization (WHO), 
an estimated 53% of retreatment TB cases were co-infected with HIV in 2011 with only 54% of these patients 
receiving concomitant ART2. In order to reduce the risk of recurrent TB, both the cure rate and the case 
detection rate need to be improved. In South Africa the treatment interruption rate on the standard WHO 
retreatment regimen is 12%2. This non-adherence to the retreatment regimen likely contributes to the 
increasing burden of MDR TB. There is a critical need for an evidence-based retreatment regimen to improve 
treatment outcomes of recurrent TB, a regimen that can reduce morbidity and mortality in a shorter time period. 
The translation of these findings to the clinical setting is urgently required as it has the potential to change 
current retreatment protocols which are protracted with low success rates. 
 
The existing World Health Organization Standardized Category II Retreatment Regimen (WSRR)4, adds a 
single injectable drug, streptomycin, to the first line 4 drug TB treatment regimen (RHZE) in the intensive 
phase. This regimen, used to treat 1 million patients each year, was based on expert opinion5, and has yet to 
be tested in a randomized controlled clinical trial6. Previous studies of the WSRR include a systematic review, 
a meta-analysis and a prospective cohort study6,7.  The systematic review , of published evidence of treatment 
of patients with a history of previous treatment or documented Isoniazid mono-resistance, included 33 trials, 
showed that in 1,907 patients lower  failure, relapse, and drug resistance were associated with longer duration 
of Rifampicin, daily treatment  and the use of a greater number of effective drugs.6   
 
Streptomycin was incorporated into the WSRR, when Rifampicin was first introduced for only 8 weeks to the 
TB treatment regimen. Rifampicin has since been used for the full duration of standard TB treatment (at least 
6 months), making the current first line TB treatment efficacious in treatment naïve patients. In addition, the 
WSRR was defined for settings with low prevalence of initial drug resistance; for patients treated on a regimen 
that included Rifampicin for only the first 2 months; and was implemented in the pre-HIV era5.  
 
A prospective cohort study in Uganda (a high HIV prevalence setting), to assess treatment outcomes with the 
WSRR, demonstrated that 20% (29/148) of HIV-uninfected and 26% (37/140) of HIV-infected patients had 
an unsuccessful treatment outcome7. Factors associated with poor outcomes included suboptimal adherence, 
HIV infection, increasing age, and duration of TB symptoms. HIV infected individuals were more likely to 
die than HIV uninfected individuals.   
 
There is a critical need for an evidence-based retreatment regimen that is applicable to areas with high 
prevalence of HIV-TB, which can shorten the duration of treatment, improve cure and completion rates, reduce 
morbidity, mortality and relapse rates. The proposed study aims to evaluate the efficacy of a shorter 
retreatment TB regimen, utilizing Moxifloxacin, a quinolone with potent activity against Mycobacterium 
tuberculosis (MTB)8.  
 
 
 
1.2  
Streptomycin  
 
In recent literature there is waning support for the WHO Category II regimen6,7. In 2009, a meta-analysis and 
extensive systematic review (of randomized controlled trials and observational studies) was undertaken to 


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determine the rates of treatment failure, relapse and drug resistance in patients on the WHO retreatment 
regimen6. After a comprehensive search of electronic databases, the authors could find no randomized 
controlled trials that evaluated the effectiveness of the WHO Category II regimen. From the observational 
studies reviewed the authors extracted treatment failure rates and calculated that failures ranged from 18% - 
44% in those with INH resistance. High rates of treatment failure on the Category II regimen have also been 
demonstrated elsewhere.   
 
In 2010, the country of Georgia’s National TB Programme (NTP) undertook an evaluation of treatment 
outcomes of patients on the WSRR regimen. The evaluation showed that there were poor outcomes among 
patients on the WSRR regimen and high rates of streptomycin resistance were observed among previously 
treated patients16. The NTP has since excluded streptomycin from the TB retreatment regimen arguing that 
there was a lack of evidence to support adding streptomycin to the WSRR regimen. 
 
The category II regimen has been adopted in more than 90 countries however there is little hard evidence to 
support its efficacy. Instead, several authors have suggested that a new and more effect retreatment regimen 
is needed6,7,15. 
 
 
1.3  
Rationale for Moxifloxacin 
 
Moxifloxacin is an 8-methoxyquinolone compound9.  Several studies have demonstrated that Moxifloxacin is 
an effective treatment against TB and has potential to shorten the course of TB treatment8,10,11. In, 2003, a 
randomized controlled trial in Tanzania measured the bactericidal activity of Moxifloxacin in patients with 
Pulmonary TB (PTB) 11. The study compared 3 groups of pulmonary TB patients. Group 1 received Isoniazid, 
Group 2 received Rifampicin and Group 3 received Moxifloxacin. Patients completed 5 days of monotherapy 
and sputum samples were collected before treatment was started and then daily for the duration of treatment.  
Early bactericidal activity (EBA) was measured as time taken to kill 50% of viable bacilli and the decrease in 
sputum viable count. The average time to bactericidal activity of Moxifloxacin was 0.88 days and the mean 
EBA was 0.53.  For Isoniazid and Rifampicin the mean EBA was 0.77 and 0.71 respectively. The study 
concluded that Moxifloxacin is highly bactericidal with similar activity to Rifampicin in human patients. 
Gillespie et al (1999), tested Moxifloxacin activity against 4 other quinolones against an array of clinical 
isolates of mycobacteria. When compared with other quinolones; Moxifloxacin had a lower MIC against 
Mycobacterium tuberculosis than Ciprofloxacin, Levofloxacin, Sparfloxacin and Isoniazid.9     
 
In terms of its safety profile, Moxifloxacin is well tolerated.11,12, 14  Two randomized controlled trials assessed 
the effectiveness and safety of Moxifloxacin.11, 13 Nausea is the most common side effect associated with 
Moxifloxacin however, very rarely does this result in drug discontinuation11.  
 
 
In a Phase II randomized controlled trial which substituted Moxifloxacin with Ethambutol, it was determined 
that Moxifloxacin is well tolerated  and resulted in a higher frequency of negative cultures in earlier time 
points among  patients with smear positive pulmonary tuberculosis.11 This was an important study as it 
demonstrated that Moxifloxacin is a suitable substitute for Ethambutol. 
 
The principle of not adding a single drug to a failing regimen is well-known and the authors are well aware of 
this rule. The difference in this study is that all patients will be screened for Rifampicin susceptibility using 
Gene Xpert and any patient displaying Rifampicin resistance will be excluded. In addition, full susceptibility 
testing using MGIT, HAIN line probe assay and conventional culture will be conducted. Patients displaying 
multi drug resistance will be withdrawn from the study and referred for appropriate treatment at the provincial 
referral hospital which is within 10kms from trial site. 
 


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Moxifloxacin has been selected for use in this study due to its excellent safety profile and favourable outcomes 
in treating Tuberculosis. Several scientists in the field of TB research have recommended that further research 
on Moxifloxacin is needed to establish its ability to shorten the course of TB treatment.9,11, 14  
 
 
1.4 
Lipoarabinomannan 
 
Lipoarabinomannan (LAM), a glycolipid released from the cell wall of metabolically active or degrading 
mycobacterium, is filtered by the kidneys and excreted in urine. A new rapid, point-of-care urinary LAM 
antigen test, which does not require laboratory support, results in 25 minutes. This could improve the rate and 
speed of detecting tuberculosis (TB) in resource-limited settings. Preliminary studies have shown the rapid 
urine LAM test to have moderate sensitivity and high specificity for detecting culture-confirmed pulmonary 
TB.15 In addition, the urine LAM test may perform better among HIV-infected adults with lower CD4+ T cell 
counts, and detects extra-pulmonary tuberculosis.15-17 Additional data, including our own study, suggests that 
urine LAM positivity may be directly related to mycobacterial load.18,19 
 
A point-of-care urinary LAM antigen test may have several roles. First, it may serve as an appropriate 
diagnostic test among TB suspects. Since the test performs well among HIV-infected patients, then the rapid 
test may also perform well among HIV-negative patients with a high bacillary load. If confirmed, then urine 
LAM testing could be expanded to HIV-uninfected patients who are active TB suspects. Second, since the test 
may be related to bacillary load, then one would expect LAM detection to decrease over the course of anti-
tubercular therapy. If confirmed, then urine LAM testing could be used as a biomarker of response to anti-
tubercular therapy. 
 
This sub-study would be nested within the CAPRISA 011 Impress Study. All participants included in the 
parent study would be included in the urine LAM sub-study. 
 
 
1.5. 
Pharmacokinetic Study: 
 
The role of therapeutic drug monitoring in anti-tuberculous therapy has gained renewed interest in the wake 
of an unwavering TB epidemic, the emergence of drug resistance, and suboptimal treatment outcomes in 
certain sub-populations of patients with TB15,16. 
 
Moxifloxacin: 
 
Moxifoxacin has been shown to be effective in the treatment of tuberculosis and may shorten time to culture 
conversion9,14, Moxifloxacin has few clinically relevant drug-drug interactions, although a potential drug-drug 
interaction exists between Rifampicin and Moxifloxacin. Moxifloxacin is not a substrate for the cytochrome 
P450 enzyme system, the locus of many drug-drug interactions involving Rifampicin. However, Rifampicin 
also induces the activity of the cytosolic enzymes glucuronosyltransferase and sulphotransferase, and 
Moxifloxacin is metabolized by glucuronide and sulfate conjugation.  As a consequence, Rifampicin may up-
regulate the metabolism of Moxifloxacin and result in decreased Moxifloxacin concentrations. One study 
found that concomitant Rifampicin administration results in 27% decrease in Moxifloxacin AUC.17 Additional 
studies are needed to determine whether this difference is clinically relevant. Because Rifampicin is included 
in all of the treatment regimens in which Moxifloxacin is likely to be used (except those used for treatment of 
Rifampicin-resistant tuberculosis), it is important that the clinical relevance of this potential interaction be 
evaluated.  
 
Moxifloxacin is metabolized by glucuronide and sulfate conjugation with the sulfate conjugate (M1) 
accounting for 38% and the glucuronide conjugate (M2) accounting for 14% of the oral dose.  Another protein, 
P-glycoprotein, plays an important role in absorption, distribution and elimination of xenobiotics and may 


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affect drug concentrations of Moxifloxacin and Rifampicin containing TB drug therapy.18,19   Rifampicin and 
the quinolones have been reported to be substrates of P-glycoprotein.20-22  More than 20 single nucleotide 
polymorphisms have been identified in the MDR1 gene, and interethnic differences in the frequencies of 
MDR1 mutations leading to altered P-glycoprotein function are likely to contribute to interethnic differences 
in drug efficacy and toxicity.  Genetic variation in the MDR1, UDP-glucuronosyl transferase and other relevant 
genotypes of drug metabolizing enzymes may modify Moxifloxacin and Rifampicin containing TB drug 
concentrations/pharmacokinetic values. Further evaluations among patients with tuberculosis disease are 
warranted to evaluate clinical relevance and effects on therapeutic outcomes.  
 
The pharmacokinetic-pharmacodynamic marker that best predicts the efficacy of fluroquinlones, including 
Moxifloxacin is the area under the curve (AUC) to MIC ratio.23 The AUC/MIC ratio has been shown to be a 
reliable measure of Moxifloxacin activity. AUC/MIC ratio of > 100 has also been demonstrated to be 
associated with better TB treatment outcomes and greatest bacteriological activity against Mycobacterium 
tuberculosis and a decreased probability of resistance.23-27  
 
There is very limited data on the effects of drug concentrations of the quinolones as part of first line TB drug 
regimens on TB treatment outcomes. Moxifloxacin has a variable pharmacokinetic profile and a number of 
covariates including but not limited to body mass index (BMI), co morbidities, disease severity, may affect 
Moxifloxacin drug concentration. This study will provide valuable information on the contribution of 
Moxifloxacin drug concentrations as part of a Rifampicin containing TB drug regimen on therapeutic 
outcomes in patients with recurrent TB.  
 
Rifampicin containing TB therapy: 
 
Since the global adoption of the Directly Observed Therapy short-course strategy, Rifampicin has remained 
the cornerstone of the multi-drug antimycobacterial therapy28-31. The critical role of Rifampicin in first-line 
therapy is well documented, and has steadily gained support due to its potent early bactericidal activity against 
Mycobacterium TB as well as its sustained activity against persistent bacilli, particularly during log-phase 
growth spurts32. Initial therapeutic targets for Rifampicin were guided by studies in healthy volunteers, and 
the subsequent dosage recommendations were based on the early high cost of the drug and fears of drug 
toxicity in the absence of studies on higher than recommended dose ranges16,33. Existing pharmacokinetic 
studies have demonstrated that current dosing practices result in Rifampicin concentrations on the lower limit 
of its therapeutic range, if not below it34-36. This is significant because the action if Rifampicin has been 
demonstrated to be concentration dependent37. Ratios of both Cmax to MIC and AUC to MIC are important, 
and a Cmax  of 8 to 24 mcg/ml is recommended for optimal bactericidal activity and post-antibiotic effect16. 
Various factors have been demonstrated to be associated with low plasma drug concentrations which include 
reduced bioavailability in the context of widespread use of fixed dose combination preparations, male gender, 
low body weight, anaemia, hypoalbuminaemia, HIV infection, gastrointestinal disease, diabetes mellitus36. 
More recently, various pharmacogenetic postulates for suboptimal drug levels have emerged and will require 
further evaluation. A major limitation of existing pharmacokinetic data on antimycobacterial drugs is the 
failure to link pharmacokinetic parameters to clinical outcomes33. The few studies that have attempted to 
investigate the relationship between antimycobacterial drug levels and clinical outcomes all demonstrate the 
need to investigate current dosage practices with the view to achieving therapeutic targets15,30,33,38. The studies 
however, were not able to convincingly demonstrate that suboptimal drug levels were in themselves predictors 
of poor outcomes.  
 
The pharmacokinetic sub-study aims to assess the relationship between Moxifloxacin and Rifampicin 
containing TB treatment drug levels and therapeutic outcomes and would be nested within the CAPRISA 011 
Impress Study. All participants who consent to participation in this sub-study will be included. 
 
 


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1.6. Use of Computerized dispensing and cellphone technology: innovative tools to enhance patient 
adherence, tracking and retention  
 
The widespread availability of cell phone technology in resource limited settings has prompted interest in 
using this tool as a way to enhance adherence to medication. Cell phone networks are well developed in South 
Africa 39 and the number of cell phones in use countrywide was estimated at approximately 59,500,000 
according to the GSMA Africa Mobile Observatory conducted in 2011, whereby 117.6 per 100 inhabitants in 
South Africa were estimated to have a cell phone.  By mid-2013, total cellphone subscriptions in South Africa 
were estimated at over 68 million40. Thus, access to this technology is rapidly increasing.  In a small qualitative 
study of cell phones used to report data about patient interactions, South African community-based ART 
counsellors described them as easy to use and without stigma41.  Automated individualized text message 
reminders sent to 300 South African patients with TB about taking their anti-TB medications were reported to 
be feasible, easy, inexpensive, and resulted in a less than 2% TB treatment failure rate42.   
 
Text messaging has been used as an intervention in various clinical trial settings and has been shown to be 
both cost effective and inexpensive with immediate results43,44.  It is available on every type of cellular 
telephone, is low cost, the patient does not require special skills, training or expertise  to receive, understand 
and interpret a text message, and it is advantageous as the patient can access the message at a later time even 
if the phone is switched off  when the message was sent. Text messaging may also show potential as a tool for 
behaviour modification in disease prevention and management by virtue of the ability to provide customized, 
individually tailored health related communication. Timed sms’es have been shown to improve self-reported 
adherence from a baseline of 79% to 94%,  as well as virological outcomes in HIV-1-infected patients, where 
baseline rate of 42% of undetectable HIV RNA viral load had increased to > 70 % at month 3, 6 and 945. In a 
randomised control trial conducted in Kenya, it was demonstrated that the receipt of a sms did not directly 
result in any adverse effects (e.g. injury, breach of confidentiality, etc.) for the recipients46.  The use of cellular 
phone technology is also being widely investigated in patients who cannot utilize Directly Observed 
Treatment, Short course (DOTS) or were not successfully treated under DOTS therapy , in order to promote 
drug compliance during tuberculosis treatment47. 
 
The computerized dispensing system, iDART,  has the potential to be linked to cellular phone  technology that 
will enable a broader scope of functionality in a clinical trial setting48. This technology, known as 
Communicate, is an iDART compatible software   package that uses cellphone functions to provide 
communication and information services amongst caregivers and patients in the form of sms, news alerts as 
well as schedule reminders. 
 
 
1.7 SHIP Project  
 
Tuberculosis (TB) is a major health problem globally, and especially in South Africa. More effective 
intervention strategies, including TB vaccines, are urgent.  
 
The IMPRESS sample banks and datasets, or active recruitment and sample collection platforms, will be used 
to identify and validate correlates of risk of TB disease, recurrent TB disease and/or protection against 
recurrent TB induced by the novel TB vaccine candidate, ID93 + GLA-SE. Prediction of, and protection 
against, recurrent TB is a major focus of new studies, given the potential for improved control of multidrug-
resistant TB (MDR-TB), and leverage of high TB case accrual rates to perform small, efficient proof-of-
concept TB vaccine efficacy trials.  
 
Our aim is to develop and/or validate correlates based on common biological pathways that are fundamentally 
important in determining protection versus susceptibility to TB to allow prediction of TB disease risk. 
Prospective correlates of risk will allow selective enrollment of individuals who are likely to progress to TB 
disease into efficacy trials of new vaccines, dramatically reducing sample size and cost. Correlates of risk will 


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also guide approaches to identify correlates of protection, which could be used for assessment of vaccines in 
early phase trials. Finally, gains in understanding biological pathways underlying host control of M. 
tuberculosis will inform rational development of new vaccines and/or immunotherapeutics. 
 
We have assembled a multi-institutional network of investigators at four South African and two US 
institutions, who collectively possess the necessary skills, capability and capacity, a diverse set of candidate 
correlates and TB immunopathogenesis biomarkers, and thousands of banked human samples. We will have 
unrivalled statistical power from one of the world’s largest sets of data and banked clinical specimens to 
scrutinize the key transition points in TB immunopathogenesis.  
 
We propose to systematically test if candidate correlates of risk of TB or treatment success can predict key 
transition points in the timeline of TB pathogenesis. 
 
2.0    STUDY AIMS AND OBJECTIVES  
 
2.1  
Primary objective 
 
The primary objective is to determine if a Moxifloxacin-containing regimen, [Isoniazid (H), Rifampicin (R), 
Pyrazinamide (Z), Moxifloxacin (M)], substituting Moxifloxacin for Ethambutol, of 24 weeks duration is 
superior to a control regimen [Isoniazid (H), Rifampicin(R), Pyrazinamide (Z), Ethambutol (E)] of 24 weeks 
duration in improving treatment outcomes in patients with recurrent TB. 
 
 
2.2 
 Secondary Objectives  
 
2.2.1 To determine the time to culture-conversion of the Moxifloxacin regimen and the Ethambutol regimen 
using data from 2-, 4-, 6-, and 8-week cultures  
2.2.2 To compare the proportion of patients with any Grade 3 or 4 adverse reactions  
2.2.3 To compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. 
HIV-uninfected patients 
2.2.4 To compare the rates of treatment failure and recurrence of the Intervention and Control arm. 
2.2.5  To compare TB cure rates at month 6 and at end of TB treatment between the Intervention and Control 
Arm 
 
 
2.3 
Ancillary Objectives  
 
2.3.1 To determine if the LAM antigen test is an appropriate diagnostic test for TB suspects 
2.3.2 To determine the effect of the drug concentration and pharmacokinetic/pharmacodynamic (PK/PD) 
parameters of Moxifloxacin and Rifampicin containing TB therapy on TB treatment outcomes 
(including but not limited to sputum culture conversion rates) 
2.3.3 To determine the extent of the drug interaction between Moxifloxacin and Rifampicin containing TB 
treatment, and the clinical relevance of this interaction. 
2.3.4 To determine the presence of specific polymorphisms of drug metabolizing enzymes and investigate 
the effect of these on Moxifloxacin and Rifampicin containing TB drug concentrations (including but 
not limited to polymorphisms of MDR1, SGT and UGT genotypes). 
2.3.5 To determine the effect of Moxifloxacin and Rifampicin containing TB drug concentrations on drug 
resistance. 
2.3.6    To assess the effect of relevant covariates on Moxifloxacin and Rifampicin containing TB drug 
concentrations 


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2.3.7 To assess acceptability and feasibility of short messaging service (sms) reminders amongst participants 
with recurrent tuberculosis enrolled in a clinical trial in an urban setting in Durban, South Africa 
2.3.8 Using computerised dispensing to  generate missed visit reports and other data that will be combined 
with cellular phone technology to  assist with monitoring patient adherence, tracking and retention  
2.3.9 Identify and validate correlates of risk of TB disease, recurrent TB disease and/or protection against 
recurrent TB induced by the novel TB vaccine candidate, ID93 + GLA-SE  
 
3.0 
 STUDY DESIGN AND SETTING 
 
 
This is an open label randomized controlled clinical trial comparing two regimens for treatment of smear-
positive pulmonary TB, among patients previously treated for TB. Patients will be randomized to receive one 
of the two TB retreatment regimens as listed below. In the Intervention Arm, Moxifloxacin will be substituted 
for Ethambutol.  “Study drugs” refer to all the drugs listed in Table 1.  
 
 
Table 1: Study Regimens  
Study Regimens 
 
Intensive phase 
Continuation phase 
Intervention Arm * 
HRZM daily (first 2 months ) 
HRM daily (4 months) 
Control Arm ** 
HRZE daily (first 2 months ) 
HR daily (4 months ) 
 H – Isoniazid; R – Rifampicin; Z – pyrazinamide; E – Ethambutol; M - Moxifloxacin 
* When patients become smear negative, they will be switched from the intensive phase to continuation phase with Isoniazid, Rifampicin and 
Moxifloxacin for 4 months  
**When patients become smear negative, they will be switched from the intensive phase to continuation phase with RIF and INH for 4 months. 
 
 
In this study the total duration of TB therapy will be 24 weeks (6 months) for the Intervention Arm, and the 
Control Arm. The duration of TB treatment may increase due to a delay in the time to sputum conversion. 
This will result in the extension of TB treatment beyond 6 months. 
 
 
 
3.1 
 Study setting: study site and populations  
 
The study will be conducted at the CAPRISA eThekwini Clinical Research Site (eCRS), adjoining the largest 
government outpatient TB facilities, the Prince Cyril Zulu Communicable Disease Centre (PCZCDC). The 
PCZCDC provides free diagnosis and treatment for patients with TB in Durban. The clinic is readily accessible 
by public transport. Over the last 3 years, TB cases in the Durban region have increased by 38%.  In 2001, 
7,819 received TB care, 70% had pulmonary tuberculosis. In 2008, 4179 TB patients were managed at the 
clinic and of these, 2204 had smear positive TB.  Approximately 35% of patients have a past history of TB.  
The majority (91%) of TB patients are black Africans, unemployed (53%), women (39%), 69% are HIV co-
infected and the median age was 33 years (range: 5-72 years).  The change in number from 2001 to 2008 is 
due to the decentralization of TB services. In order to make treatment even more accessible and also improve 
case holding.  Laboratory support is available onsite.  
 
 
 


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4.0  
INCLUSION AND EXCLUSION CRITERIA   
 
4.1 Inclusion  
 
4.1.1  Adults ≥ 18 years of age 
4.1.2  Previous history of anti-TB chemotherapy 
4.1.3   HIV status:  HIV infected and uninfected patients are allowed in the study: 
4.1.3.1 All patients must agree to HIV testing to confirm HIV status.   
4.1.3.2 Patients already on ARVs will be allowed in the study provided that the ART   regimen is 
not contraindicated with any of the study agents (see 4.2.1 below).   
4.1.3.3 HIV infected patients at any CD4 count irrespective of ART commencement and   duration 
will be included in the study  
4.1.4  Smear positive  
4.1.5 Rifampicin susceptible as determined by Gene Xpert at screening. Gene Xpert will be used to 
determine Rifampicin resistance, hence the study team will made aware of resistance prior to study 
enrolment. 
4.1.6 Karnofsky score  >  70 
4.1.7 Female candidates of reproductive potential must agree to use two reliable methods of contraception 
while on study: a barrier method of contraception (condoms or cervical cap) together with another 
reliable form of contraceptive (condoms with a spermicidal agent, a diaphragm or cervical cap with 
spermicide, an Intrauterine Device (IUD), or hormone-based contraceptive) 
4.1.8 A negative pregnancy test  
4.1.9 Laboratory parameters done at, or  14 days prior to, screening: 
 
• 
Haemoglobin level of at least 7.0 g/dL 
• 
Serum aspartate transaminase (AST) and alanine transaminase (ALT) activity less than 3 
times the upper limit of normal 
• 
Serum total bilirubin level less than 2.5 times upper limit of normal 
• 
Creatinine clearance (CrCl) level greater than 60 mls/min 
• 
Platelet count of at least 50 x109cells/L 
• 
Serum potassium greater than 3.0 mmol/L 
 
 
 
4.2 
 Exclusion 
 
4.2.1  Patients on a Nevirapine (NVP)-containing ART regimen at screening 
4.2.2 Pregnant or breastfeeding  
4.2.3   Received an antibiotic active against M. tuberculosis in the last 14 days (e.g. fluoroquinolones, 
macrolides, standard anti-tuberculosis drugs). 
4.2.4  Patients with known   M.  tuberculosis resistance to any of the study drugs at screening  
4.2.5  History of prolonged QT syndrome or current or planned therapy with quinidine, procainamide, 
amiodarone, sotalol, or ziprasidone during the intensive phase of tuberculosis treatment. 
 4.2.6 Known allergies or intolerance to any of the study drugs. 
 
NOTE: All potential participants will undergo screening evaluations to determine eligibility. The site 
investigator (or designate) will assess eligibility and ensure that the participant meets all of the inclusion 
criteria.  
 


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5.0  
RANDOMIZATION PROCEDURES 
 
Patients will be randomized to the two arms using permuted block randomization (e.g. blocks of variable sizes 
4 or 6) stratified by HIV status. The randomization will be done by a statistician and the randomization codes 
will not be available to study staff until the participant is randomized.  This will be done by providing sealed 
opaque randomization envelopes to the research staff at the CAPRISA – eThekwini CRS.  The envelopes will 
be stored in a locked cupboard and opened in sequential order by study team members authorized to perform 
randomization procedures by the Principal Investigator.  After opening the envelopes, staff will record the date 
and time of opening the envelope and their staff details. The patient’s allocated arm will then be recorded on 
a randomization log.  
 
6.0  
STUDY TREATMENT  
 
6.1  
Regimens, Administration and Duration 
 
Once randomized to either the Control or Intervention arms the study drug is to be self-administered once 
daily before meals. Treatment should be commenced no more than 3 days after randomization. The Control 
and Intervention arms will follow the South African National Tuberculosis dosing guidelines for re-treatment 
cases as closely as possible. All patients will receive pyridoxine 50mg daily whilst in the study. 
 
    
Table 2:  Study drug regimens and duration: Control arm 
Pre-treatment 
body weight 
Intensive phase 7 days a 
week for 8 weeks 
 
 (56 doses) 
Continuation phase – 7 days a week for 16 weeks  
 
 
(112doses) 
(kg) 
RHZE 
(150,75,400,275 mg) 
RH 
(150,75 mg) 
RH 
(300,150mg) 
 
 
30-37 
2 tabs 
2 tabs 
 
38-54 
3 tabs 
3 tabs 
55-70 
4 tabs 
 
2 tabs 
>71 
5 tabs 
2 tabs 
     H – Isoniazid; R – Rifampicin; Z – pyrazinamide; E – Ethambutol 
. 
 
 
 
 
 
 
 


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Table 3: Study drug regimens and duration: Intervention arm 
 
Pre-
treatment 
body 
weight 
Intensive phase 7 days a week for 8 
weeks  
 
(56 doses) 
 
Continuation phase – 7 days a week for  16 
weeks  
 
(112 doses) 
(kg) 
RH 
(150,75m
g) 
RH 
(300,150
mg) 
 
Z 
(500m
g) 
M 
(400m
g) 
RH 
(150,75 
mg) 
M 
(400 
mg) 
RH 
(300,150
mg) 
M 
(400mg
) 
30-37 
2 tabs 
 
2 tabs 
1tab 
2 tabs 
1 tab 
 
38-54 
3 tabs 
3 tabs 
1tab 
3 tabs 
1 tab 
>55 
 
2 tabs 
4 tabs 
1tab 
 
2 tabs 
1 tab 
H – Isoniazid; R – Rifampicin; Z – pyrazinamide, M - Moxifloxacin 
      In this study the total duration of TB therapy will be 24 weeks for the intervention arm, and the control arm. The duration of TB treatment 
may be extended depending on the time to sputum conversion.  
 
In this study the total duration of TB therapy will be 24 weeks for the Intervention arm, and for the Control 
arm. The duration of TB treatment may increase due to a delay in the time to sputum conversion. This will 
result in the extension of TB treatment beyond 6 months. The required number of doses must be completed 
by the patient for the intensive phase of TB treatment before the patient can initiate the continuation phase of 
TB treatment. The study pharmacist and study clinician will monitor the number of doses ingested, by pill 
count, for each phase of treatment. The patient’s weight will be assessed monthly and the dose of the study 
product will be adjusted in accordance with the patient’s weight which will be assessed monthly. 
 
 
In addition to the 6 months of TB treatment regimen, patients in the Intervention Arm, who provide informed 
consent to take part in the PK sub-study may be requested to take a single dose of Moxifloxacin 400mg, at the 
Month 7 visit (or subsequent visit if Month 7 visit has been missed). This PK sample for single dose 
moxifloxacin may be deferred to month after TB treatment completion on participants who have TB treatment 
extended beyond 6 months 
 
 
 
6.2  
Study product adverse effect information 
Table 4 outlines possible adverse effects and drug interactions. However, this list is not all inclusive and 
each adverse effect must be examined in conjunction with the full clinical picture. At each clinic visit 
patients will be asked about adverse events that have occurred since their previous visit and physical 
examination will be performed. 
Table 4:  Possible adverse effects and drug interactions. 
 
Study Drug 
Adverse effects  
Drug interactions 
Comments 
Rifampicin 
Gastro-intestinal: nausea, 
anorexia, mild abdominal 
pain, diarrhea. Cutaneous 
reactions: mild flushing 
and pruritus. Hepatitis 
especially if alcoholic or 
history of liver disease. 
Efavirenz, nevirapine, protease 
inhibitors. Rif is an enzyme inducer and 
increases metabolism of oral 
anticoagulants (warfarin), oral diabetic 
drugs, digoxin, phenobarbitone and 
other anti-epileptics. 
Colours 
urine, sweat 
and tears 
orange-pink. 


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Serious: flu-like syndrome 
and shock 
Isoniazid 
Peripheral neuropathy, 
hepatitis (mostly in those > 
35yrs), generalized skin 
rash, fever, joint pains – 
rare. 
Inhibits metabolism of anti-epileptics.  
 
Ethambutol 
Progressive loss of vision 
caused by retrobulbar 
neuritis, usually manifests 
first as loss of colour vision 
and usually presents after 
the client has been on 
treatment for at least two 
months. This is usually 
caused by excessive doses 
of Ethambutol. Skin rash, 
joint pain, peripheral 
neuropathy. 
There are no known drug–drug 
interactions involving Ethambutol. 
Do not 
administer if 
optic neuritis 
present. 
Pyrazinamide 
Liver damage: anorexia, 
mild fever, tender 
enlargement of the liver 
and spleen may be 
followed by jaundice.  
Arthralgia: This is common 
and mild. The pain affects 
both large and small joints, 
the level of uric acid is 
increased and gout may 
occur. 
Skin rash on sun exposed 
areas. 
Low potential for drug interactions. 
 
Moxifloxacin 
Prolonged QT interval, 
well tolerated – low rates 
of gastrointestinal adverse 
effects.  
Potential interaction: Rifampicin, 
iron/iron containing supplements, 
aluminium/magnesium containing 
antacids, zinc/zinc containing 
supplements, didanosine, sucralfate. 
 
 
6.3  
Pharmacy: Product Supply, Distribution, Accountability and Storage 
 
All TB treatment with the exception of Moxifloxacin will be procured from the Department of Health and 
where possible fixed dose combinations of drugs will be utilized (outlined in Table 2 and 3). Moxifloxacin 
400mg tablets will be procured in bulk quantities from Bayer Healthcare and will be packaged for patient use 
at the study pharmacy under Good Pharmacy Practice guidance.   
 
The study pharmacy will maintain accountability records of all study products dispensed. In addition, records 
of manufacturer, batch number and expiry information will be maintained by the study pharmacist. Unused 
product will be re-issued to the participant at the discretion of the study pharmacist and in accordance with the 
stipulated dosing schedule.  
 
Dispensing of study product will be done either directly to the study patient or to authorized study staff if the 
patient is unable to present in person to the study pharmacy. 


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Study No: CAP 011 
 
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Study product will be stored between 15- 25C and temperature records will be maintained at the study 
pharmacy. Destruction of unused and never dispensed study product will be managed in accordance with the 
study pharmacy SOP on study product destruction after study PI approval.  
 
 
 
 
6.4  
Adherence to study product 
Adherence to study product will be assessed at the study pharmacy at each study visit. This will be achieved 
by pill count reconciliation and will be documented on a case report form (CRF). Patient self-reported reasons 
for non-adherence will be assessed and adherence counseling will be provided if needed.  
 
 
   
6.5  
Antiretroviral treatment and PCP prophylaxis  
 
Patients, who initiate the study whilst on antiretroviral therapy or during the course of the study require 
antiretroviral therapy, will be given a regimen that substitutes nevirapine with efavirenz. Patients found to be 
HIV infected may be given cotrimoxazole/dapsone prophylaxis in accordance with HIV/AIDS guidelines 
implemented locally.  
 
 
6.6 
Procedure for Urine LAM testing: 
 
Urine samples will be tested for LAM antigen using the DetermineTM TB LAM Ag test (Alere, Waltham, 
USA). First, participants will be given a urine specimen container and a private space to provide a urine 
sample.  The site nursing staff will use a manufacturer provided pipette to transfer 2 drops (approximately 60 
L) of urine to a small area of the test card. Two people will then independently interpret each result between 
25-35 minutes after starting the test. A small reference card, which will aid in correctly interpreting the result, 
will be available. If positive, the test result will be scored from 1+ to 5+, depending on the severity of the 
colorimetric line. A score of 1+ represents a weakly positive test result, and a score of 5+ represents a strongly 
positive test result. Once completed, the test card will be discarded and the urine sample will be placed in 
frozen storage along with other biologic specimens. The results of the rapid urine test will not be used for 
clinical treatment decision. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study No: CAP 011 
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7. CLINICAL AND LABORATORY EVALUATIONS   
7.1 Schedule of Events (SoE) 
Table 5: Study Table of Evaluations   
Procedures 
Scree
ning 
Basel
ine 
Week 
Study Months  
2 
4 
6 
2 
3 
4 
5 
6 
7 
8 
10 
12 
14-24 
(*2 
monthly) 
End 
TB 
Treat 
Recurr
ence6 
Termi
nation 
Time 
of 
IRIS 
Time of 
Serocon
version 
Inclusion & Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV test  (performed monthly for 
HIV negative participants) 
X1 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical , Medication and TB 
History & Physical Exam 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals (including Pregnancy 
test ) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception confirmation 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
GeneXpert  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum Smear 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Culture : INTERVENTION 
ARM: until 6 months  
 
X 
X X 
X X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
Culture: CONTROL ARM: 
until 6 months  
 
X 
X X 
X X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
Susceptibility  
 
X 
 
 
 
X 
 
 
 
X* 
 
X* 
 
 
 
X 
X 
 
 
 
PAXgene for SHIP Study 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
Urine (Lam Testing) 
 
X 
 
 
 
X 
 
 
X 
 X 
 
 
 
 
 
X 
 
 
 
 
Chest radiograph 
 
X2 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
ECG ** 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Vision testing (Snellen and 
Ishihara) Control Arm only  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Site: CAPRISA  
 
Study No: CAP 011 
Page 25 of 58 
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11 May 2015 
Procedures 
 
Scree
ning 
 
Basel
ine 
 
Week 
Study Months  
 
 
2 
4 
6 
2 
3 
4 
5 
6 
7 
8 
10 
12 
14-24 
(*2 
monthly) 
End 
TB 
Treat 
Recu
rrenc
e 
Termina
tion 
Time 
of 
IRIS 
Time 
of 
Seroco
nversio
n 
AST, ALT, Bilirubin, Hb, 
platelets, & Full blood count, 
Creatinine clearance, 
potassium, total protein, 
alkaline phosphatase and as 
clinically indicated 
X 
X2 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
CD4 Count (HIV Infected 
patients only) 
X 
 
 
 
 
As per SA HIV guidelines  
 
 
 
X 
 
Viral Load (HIV Infected 
patients only) 
X 
 
 
 
 
 
 
X 
 
X 
 
HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
PK Samples (Intervention 
Arm) 
 
 
 
X 
 
X
3 
 
 
 
X 
X4 
 
 
 
 
 
 
 
 
 
PK Samples (Control Arm) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen Storage 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PBMCs*** 
 
X5 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
1: HIV Testing is required at screening for all potential participants. Thereafter, HIV testing will be required for HIV negative participants only as per SoE above.  
2: A chest radiograph/Bloods will be repeated if they are more than 14 days old 
3: PK blood samples, in the intervention arm only, will be taken once during the intensive phase of TB treatment at either Week 4 OR Month 2 (PK bloods may be repeated at Month 2 if  these were 
not taken, incorrectly done or incomplete at Week 4 OR at the discretion of the investigator), and at the end of TB treatment (Month 6)  
4: Additional PK samples will be taken at M7 (or the first visit after if Month 7 is missed) in Intervention Arm before and after the ingestion of the single additional dose of Moxifloxacin. This 
additional PK sample may be deferred to month after TB treatment completion on participants who have TB treatment extended beyond 6 months 
5: If PBMCs are not collected at baseline samples may be taken at Week 4 or Month 2 
6. End of TB Treatment visit will be conducted within 7 days of completion of TB treatment.  
* Samples will be collected and stored for future susceptibility testing,  
**ECG’s will be done at baseline, Month 2 and  Month 4 and Month 6. ECG’s will be performed 2 monthly during treatment with Moxifloxacin 
***Additional PBMC’s will be collected at IRIS and at the time of seroconversion 
 
The study SoE will be followed except when procedures are clinically indicated as not required. 
 


PI: Dr N Padayatchi 
Site: CAPRISA  
 
Study No: CAP 011 
Page 26 of 58 
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11 May 2015 
7.2  
Timing of Evaluations 
 
Refer to Table 5 above for a summary of the evaluations. 
7.2.1  Screening Evaluations  
 
Informed Consent  
After identifying potential patients for the study, written informed consent must be obtained from these 
patients.  
 
HIV Testing  
HIV testing will be carried out using a licenced rapid HIV test. HIV positive results will be confirmed by a 
second licenced rapid HIV test. Discordant results will be confirmed by ELISA.  
 
Clinical and Laboratory Evaluations  
Patients will have height and weight measured, and blood will be drawn for an AST, ALT, total bilirubin, 
potassium, alkaline phosphatase, total protein Creatinine clearance, unless results from these tests within the 
previous 14 days are available.  A pregnancy test (using urine sample) is required at every visit if patient is a 
woman of child-bearing potential. 
 
A chest radiograph will also be taken, unless a chest radiograph done within the previous 14 days is available 
for review.  A sputum sample will be obtained for smear and GeneXpert analysis to ascertain Rifampicin 
resistance and confirm TB infection. Screening evaluations to determine eligibility must be completed <14 
days prior to randomization. 
 
In addition to data being collected on participants who enrol into the study, demographic, clinical, and 
laboratory data on screening failures will be captured in a Screening Failure Results form and entered into the 
study database. 
 
7.2.2  Baseline, Randomization and On Study Evaluations 
 
Eligibility criteria will be assessed by a study clinician prior to randomization. On-study entry evaluations will 
occur after randomization. Entry evaluations must be completed no more than 3 days after randomization. 
When the results of the blood tests and chest radiograph are available, and if the patient meets the enrolment 
criteria, the site must then randomize each new patients according to Section 5 (Randomization Procedures) 
above. Note, the result of HIV testing is required for randomization.  Baseline evaluations (according to SoE, 
Table 5) will be completed on the same day of the randomization (unless otherwise stated by the Study PI or 
study clinician) and patients should start on assigned study therapy as soon as possible after randomization but 
no more than 3 days following randomization. 
 
7.2.3  Post Entry Evaluations  
 
Study visits - intensive phase of therapy   
 
 
Intervention Arm - study visits Week 4 and Month 2 will be considered as intensive phase  
 
Control Arm - study visits Week 4, Month 2 will be considered as intensive phase 
A delay in the time to sputum conversation may result in an extension of the intensive phase. 
 
 
Regardless of arm, at each study visit for which the patient is in the treatment phase, a sputum sample will be 
obtained.  Sputum induction will be resorted to in the event that the participant is unable to provide a 


PI: Dr N Padayatchi 
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spontaneous, good quality sputum specimen. Laboratory tests for safety monitoring will also be obtained at 
study visits during the intensive phase of therapy.  Vision testing will be performed at baseline and repeated 
at Month 2 for Control Arm only.  Patients found to have HIV infection will have blood drawn for a CD4 cell 
count and HIV RNA level at the first study visit after HIV infection is confirmed (as per the study SoE). PBMC 
samples will be collected if a patient seroconverts whilst on study.  
 
Follow up management of HIV-infected patients will be as per SA HIV guidelines.  
 
 
Study visits – continuation phase of therapy  
 
Intervention arm - study visits Month 3 to Month 6 will be considered as continuation phase. 
 
Control arm - study visits Month 3 to Month 6 will be considered as continuation phase. 
 
Month 4 – Patients will have an assessment for toxicity from the four-drug phase of therapy.  This will consist 
of a symptom-driven examination, and laboratory testing (complete blood count and serum AST, total 
bilirubin, and serum creatinine).  A sputum specimen will be obtained for culture. 
 
Month 4-6–Patients will continue to have study visits monthly during the continuation phase of therapy.  
Sputum cultures will be obtained at Month 4, Month 5, Month 6 during the continuation phase of therapy.  
Laboratory testing, other than sputum cultures, will be at the discretion of the principal investigator/study 
clinician. 
 
 
Pharmacokinetic studies 
 
PK studies will be conducted on a subset of the study population. PK analyses will assess the potential 
interaction between Moxifloxacin and Rifampicin containing TB treatment in patients with recurrent TB, and 
to determine the effect of Moxifloxacin and Rifampicin containing TB therapy drug concentrations on TB 
treatment outcomes. 
 
Lipoarabinomannan studies  
 
All participants included in the parent study would be included in the urine LAM sub-study. 
Participants would provide urine samples at baseline, as well as 2- and 5 months into anti-tubercular therapy. 
One additional urine sample will be collected at the end of the assigned treatment course for each participant. 
Each urine sample would then be tested using one rapid urine LAM test strip in a designated laboratory. Once 
completed, the test card will be discarded and the urine sample will be stored in a freezer for future testing. 
 
7.2.4  Study Visit Window and Unscheduled Visits 
 
The window period for all scheduled monthly study visits ±7 days.  Any visit for which a patient attends 
outside of the specified visit window but not in addition to those required as per the ‘schedule of 
evaluations’ should be considered as an early/late visit. The assessments which are undertaken as part of an 
early/late visit should reflect those for the visit which will be or has been missed. Any additional 
assessments should be undertaken as clinically indicated. 
 
 
 
 


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Page 28 of 58 
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7.3  
Instructions for Evaluations 
  
7.3.1 Sputum smear, culture and susceptibility 
 
At the time points indicated in the SoE, a sputum sample will be collected for AFB smear, mycobacterial 
culture and susceptibility. 
 
7.3.2 Specimen Storage 
 
Specimens for storage will be stored according to timelines stated in the SoE. In addition to the scheduled 
timelines, samples found to be culture positive at baseline, Month 4 through Month 8 should be stored.  In 
addition, sputum isolates from smear testing will be stored.  
 
7.3.3 Complete Physical Exam 
 
A complete physical examination will be performed at screening only and will include at a minimum 
Karnofsky performance score, vital signs (i.e., temperature, pulse, respiratory rate, and blood pressure), height, 
weight, and full examination.  
7.3.4   Targeted Physical Exam 
 
A targeted physical examination will be performed at every study visit from baseline and on subsequent 
clinically required visits 
7.3.5  Pregnancy Testing 
For women of reproductive potential: The pregnancy test performed at study according to SoE must be 
negative. 
 
7.3.6 PK sample collection  
 
Plasma samples for storage will be drawn at the following time points in the visit schedule: 
• Week 4 (Intervention Arm) OR Month 2 (Intervention Arm) 
• Month 2 (Control Arm) 
• Month 6 (Intervention Arm) 
• Month 7 (Intervention Arm) or one month post end of TB treatment  
 
The duration of the intensive phase of TB treatment may increase due to a delay in the time to sputum 
conversion. If the duration of TB treatment is extended: 
- 
For Month 6 PK blood draw, End of continuation phase TB treatment (Month 6- Intervention Arm) 
sometimes the PK is not at end of the continuation phase because TB treatment is extended.  
- 
Month 7 PK blood will be completed at the month following the completion of TB treatment. 
 
Participants will be counselled to take their doses of TB treatment at a similar time once daily until the day 
before their scheduled study visit. The TB treatment dose on the day of the PK study visit will be ingested by 
participant at the study clinic. Plasma samples will be taken in the study clinic prior to the dose of TB therapy 
(Intervention Arm) and at specified time points in the course of the study visit. The plasma will be placed on 
ice and sent to the CAPRISA laboratory to be centrifuged and stored at –80 degrees Celsius for analysis at a 
later time. 
 
 


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Study No: CAP 011 
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Pharmacogenetic Studies: 
 
Drug metabolizing enzymes will be assessed to investigate the effect of specific polymorphisms on drug 
concentrations/pharmacokinetics of moxifloxcin and rifampicin containing TB therapy. 
 
 
7.3.7 Urine samples for testing and storage will be drawn at the following time points in the visit schedule: 
• Baseline (Both Arms) 
• Month 2 (Both Arms) 
• Month 5 (Both Arms) 
• Month 6 (Both Arms)End of TB Treatment (Both Arms)  
 
 
7.3.8 Procedures for computerized dispensing and cellphone technology: innovative tools to enhance patient 
adherence, tracking and retention: 
 
Participants who are enrolled and agree to receive a sms within the IMPRESS study will have their cellphone 
numbers entered onto the Communicate database. Different sms campaigns will be created, using the various 
cellular phone technology –based functions available: 
• An appointment reminder to go out 3 days before the participant is scheduled to present to the clinic, 
or sooner if visits are scheduled frequently over a short period of time: “Please do not forget your 
appointment at the clinic in three days’ time” 
• For those participants who are included in the pharmacokinetic sub-study, a broadcast sms sent out the 
evening before a scheduled visit, which reminds the patient not to take an evening/morning dose, prior 
to sample collection at the clinic for pharmacokinetic (PK) study, the next morning: “Please do not 
take your TB medication the night or morning before coming to the clinic. Carry TB drugs with you to 
be taken at the clinic.” 
• A sms to prompt defaulters to return to the clinic: “You have missed your appointment at the clinic. 
Please return to the clinic as soon as possible.” 
• An motivational broadcast sms to enhance patient compliance by re-enforcing adherence, programmed 
to be sent one week after enrolment, and periodically thereafter: at the end of month 1 of treatment and 
then at the beginning of the continuation phase: “TB can be cured and the spread of TB stopped if the 
full course of treatment is taken correctly, so that people can lead fuller, safer and healthier lives.” 
 
 
8.0  
CLINICAL MANAGEMENT ISSUES 
8.1  
Clinical Management Issues  
 
The IMPRESS study will use the Division of AIDS Table for Grading the Severity of Adult and Paediatric 
Adverse Events (DAIDS AE Grading Table) Version 1.0, December 2004 (Clarification, August 2009)  
• Patients need to be assessed for evidence of musculoskeletal toxicity at every study visit through 
history taking and physical examination. 
• Ocular toxicity will be assessed using the Snellen and Ishihara tests at baseline and month 2 and/or 
when clinically required (Control Arm only).  Patients will be educated about symptoms of ocular 
toxicity before treatment initiation, and will be assessed for ocular toxicity for the duration of TB 
therapy when Ethambutol forms part of the TB regimen. The Snellen and Ishihara tests will be repeated 
if any symptoms of ocular toxicity or any change in vision occurs.  


PI: Dr N Padayatchi 
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Study No: CAP 011 
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• All patients will undergo ECG monitoring at baseline, Month 2, Month 4,Month 6 (and 2 monthly 
whilst being administered with Moxifloxacin). This will be repeated if patients complain of chest pain 
or syncope. Moxifloxacin will be substituted for Ethambutol if there is evidence of QT prolongation, 
or if patients QRS complexes change in amplitude from baseline.  
• Patients must not have evidence of severe or life-threatening liver disease at baseline (Bilirubin, AST 
and ALT < 5 times the ULN), no evidence of renal impairment i.e. creatinine clearance of > 60 
mls/min, serum potassium of > 3.0 mmol/l.  
 
 
 
8.2    Specific Clinical Management Scenarios 
 
8.2.1 Missed TB doses 
 Extend treatment to allow patient time to complete requisite doses. 
 
 
8.2.2  Positive smear at M4, M6 
 Investigate for treatment failure, and change therapy if accompanied by clinical or radiologic deterioration or 
relapse of symptoms and follow local TB management guidelines. 
 
8.2.3 MDR TB 
Patients withdrawn from study because their initial TB isolate is found to be MDR –TB will not be followed 
up further, unless required for patient safety (e.g. an adverse event present, in which case follow-up should 
occur as clinically indicated). 
 
 
8.2.4 Withdrawal of study drug  
An investigator may withdraw one or all drugs in the study treatment in the event of a serious or life-
threatening adverse event, if this is deemed to be in the patients’ best interest. This needs be discussed with 
the study PI or designee before the decision is made, unless in an emergency situation. All safety issues need 
to be followed up until resolution to < Grade 2 (DAIDS Table for Grading Adult and Paediatric Toxicity 
Events)  
 
8.2.5  Reporting AE’s  
The study drugs are Moxifloxacin, Ethambutol, Isoniazid, Rifampicin, and Pyrazinamide. The most common 
adverse effects known to be associated with the study drugs are summarized in the protocol (see Table 4 
above). The investigators are responsible for reporting all Grade 3 and Grade 4 adverse events that are observed 
or reported during the study, regardless of whether they are thought to be related to the study drugs in patients 
chart notes. All Adverse Events including SAEs will be reported in accordance with ICH and SA GCP 
guidelines.  
 
 
8.3  
Guiding Principles of Adverse Event Management 
 
For adverse events, that is in the investigator’s judgment may be due to study drugs, the following approach 
to management should be applied: 
 
8.3.1  Grade 1 Adverse Events  
 


PI: Dr N Padayatchi 
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Study No: CAP 011 
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In general, for grade 1 events the patient will be followed carefully and the study drugs will be continued.  
8.3.2 Grade 2 Adverse Events 
 
For grade 2 events the patient will be followed more closely, with additional laboratory and/or clinic visits as 
necessary; drugs should be continued unless in the view of the investigator this would be unsafe.  
8.3.3  Grade 3 and 4 Adverse Events  
 
Any grade 3 or 4 event should be carefully assessed. The research clinician should rule out other possible 
causes of the symptoms before discontinuing study medication. When possible, concomitant medications 
should be with-held first at the discretion of the research clinician if causality is suspected. If after careful 
assessment and in the clinician’s judgment the event is due to study drug(s), the causative study drug(s) may 
be withheld. The patient should be permanently discontinued from study medications if it is in their best 
interests to do so. Further treatment of the TB will be directed by the clinician in consultation with the 
investigator. The patient will continue to be followed according to the protocol. Other adverse events of any 
grade not thought to be due to the study drugs, should be managed at the discretion of the research clinician; 
study treatment should be continued, if possible. 
 
 
8.4  
 Reporting Serious Adverse Events (SAEs) 
 
The following Serious Adverse Event will be reportable to the database and regulatory authorities: AE’s that: 
 
• Results in death  
• Is immediately life threatening at the time of occurrence 
• Results in persistent or significant disability or incapacity  
• Requires in-patient hospitalization or prolongs hospitalization 
• Results in a congenital anomaly or birth defect 
• Is deemed an “important medical event” by the Investigator (may not be immediately life threatening or 
result in death or hospitalization but may jeopardize the patient e.g. convulsions. This will include any 
adverse event that is unexpected, but related to the study product, e.g. asymptomatic prolonged QT interval 
associated with Moxifloxacin. 
 
 
8.5 
 Safety Monitoring  
 
Procedures for assessing safety 
At each clinic visit patients will be asked about changes (adverse events) that have 
occurred since their previous visit.  Physical assessments will be performed at baseline and on subsequent 
scheduled visits. 
Safety laboratory investigations will be performed at screening and in accordance with the schedule of 
evaluations, as well as determined by the study clinician based on the evaluation. 
1. Screening tests and scheduled subsequent visits will include: Liver function, renal function, full blood 
count: At screening, baseline and every second month until Month 8 of follow up. Thereafter, tests will 
be performed at the end of TB treatment, time of TB recurrence and at the study termination visit. 
2. 2. Pregnancy test: At screening, baseline and every month thereafter as per the SoE. 
 
 
For isolated asymptomatic or symptomatic Grade 3 elevation of total bilirubin all medications should be 
discontinued and held for up to 14 days until levels and symptoms are Grade  2, at which time therapy may 
be reintroduced. If there is > Grade 2 elevation of total bilirubin with transaminase elevation of grade > 3, this 


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should be treated as Grade 4. If Grade 3 toxicity develops after re-introduction of the study medications or if 
the Grade 3 toxicity does not resolve within 14 days, then the participant will be discontinued from study 
medications. The participant will continue to be followed on study, off study drugs. All medications may be 
restarted if the laboratory abnormalities were thought secondary to a concomitant illness.  
 
Participants who develop Grade 4 elevations of the total bilirubin will be discontinued from study medications. 
The participant will continue to be followed on study, off study drugs. 
 
Any additional test that the investigator deems necessary for the clinical evaluation of the subject can be 
performed. 
 
Any adverse events detected will be graded according to a modified version of the toxicity criteria produced 
by the Division of AIDS and coded using MedDRA. 
 
 
 
 
QTc Prolongation 
 
Participants in this trial may receive Moxifloxacin which has the potential to prolong the QTc interval.  All 
QTc measurements will be corrected with the Fridericia correction. 
 
The protocol-specific criteria for grading prolonged QTc are as follows: 
 
 
 
If Grade 2 QTc prolongation develops during the course of the study and is felt to be due to study medications, 
the participant will be monitored more closely, with twice weekly visits and QTc evaluation. If Grade 3 QTc 
prolongation occurs, all study drugs will be discontinued and the participant will be referred to hospital for 
further assessment and management. If the QTc prolongation is considered most likely to be due to 
concomitant illness or medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken.  
 
If a participant develops Grade 4 QTc prolongation, he or she will be hospitalized and discontinued from study 
medications. If the prolongation is felt to be caused by a concomitant medication and resolves with 
discontinuation of that agent, study medications may be restarted. Otherwise, the participant will be referred 
to the NTP for treatment of his or her TB according to local standards of care. The participant will continue to 
be followed on study, off study drugs. 
 
Serious adverse events will be reported to the MCC and the UKZN Biomedical Research Ethics Committee. 
(BREC) according to their specific requirements. 
 
 
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 > 0.47- < 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, 
eg, 
Torsade de pointes 
or other associated 
serious ventricular 
dysrhythmia 


PI: Dr N Padayatchi 
Site: CAPRISA  
 
Study No: CAP 011 
Page 33 of 58 
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11 May 2015 
 
 
Outcome status 
 
Definition of treatment failure: 
Patient whose baseline smear (or culture) was positive and remains or becomes positive again at 5 months or 
later during treatment. This definition excludes those patients who are diagnosed with RR-TB or MDR-TB 
during treatment. 
 
Definition of treatment cure 
Patient whose baseline smear (or culture) was positive at the beginning of the treatment and is smear/ culture 
negative in the last month of treatment and on at least one previous occasion at least 30 days prior. 
 
Discontinuation of study treatment 
The investigator may discontinue a patient from treatment in the event of a severe or serious adverse event, or 
at any time he/she thinks it’s in the patient’s best interest.  If there is a medical reason for withdrawing study 
treatment, the patient will remain under the supervision of the investigator until satisfactory health has returned 
irrespectively of the reason for discontinuation. The frequency of patient review will be determined by the 
clinical need to ensure optimal care.  
 
 
Withdrawal from the study 
Patients withdrawn from study due to a protocol violation will be included in the safety database of the study. 
Patients withdrawn from study because their initial TB isolate is found to be MDR –TB will not be followed 
up further, unless required for patient safety (e.g. an adverse event present, in which case follow-up should 
occur as clinically indicated). Similarly, patients withdrawn from study because their initial cultures are 
negative do not need to be followed up further (unless there is an ongoing adverse event). Participation in the 
study is strictly voluntary. A participant has the right to withdraw from the study at any time for any reason. 
Patients who withdraw their consent will not have to undergo any follow up procedures. 
 
This study will be reviewed by a Safety Monitoring Committee (SMC) that meets for scheduled reviews of 
studies every year. A full SMC review will include an efficacy review and a futility review for detecting a 
survival difference.  A full review will be scheduled at least annually after opening to accrual or on a frequency 
determined by the SMC. For each full review, summaries provided to the SMC will be broken down by 
treatment arm. Participants’ baseline demographic and health characteristics will be summarized. Review of 
study conduct will address site accrual, premature study discontinuations and their reasons (administrative or 
loss to follow-up), tracking of potential losses to follow-up, data completeness. The SMC will also review 
participants’ safety data, frequency and causes of death, as well as incidence of TB recurrence.  
 
In addition, quarterly internal reviews of patient charts, SAE reports and regulatory submissions will be 
conducted.    
 
9.0 
 STATISTICAL CONSIDERATIONS  
 
9.1  
Sample size determination:  
 
A total of 330 patients will be enrolled. A two group continuity corrected chi square test with a 0.05 two-sided 
significance level will have 80% power to detect the difference between 75% of patients having culture 
conversion in the Intervention arm and 60% of patients having culture conversion in the Control arm. A 
previous unpublished retrospective review at the study site comparing the treatment outcome in retreatment 


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patients with TB using the standard 4 drug regimen, showed a cure and completion rate of 60.1%. According 
to WHO surveillance data, the retreatment regimen is successful in about 70% of patients, and other 
retrospective studies show treatment success rates of 26 – 92%.  Thus, 75% is a realistic cure and completion 
rate to aim for in the Intervention group. A previous unpublished retrospective review at the study site 
comparing the treatment outcome in retreatment patients with TB using the standard 4 drug regimen, showed 
a cure and completion rate of 60.1%. According to WHO surveillance data, the retreatment regimen is 
successful in about 70% of patients, and other retrospective studies show treatment success rates of 26 – 92%.  
Thus, 75% is a realistic cure and completion rate to aim for in the Intervention group.    
 
 
9.2 
 Analysis including statistical methods  
 
To answer the primary objective of this study the sputum culture conversion rates at the end of the intensive 
phase and at month 6 will be compared between the two treatment arms.  This will be done by calculating the 
proportion of culture conversions in each of the two arms and comparing these using the chi-square test.   
 
 
9.3 
Explanation on how the results of this study will be used  
 
Many published reports have questioned the effectiveness of the standard WHO retreatment regimen and, 
more importantly the potential for amplification of TB drug resistance. Despite the enormous patient and 
public health cost of drug resistant TB, there has been a lack of research effort directed at investigating 
alternate regimens aimed at optimising treatment outcomes among retreatment patients who are most at risk 
of developing acquired drug resistant TB. This study proposes to use a regimen that omits an injectable agent, 
enhances time to culture conversion thereby shortening duration of treatment, increasing adherence and 
completion rates and reducing the likelihood of acquiring drug resistance.  The availability of new generation 
rapid diagnostic technologies offers a unique opportunity of providing a targeted retreatment approach without 
compromising the efficacy of second line agents used to treat drug resistant TB. The goal of global tuberculosis 
research and control efforts to date has been the development of shorter TB treatment regimens. Investigating 
a retreatment regimen that can shorten duration of therapy is central to enhancing programmatic outcomes and 
this study is commensurate with this goal.  Treatment default is associated with length of treatment, thus 
shortening treatment duration could improve outcomes, and reduce labour and financial implications of 
national TB control programs especially in countries with a high TB incidence.  This study will explore an 
alternate retreatment regimen suitable for a national TB control program in a TB-HIV endemic setting. 
10.0 
 HUMAN PARTICIPANTS 
 
10.1  Patient Recruitment   
 
Patients will be recruited from various health care facilities. Recruiters will be stationed within the TB facility 
and potential patients can be approached through several mechanisms:  
 
HCT services – HIV testing and counselling is routinely offered at the PCZCDC which provides an ideal 
opportunity to conduct pre-screening  
Each Health Care Facility has an in house National Health Laboratory Service. All new patients with a 
positive smear and GeneXpert Rifampicin sensitive can be identified at the laboratory and followed-up 
by a CAPRISA recruiter based at the facility. CAPRISA Recruiters can also identify patients with a past 
history of TB and the CAPRISA site can perform a GeneXpert and smear testing.  
Clinic referrals - Clinicians or Professional Nurses at the facility will be trained on the study protocol and 
will refer patients for enrolment. 
 


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11 May 2015 
 
 
10.2 
Ethics 
 
Existing WHO and South African TB treatment guidelines recommend the provision of streptomycin as part 
of TB retreatment standard of care. However, both sets of guidelines are currently being revised, with WHO 
and the South African government indicating that streptomycin will no longer be recommended for TB 
retreatment in the next iteration of their respective guidelines (personal communications: Richard Chaisson, 
STOP TB working group; Norbert Ndjeka, SA National Director MDR TB). Some high TB burden countries 
have already successfully removed streptomycin from their NTP guidelines 49. This proposed study could 
provide the evidentiary basis for such a policy shift in South Africa and elsewhere.  
 
10.3 
 Regulatory and ethical review 
 
The study will be conducted under the oversight of the University of KwaZulu-Natal, Nelson R Mandela 
School of Medicine Biomedical Research Ethics Committee (BREC) and the South African Medicines Control 
Council (MCC). The study protocol will be submitted to the ethics committee and regulatory entities by the 
Principal Investigator and reviewed and approved by the ethics committee prior to study initiation.  The 
investigator will provide progress reports and all other information required by the ethics committee/regulatory 
institutions to conduct its reviews. On approval of the study we will register the study with SANCTR (South 
African National Clinical Trials Register). We will also seek approval for the study from the eThekwini 
Municipality.   
 
 
10.4  Informed consent process 
 
Written informed consent will be obtained from each study participant prior to screening and enrolment (see 
Appendix I). Written informed consent will also be obtained for long-term specimen storage and possible 
future analyses. However, consent for specimen storage is not a pre-condition for study participation. 
Participants will be provided with a copy of their informed consent forms if they wish to receive them.  
 
Study informed consent forms will describe the purpose of the study, the procedures to be followed, and the 
risks and benefits of participation. The informed consent forms will also be translated into isiZulu and the 
accuracy of the translation will be verified through independent back-translation. 
The study consent process will include an assessment of each potential participant’s understanding of the study 
and the risks and benefits of study participation, which are essential for an informed decision. Participants who 
are not able to demonstrate adequate understanding of key concepts will not be enrolled in the study. 
 
 
 
10.5  Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be identified by 
coded number only to maintain participant confidentiality. All records will be kept locked. All computer entry 
and networking programs will be done with coded numbers only. Clinical information will not be released 
without written permission of the participant, except as necessary for monitoring by the ethics committee or 
the sponsor’s designee. CAPRISA External monitors will also review clinical information. QA officers and 
Head of QA will not be on delegation of Authority Log as these staff serve as external monitors. 
 
 


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10.6  Good Clinical Practice 
 
The study will be carried out according to ICH-GCP and South African Good Clinical Practice Guidelines 
(SA GCP). The Principal Investigator and/or designee will ensure that the study staff are conducting the trial 
in accordance with SA GCP and  ICH-GCP  guidelines, ensure appropriate human subjects training for all 
study staff and safety of all trial participants. The study protocol and patient informed consents and all future 
revisions of these latter documents, will be reviewed and approved by the UKZN Biomedical Research Ethics 
Committee (UKZN BREC) and South African Medicines Control Council (MCC) prior to implementation. 
Quality control officers will perform daily quality checks on patient data and a Data manager will oversee the 
maintenance and completeness of the patient data.  
 
All Serious Adverse Events (SAE’s) will be reported to UKZN BREC and MCC within 7 business days of 
site awareness. A Safety Monitoring Committee (SMC) will meet annually to analyse and discuss safety data 
and make recommendations for the continuation of the trial and patient care. 
11.0  DATA MANAGEMENT  
 
The entry, storage and cleaning of study data will be conducted under the oversight of the CAPRISA Data 
Management core. 
 
11.1  Data Collection and Methods 
 
Case Report Forms (CRFs) will be provided for each patient. At screening participants will be issued a 
Screening Identification number (SID) by the site. At enrolment participants will be identified by a patient 
identification number (PID) provided by the CAPRISA Data Management Center. This PID is used on all 
CRFs to identify the participant for the duration of the study.  
Data will be collected at scheduled clinic visits. Patients will be required to attend at the clinic for a screening 
visit and if found to be eligible, informed consent will be administered and the patient will be enrolled into the 
study. Post enrollment visits will be scheduled once a month for the Treatment phase of the study.  
 
11.2 
 Information management and analysis software 
 
CAPRISA uses the DataFax system to store data electronically. The current version of DataFax use is 
Version 4.1 
Statistical Analysis Software (SAS) is used for analysis purposes. The current version in use is version 9.3. 
  
11.3  Data entry, editing and management, including handling of data collection forms, different 
versions of data 
 
Instructions concerning the recording of study data on CRFs will be provided by the CAPRISA Data 
Management core. Completed CRFs must be checked by the designated on-site Quality Control officer and 
upon approval, must be submitted via fax into the DataFax system.  CAPRISA Data encoders and Data 
Managers located at the Nelson R. Mandela School of Medicine verify and validate the patient data. Quality 
control reports are produced, and approved data then added to the study database according to CAPRISA data 
management (SOPs) Study Operating Procedures. 


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It is the responsibility of the CAPRISA data management core to assure the quality of computerized data for 
the study. Study staff will be trained in source documentation requirements in accordance with the CAP011 
SOP for Source Documentation and in proper forms completion techniques. 
 
Database files will be password-protected, and access to the files will be limited to authorized study staff 
members only. Quality control and validation checks will be performed and data cleaning steps will be 
undertaken prior to finalizing the study database for analysis. Analyses will be conducted by study statisticians. 
 
 
11.4  Data Storage 
 
Original and DataFax electronic copies of study CRFs and related documents will be stored securely both 
during and after study completion. During the study, the original completed forms for each participant will be 
kept on-site at the CAPRISA eThekwini CRS.  The forms will be stored in an access secured, double-locked, 
fire and waterproof room. Upon completion of the study, and finalization of the database for analysis, the 
original forms will be bound and kept off-site (separate site) for long-term storage. CAPRSIA has a standing 
agreement with Metrofile to archive large amounts of documents.  CRF data on the DataFax server will be 
accessible to the study staff and the statistician in a read-only mode. The data management team will have 
write-access, with access being restricted by passwords and validation levels. Study staff that has access to the 
data on the computer systems will be trained in how to access the system and the importance of system security. 
All information will be backed-up at regular intervals, and backups will be stored in file cabinets or secure 
areas with limited access 
 
11.5  Quality control/assurance 
 
A quality check of the study forms will be conducted before the forms are data faxed. The QC procedures 
will specify the following types of checks: 
 
• 
There are no illegible handwritten items, spelling errors, etc. 
• 
Responses are clearly within designated spaces. 
 
• 
All fields are completed with participant data or reason for no data is noted in or near 
           the field. 
 
• 
The participant's PID is recorded on all pages of the forms. 
 
 
• 
The CAPRISA laboratory manager will also be responsible for checking that all the laboratories 
involved in the study are complying with QA procedures. The CAPRISA pharmacist will check that 
all drug related documentation meets Good Clinical Practice (GCP) requirements for drug 
accountability. 
 
 
QA/QC of data will be undertaken according to the SOPs. 
 
 
 
 
 


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12.0    BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other pathogens can occur through contact with contaminated needles, blood, 
blood products, and other secretions, appropriate blood and secretion precautions will be employed by all 
personnel in the drawing of blood and collection of other specimens and shipping and handling of all 
specimens for this study, as currently recommended by the Centers for Disease Control and Prevention and 
the National Institutes of Health. 
 
All dangerous materials, including diagnostic specimens and infectious substances, must be transported using 
packaging mandated by CFR 42 Part 72. Please refer to instructions detailed in the International Air Transport 
Association (IATA) Dangerous Goods Regulations.  
 
 
 


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Menzies D, Benedetti A, Paydar A, et al. Standardized treatment of active tuberculosis in patients with 
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Jones-Lopez EC, Ayakaka I, Levin J, et al. Effectiveness of the standard WHO recommended 
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Rodriguez JC, Ruiz M, Lopez M, Royo G. In vitro activity of moxifloxacin, levofloxacin, gatifloxacin 
and linezolid against Mycobacterium tuberculosis. Int J Antimicrob Agents 2002;20:464-7. 
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Gillespie SH, Billington O. Activity of moxifloxacin against mycobacteria. The Journal of antimicrobial 
chemotherapy 1999;44:393-5. 
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Rustomjee R, Lienhardt C, Kanyok 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;12:128-38. 
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Burman WJ, Goldberg S, Johnson JL, et al. Moxifloxacin versus ethambutol in the first 2 months of 
treatment for pulmonary tuberculosis. American journal of respiratory and critical care medicine 
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Ball P, Stahlmann R, Kubin R, Choudhri S, Owens R. Safety profile of oral and intravenous 
moxifloxacin: cumulative data from clinical trials and postmarketing studies. Clinical therapeutics 
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13. 
Dorman SE, Johnson JL, Goldberg S, et al. Substitution of moxifloxacin for isoniazid during intensive 
phase treatment of pulmonary tuberculosis. American journal of respiratory and critical care medicine 
2009;180:273-80. 
14. 
Nuermberger EL, Yoshimatsu T, Tyagi S, et al. Moxifloxacin-containing regimen greatly reduces time 
to culture conversion in murine tuberculosis. American journal of respiratory and critical care medicine 
2004;169:421-6. 
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Chang KC, Leung CC, Grosset J, Yew WW. Treatment of tuberculosis and optimal dosing schedules. 
Thorax 2011;66:997-1007. 
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Peloquin CA. Therapeutic drug monitoring in antituberculosis chemotherapy. Therapeutic drug 
monitoring 1999;21:426-7. 
17. 
Nijland HM, Ruslami R, Suroto AJ, et al. Rifampicin reduces plasma concentrations of moxifloxacin in 
patients with tuberculosis. Clinical infectious diseases : an official publication of the Infectious Diseases 
Society of America 2007;45:1001-7. 
18. 
Fromm MF. The influence of MDR1 polymorphisms on P-glycoprotein expression and function in 
humans. Advanced drug delivery reviews 2002;54:1295-310. 
19. 
Van Bambeke F, Michot JM, Tulkens PM. Antibiotic efflux pumps in eukaryotic cells: occurrence and 
impact on antibiotic cellular pharmacokinetics, pharmacodynamics and toxicodynamics. The Journal of 
antimicrobial chemotherapy 2003;51:1067-77. 
20. 
de Lange EC, Marchand S, van den Berg D, et al. In vitro and in vivo investigations on fluoroquinolones; 
effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin. European journal 
of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 
2000;12:85-93. 


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21. 
Schuetz EG, Schinkel AH, Relling MV, Schuetz JD. P-glycoprotein: a major determinant of rifampicin-
inducible expression of cytochrome P4503A in mice and humans. Proceedings of the National Academy 
of Sciences of the United States of America 1996;93:4001-5. 
22. 
Ito T, Yano I, Tanaka K, Inui KI. Transport of quinolone antibacterial drugs by human P-glycoprotein 
expressed in a kidney epithelial cell line, LLC-PK1. The Journal of pharmacology and experimental 
therapeutics 1997;282:955-60. 
23. 
Shandil RK, Jayaram R, Kaur P, et al. Moxifloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against 
Mycobacterium tuberculosis: evaluation of in vitro and pharmacodynamic indices that best predict in 
vivo efficacy. Antimicrobial agents and chemotherapy 2007;51:576-82. 
24. 
Ginsburg AS, Grosset JH, Bishai WR. Fluoroquinolones, tuberculosis, and resistance. The Lancet 
infectious diseases 2003;3:432-42. 
25. 
Gumbo T, Louie A, Deziel MR, Parsons LM, Salfinger M, Drusano GL. Selection of a moxifloxacin 
dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro 
pharmacodynamic infection model and mathematical modeling. The Journal of infectious diseases 
2004;190:1642-51. 
26. 
Schentag JJ, Meagher AK, Forrest A. Fluoroquinolone AUIC break points and the link to bacterial 
killing rates. Part 1: In vitro and animal models. The Annals of pharmacotherapy 2003;37:1287-98. 
27. 
Schentag JJ, Meagher AK, Forrest A. Fluoroquinolone AUIC break points and the link to bacterial 
killing rates. Part 2: human trials. The Annals of pharmacotherapy 2003;37:1478-88. 
28. 
Ahmad Khan F, Minion J, Al-Motairi A, Benedetti A, Harries AD, Menzies D. An updated systematic 
review and meta-analysis on the treatment of active tuberculosis in patients with HIV infection. Clinical 
infectious diseases : an official publication of the Infectious Diseases Society of America 2012;55:1154-
63. 
29. 
Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British 
Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications. The 
international journal of tuberculosis and lung disease : the official journal of the International Union 
against Tuberculosis and Lung Disease 1999;3:S231-79. 
30. 
Hall RG, Leff RD, Gumbo T. Treatment of active pulmonary tuberculosis in adults: current standards 
and recent advances. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 
2009;29:1468-81. 
31. 
Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. The international journal 
of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and 
Lung Disease 2000;4:796-806. 
32. 
Dhillon J, Fourie PB, Mitchison DA. Persister populations of Mycobacterium tuberculosis in sputum 
that grow in liquid but not on solid culture media. The Journal of antimicrobial chemotherapy 2013. 
33. 
van Ingen J, Aarnoutse RE, Donald PR, et al. Why Do We Use 600 mg of Rifampicin in Tuberculosis 
Treatment? Clinical infectious diseases : an official publication of the Infectious Diseases Society of 
America 2011;52:e194-9. 
34. 
McIlleron H, Wash P, Burger A, Norman J, Folb PI, Smith P. Determinants of rifampin, isoniazid, 
pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrobial 
agents and chemotherapy 2006;50:1170-7. 
35. 
Tappero JW, Bradford WZ, Agerton TB, et al. Serum concentrations of antimycobacterial drugs in 
patients with pulmonary tuberculosis in Botswana. Clinical infectious diseases : an official publication 
of the Infectious Diseases Society of America 2005;41:461-9. 
36. 
Um SW, Lee SW, Kwon SY, et al. Low serum concentrations of anti-tuberculosis drugs and 
determinants of their serum levels. The international journal of tuberculosis and lung disease : the official 
journal of the International Union against Tuberculosis and Lung Disease 2007;11:972-8. 
37. 
Gumbo T, Louie A, Deziel MR, et al. Concentration-dependent Mycobacterium tuberculosis killing and 
prevention of resistance by rifampin. Antimicrobial agents and chemotherapy 2007;51:3781-8. 
38. 
Chideya S, Winston CA, Peloquin CA, et al. Isoniazid, rifampin, ethambutol, and pyrazinamide 
pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with 


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tuberculosis from Botswana. Clinical infectious diseases : an official publication of the Infectious 
Diseases Society of America 2009;48:1685-94. 
39. 
Peyper L. Mobile phone usage in SA.  finweek coporate news. 22 January 2013 ed2013. 
40. 
Bronkhorst, Q. Mobile subscribers in SA: who’s eating whose lunch? 2013. (Accessed December, 2013, 
at http://businesstech.co.za/news/mobile/44164/mobile-subscribers-in-sa-whos-eating-whose-lunch/.) 
41. 
Skinner D, Rivette U, Bloomberg C. Evaluation of use of cellphones to aid compliance with drug therapy 
for HIV patients. AIDS Care 2007;19:605-7. 
42. 
Green D. South Africa: a novel approach to improving adherence to TB treatment.  Essential Drugs 
Monitor World Health Organisation; 2003. 
43. 
Cole-Lewis H, Kershaw T. Text messaging as a tool for behavior change in disease prevention and 
management. Epidemiologic reviews 2010;32:56-69. 
44. 
Mukund Bahadur KC, Murray PJ. Cell phone short messaging service (SMS) for HIV/AIDS in South 
Africa: a literature review. Studies in health technology and informatics 2010;160:530-4. 
45. 
Ammassari A, Trotta MP, Shalev N, et al. Timed short messaging service improves adherence and 
virological outcomes in HIV-1-infected patients with suboptimal adherence to antiretroviral therapy. 
Journal of acquired immune deficiency syndromes 2011;58:e113-5. 
46. 
Lester RT, Ritvo P, Mills EJ, et al. Effects of a mobile phone short message service on antiretroviral 
treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet 2010;376:1838-45. 
47. 
Barclay E. Text messages could hasten tuberculosis drug compliance. Lancet 2009;373:15-6. 
48. 
Cell-Life 
Capabilities 
Document. 
(Accessed 
Jan 
2012, 
at 
http://www.cell-
life.org/images/downloads/Cell-Life_Capabilities_Document.pdf.) 
49. 
Furin J, Gegia M, Mitnick C, et al. Eliminating the category II retreatment regimen from national 
tuberculosis programme guidelines: the Georgian experience. Bulletin of the World Health Organization 
2011;Article ID: BLT.11.092320. 
 
 
 


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APPENDIX I: IMPRESS PATIENT INFORMED CONSENT 
 
 
STUDY INFORMED CONSENT FORM 
TITLE OF STUDY: IMPROVING RETREATMENT SUCCESS (IMPRESS):  An open label 
randomized controlled clinical trial comparing a 24 week oral regimen containing 
Moxifloxacin with a 24 week standard tuberculosis (TB) drug regimen for the 
treatment of smear-positive pulmonary TB in patients previously treated for TB 
 
 
 
INFORMATION FOR PATIENTS 
Short Title:                         IMPRESS 
 
Principle Investigator:  
Dr Nesri Padayatchi 
Address 
 
 
719 Umbilo Road 
 
 
 
 
Doris Duke Medical Research Institute (2nd Floor) 
 
 
 
 
Nelson R Mandela School of Medicine, 
 
 
 
 
University of Kwa-Zulu Natal, 
 
 
 
 
Durban, 4013 
Telephone 
 
 
031 260 4555 
 
Regulatory Authority: 
Medicines Control Council (MCC) 
Ethics Committee:            
University of KwaZulu Natal Biomedical Research Ethics      Committee 
(UKZN BREC) 
 
 
 
 
 
 


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Instructions: 
 
1. Please read and understand the information given below. 
2. If you have any questions or need any explanations then please feel free to discuss with the 
person handing you the Inform Consent Form at any time.  
3. Once you have agreed to participate in the study and you will be asked to sign the Inform 
Consent form. We will give a copy to you and a copy will be placed in your file. The original 
will be kept in a secure room by the study coordinator. 
 
 
INTRODUCTION:  
Dear Sir/Madam, 
 
Hello and thank you for taking time to read this information. You are being invited to take part in a research 
study.  Research is a way of finding the answer to a question.  Before you decide to participate, it is important 
that you understand why the research is being done and what it will involve. Please take time to read the 
following information carefully and discuss it with others if you wish. Feel free to ask us questions if there is 
anything that is not clear or if you would like more information. You are completely free to choose whether 
or not you wish to take part.  Please take your time to decide. 
 
We have approached you to take part in this study because you had tuberculosis of the lung in the past and 
currently have another tuberculosis infection of the lung.  
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to compare the effects of a new type of combination of TB drugs for patients who 
require a retreatment for TB. There are two combinations of anti-TB drugs. Each combination comprises of 
four anti-TB drugs.  
Standard Combination: Isoniazid + Pyrazinamide + Rifampicin + Ethambutol 
New Combination       : Isoniazid + Pyrazinamide + Rifampicin + Moxifloxacin  
The new combination removes Ethambutol and replaces it with Moxifloxacin. Moxifloxacin has been in use 
throughout the world for treatment of other infectious diseases (sickness caused by germs), and there is 
evidence from several studies that it can be used to treat tuberculosis and may even shorten the length of TB 
treatment.  
 
WHO CAN TAKE PART IN THIS STUDY? 
If you are 18 years and older and currently have TB (of the lung) and you have had TB in the past as well, 
then you may qualify to take part in this study.  
IS IT NECESSARY FOR ME TO TAKE PART IN THE STUDY?   


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Whether or not you take part in the study is your decision. It is a voluntary decision. You do not have to give 
a reason if you don't want to be in it. After reading this information and agreeing with what you have read - if 
you decide to take part in the study - you will be asked to sign an Informed Consent form.   If you decide not 
to take part, there will be no loss of benefit and you will receive standard TB retreatment. If you decide to take 
part in the study, but change your mind later, you will be free to withdraw from the study at any time.  If you 
withdraw from the study it will not affect the quality of your medical care; you will be given standard TB 
treatment. 
 
WHAT DOES THE STUDY INVOLVE? 
The study is in three parts:   
Part 1:  The screening phase   
Part 2:  The treatment phase  
Part 3:  The follow-up phase 
 
WHAT DO I HAVE TO DO IF I PARTICIPATE IN THIS STUDY? 
Part 1: The screening phase 
The first part is called “screening phase” when we will perform tests to check whether you are suitable to 
participate in the study.  The tests will include taking your medical history (your health in the past), performing 
a medical examination, a chest X-Ray if required and sputum (material that you will cough up) collection 
which is for TB investigation.  Blood tests will be performed to make certain that there are no abnormalities 
(problems) that would prevent you or cause harm to you from entering the study. A test will be done to check 
if the common TB medicines are likely to be effective against the bacteria (type of germ) causing your TB. 
It is important for you and the study staff to know your HIV status. This is to determine if you require treatment 
for HIV which is provided free of charge. A HIV test will be performed with pre- and post-test counselling (a 
study counsellor or nurse will discuss this with you to guide you about HIV-AIDS and related test procedures).   
If your HIV test is positive you will be started on HIV treatment if you are not on HIV treatment already.  
If your HIV test is negative, we will encourage you to repeat the test as outlined in Attachment A. The window 
period is a time when the HIV is not detectable because the infection is still new.  If you become HIV positive 
after you have entered the study, you will be seen by the study doctor and started on ARV’s. You will also be 
required to produce blood for storage.  
The result of the HIV test will not affect your chances of being enrolled in the study. 
The blood tests at this stage will require approximately 3 or 4 teaspoons of blood. If you are a woman of 
childbearing age a urine pregnancy test will be conducted. If there are no major abnormalities (health 
problems) and you are willing to proceed further, you can join the study.   
 


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Part 2 & 3: The treatment phase & follow-up phase 
At this stage - all patients participating in the study are divided into 2 arms and each arm is given a different 
combination of TB treatment. One of these arms is the standard TB treatment and the other the New TB 
treatment combination. The results of the study shall be compared to see if one treatment is better than the 
other. The best way of fairly dividing people into arms is to use what is called “random allocation”. The 
process is the same as flipping a coin or rolling a dice. In this study, treatment arms for each patient are written 
in a sealed envelope. When it is your turn to be enrolled a member of the study team will select an envelope 
on the day of your enrolment and you will be informed which treatment arm you have been allocated to. You 
will have an equal chance of receiving any one of the 2 treatments. Neither you nor the study staff can choose 
which treatment arm you will be allocated. At the study entry visit, you will be assigned to one of these two 
treatment arms: 
 
 
 
 
 
 
 
Figure 1: Patient Allocation to Study Groups 
 
If you are placed into Intervention Arm you will be expected to take a combination of 4 drugs for the first 2 
months, thereafter take a combination of 3 TB drugs for 4 months. If you have been placed into Control   Arm, 
you will be required to take a combination of 4 drugs for the first 2 months, and then 2-combination drugs for 
a further 4 months. Your test results will be checked by the doctors and the doctor may give you more TB 
drugs. This is shown in Figure 1. While you are taking Isoniazid you will also be given pyridoxine (vitamin 
B6). This is a food supplement that helps to prevent side effects of the drug Isoniazid. CAPRISA will provide 
the pyridoxine free of charge. 
After you have successively completed your treatment, you will need to come back to the clinic once every 2 
months for 12 months. This will allow the medical staff to monitor the effects of the drugs on your TB 
infection.  
 
 
WHAT IS THE DURATION OF THE STUDY?  
If you are allocated to Intervention Arm the total study duration is approximately 18 months 
If you are allocated to Control Arm the total study duration is approximately 18months. 
Study Entry 
Intervention Arm:  
Receives a 4-drug combination 
of TB for 2 months and a 3-drug 
combination for 4 months. 
 
 
Control Arm: 
Receives a 4 drug combination 
for 2 months and a 2 drug TB 
combination for 4 months 
 
 


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It is possible that your time in the study may be extended if there is a problem with completing all the required 
doses of your TB medication or if the study doctor decides to extend you treatment based on your laboratory 
results. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
A total of 330 patients are expected to participate in the study.   
 
USE OF STORED SAMPLES 
Samples will be collected and stored for future research use. The research team may use these samples to 
confirm test results or to do an additional new test if required. Your samples will not be sold or used in other 
products that make money for researches. Should you decide not to have your samples stored this will not 
affect your ability to take part in the study. Your decision will not affect the quality of care you receive at the 
clinic 
To protect your identity your sample container will not have your name or any information that may identify 
you. Only your patient number will be used on sample containers.   If you do not agree, then samples for 
storage will not be collected. If you agree now and later change your mind, your sample will not be used for 
future testing. No matter what you decide, it will not affect your participation in the study and this will not 
affect the quality of care you receive from study staff. 
 
________ YES, I agree to have my samples stored 
 
________ NO, I do not agree to my samples being stored 
 
 
The stored samples may be used for future research, to confirm test results, or to do additional testing. Your 
samples will not be sold or used in products that make money for the researchers. Any studies that use your 
samples will be reviewed by the Biomedical Research Ethics Committee of the University of KwaZulu Natal. 
The researchers do not plan to contact you or your regular doctor with any results that are done on the stored 
samples after the study has been completed.  
This is because research tests are often done with experimental procedures so the results from one study are 
generally not useful for making decisions on managing your health. Should a rare situation come up where the 
researchers decide that a specific test result would provide important information for your health, the 
researchers will notify the study doctor who will try to contact you or your regular doctor. If you wish to be 
notified of this type of test result, you need to make sure that you contact the study nurse or doctor with any 
changes to your phone number or address. If you want your regular doctor to be told about this kind of test 
result, you need to provide the study team with the contact details of your regular doctor. 


PI: Dr N Padayatchi 
Site: CAPRISA  
 
Study No: CAP 011 
Page 47 of 58 
Version4.0
 
 
11 May 2015 
LIPOARABINOMANNAN SUB-STUDY 
You will be required to provide urine samples at baseline, as well as at 2 Months, 5 months and at the end of 
your tuberculosis treatment. The purpose of this study is to determine if urine can be used to detect 
tuberculosis. Each urine sample will then be tested in a laboratory. When this is done the urine sample will be 
stored in a freezer for future testing. 
 
PHARMACOKINETIC SUB-STUDY: 
You are invited to take part in the pharmacokinetic study within the IMPRESS study. The purpose of this 
study is to measure the amount of specific TB drugs in your blood and will add information to the IMPRESS 
study.  
Your decision to participate in this additional study, or not, will not affect your participation in the IMPRESS 
study. 
Before you agree to take part in the study or not it is important to understand the procedure, risks, benefits and 
discomforts. 
Procedures: 
If you decide to take part in this study: 
For Intervention Arm participants: 
You will be requested to undergo additional blood tests at 3 study visits (either Week 4 and/or Month 
2, Month 6 and Month 7 or one month after completing TB treatment). You will also be requested to 
return to the study clinic the morning after these study visits to do an additional blood test. 
You will be requested to take one additional dose of Moxifloxacin after the completion of your TB 
treatment at Month 7 or one month after completing TB treatment. 
The blood tests will require about 4 teaspoons of blood at each visit.  
For Control Arm participants: 
You will be requested to undergo additional blood tests at Month 2. The blood tests will require about 
2 teaspoons of blood at each visit.  
 
The study team will arrange a time for the blood sampling. On the appointed day you need to arrive at the 
study clinic early in the morning. It is important NOT to take any TB medicines before your arrival at the 
study clinic. You will be given your TB treatment at the study clinic. 
________ YES, I agree to take part in the pharmacokinetic sub-study 
 
________ NO, I do not agree to take part in the pharmacokinetic sub-study 
 


PI: Dr N Padayatchi 
Site: CAPRISA  
 
Study No: CAP 011 
Page 48 of 58 
Version4.0
 
 
11 May 2015 
COMPUTERIZED DISPENSING AND CELLPHONE TECHNOLOGY: INNOVATIVE TOOLS TO 
ENHANCE PATIENT ADHERENCE, TRACKING AND RETENTION 
 
As a participant in the IMPRESS Study, you will  also be offered the opportunity receive text messages 
reminders sent to your cell phone reminding you about appointment dates, missed appointments and/or 
medication use. 
Three types of sms’s may be sent: 
• A sms reminder of the clinic appointment date that will be programmed to go out 3 days ahead of the 
scheduled appointment, which will read as follows: “Please do not forget your appointment at 
CAPRISA clinic in three days’ time”.  
 
• For those participants who are included in the pharmacokinetic sub-study only, an sms will be sent out 
the evening before a scheduled visit, which reminds the patient not to take an evening/morning dose, 
prior to sample collection at the clinic for pharmacokinetic (PK) study the next morning: “Please do 
not take your TB medication the night or morning before coming to the clinic. Carry TB drugs with 
you to be taken at the clinic”. 
 
• A sms to prompt patients who miss their appointment to return to the clinic that will read as follows: 
“You have missed your appointment at CAPRISA clinic. Please return to the clinic as soon as 
possible”. 
 
• An motivational broadcast sms to enhance patient compliance by re-enforcing adherence, programmed 
to be sent one week after enrolment, and periodically thereafter: at the end of month 1 of treatment and 
then at the beginning of the continuation phase of TB treatment, which will read as follows: “TB can 
be cured and the spread of TB stopped if the full course of treatment is taken correctly, so that people 
can lead fuller, safer and healthier lives.” 
 
Do you consent to receiving these SMS’s:                        
                
 
________ YES, I agree  
 
________ NO, I do not agree  
 
 
 
 
 
What are the likely situations where my participation in the study may be terminated? 
 
Here are few examples of situations under which your participation in the study may be terminated: 
 
i) Your doctor is of the opinion that your TB treatment is going to fail (Treatment failure). 
 
ii) Review of your health suggests that further participation in the study may cause you more harm than benefit. 
 
iii) You are missing a number of clinic visits and repeatedly do not follow study instructions and not taking 
study drug as per the directions and this may result in more harm than benefit. 
 


PI: Dr N Padayatchi 
Site: CAPRISA  
 
Study No: CAP 011 
Page 49 of 58 
Version4.0
 
 
11 May 2015 
iv) The study is cancelled by the Medicines Control Council (MCC), or the University of KwaZulu Natal 
Biomedical Research Ethics Committee.  
 
V) A Safety Monitoring Committee (SMC) recommends that the study be stopped early.  The SMC is a group 
of experts who are not involved in the study, but who monitor it and look after the safety of patients. This 
group meets once a year and makes recommendations for the study. 
 
There may be other similar circumstances as well. 
 
The study may be suspended in following cases: 
 
i) 
Reports of severe and significant side effects. 
 
ii)    Reports suggest that the new regimen under trial is not effective in treating TB. 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
If you choose not to enter the study then you may access TB treatment from the local government clinic. The 
care that people who go into Control Arm receive on study is about the same as what you would receive outside 
the study. Certain TB drugs and HIV drugs, laboratory tests to monitor how well these drugs are working, and 
quality medical care may or may not be available to you outside the study.  The clinic staff will discuss with 
you other treatment choices in your area and the risks and the benefits of all the choices. 
For TB care, the clinic staff can refer you to the Prince Cyril Zulu Communicable Disease Clinic or another 
clinic providing for free TB investigation and treatment. This clinic should also provide HIV medication 
service to eligible patients. 
 
The CAPRISA AIDS Treatment Programme based at the CAPRISA clinic, provides a free ARV service and 
you may access your ARVs here.  
 
Also, CAPRISA clinicians can assist you with accessing HIV and TB medication at your nearest government 
clinic.   
 
WHAT ABOUT CONFIDENTALITY?  
The study research team will give you a unique number once you are enrolled into the study. A different 
number will be given for each participant in the study.  This unique number and not your name (or any other 
information that could be used to identify you) will be used for all of your study-related records. Your medical 
records and the list of names, addresses and code numbers will be kept in a locked room. Only the study staff 
will have access to these records. Any publications of this study will not use your name. The site will attempt 
to keep your personal information confidential. However, we cannot promise complete confidentiality.  Your 
personal information may be disclosed if required by law. Your details may be seen by the sites ethics 
committee, Human Research Protection, study monitors, and drug companies that support this study.  
 
 


PI: Dr N Padayatchi 
Site: CAPRISA  
 
Study No: CAP 011 
Page 50 of 58 
Version4.0
 
 
11 May 2015 
WHAT ARE THE RISKS AND DISCOMFORTS ASSOCIATED WITH THIS STUDY? 
TB DRUGS (Refer to Attachment B) 
The TB drugs may have some side effects. Some of these side effects are listed in Attachment B. This list 
includes more serious and common side effects experienced by the study drugs. If you have any questions 
concerning any additional drugs you may be put onto during your course on this study, you can ask any of the 
clinical staff at the CAPRISA site.  
Risks in Blood Drawing: 
During certain study visits, the staff nurse will draw blood from you. Taking blood may cause some 
discomfort, bruising or bleeding at the site where the needle enters your body. You also may feel lightheaded 
and in a rare case faint. The area also may become infected.  
 
WHAT HAPPENS IF I BECOME PREGNANT? 
If you are pregnant or breastfeeding you will not be allowed to take part in this study because the effects of 
the study drugs on a baby still in the womb and babies being breast fed, is unknown. If you are women and 
you are having sex, you must use two reliable methods of birth control whilst on the study. This will be 
discussed with you by the study staff. The methods of contraception include: 
• Male or female condom with or without a spermicidal agent (cream or gel that kills sperms) 
• Diaphragm or cervical cap with a spermicide 
• IUD (Intrauterine device) or hormone based contraception.  
 
If you think you may be pregnant at any time during the study, please tell the study staff right away. The study 
staff will talk to you about your choices. 
 
 
WHAT ARE THE BENEFITS ASSOCIATED WITH THE STUDY? 
If you decide to take part in this study, there may be a direct benefit to you, but no guarantee can be made. 
Medical staff at the CAPRISA site will follow your health more closely which may help you feel better. You 
also will be receiving free treatment and medical care.  
 
WILL I RECEIVE ANY PAYMENT? 
Participants enrolled into this study will be reimbursed R150 for every study required scheduled visit. See 
Attachment A for required study visits. For all split, staff initiated, interim and unscheduled visits, you will be 
reimbursed R50. 
 
 
 


PI: Dr N Padayatchi 
Site: CAPRISA  
 
Study No: CAP 011 
Page 51 of 58 
Version4.0
 
 
11 May 2015 
WHAT ARE THE COSTS TO ME? 
There will be no cost to you for the study related visits, physical examinations, laboratory tests or other 
procedures.  
 
WHAT HAPPENS IF I AM INJURED? 
Based on what we know now, it is unlikely that you will be injured as a result of being in this study. If you are 
injured as a result of being in this study, you will be given immediate necessary treatment for your injuries at 
the CAPRISA Clinical Research Site. You will not have to pay for this treatment. You will be told where you 
may receive additional treatment for your injuries. There is no program for monetary compensation or other 
forms of compensation for such injuries. You do not give up any legal rights by signing this consent form. 
 
If you become injured as a result of being in this study, you o will be given immediate treatment for injuries, 
and be referred for further treatment, if necessary. The CAPRISA Clinic has taken out an insurance policy for 
this study.  Should you acquire an injury that is as a result of the study, please inform the study staff 
immediately or contact the persons listed at the end of this form.  A CAPRISA staff member will assist you 
with any valid insurance claims. 
 
WHAT ARE MY RIGHTS AS A VOLUNTEER IN A RESEARCH STUDY? 
You can decide whether or not you wish to take part in this study. If you choose not to take part in the study, 
the care you would normally receive will not be affected. You can also leave the study if you feel comfortable 
doing so.  
The site staff will tell you about any new information from this study (or other studies using similar drugs) 
that may affect your health, welfare, or willingness to study in this study.  
 
 
 
WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about this study or a research-related injury, contact any of the following persons: 
 
Dr Nesri Padayatchi  
CAPRISA Deputy Director 
Tel:   031 260 4574 
Fax: 031 260 4566 
E-mail: Padayatchin@ukzn.ac.za  
 
 


PI: Dr N Padayatchi 
Site: CAPRISA  
 
Study No: CAP 011 
Page 52 of 58 
Version4.0
 
 
11 May 2015 
For questions about your rights as a research participant, you may contact: 
BREC Administrator or Chair - for reporting of complaints/problems- 
Biomedical Research Ethics Committee 
Private Bag X54001 
Durban 
4000 
Tel: +27 31 260 4769 
Fax: +27 31 260 4609 
Email: BREC@ukzn.ac.za 
 
 
 


PI: Dr N Padayatchi 
Site: CAPRISA  
 
Study No: CAP 011 
Page 53 of 58 
Version4.0
 
 
11 May 2015 
SIGNATURE FOR IMPRESS INFORMED CONSENT  
If you have read this consent form (or had it explained to you), all your questions have been answered, and 
you agree to take part in this study, please sign your name below. 
 
 
 
 
 
 
 
    ____ 
 
 
__ 
Participant’s Name (print) 
 
    Participant’s Signature            Date 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
__  
Study Staff Conducting Consent 
   Study Staff Signature           Date of Discussion 
(print) 
 
 
 
 
 
 
    
 
 
 
__ 
Witness’s Name (print) 
 
 
Witness’s Signature      Date  
(As appropriate) 


PI: Dr N Padayatchi 
Site: CAPRISA   
Study No: CAP 011 
Page 54 of 58 
 
Version 4.0, 11 May 2015 
ATTACHMENT A: Schedule of Visits 
 
 
Procedures 
Scree
ning 
Base
line 
Week 
Study Months  
2 
4 
6 
2 
3 
4 
5 
6 
7 
8 
10 
12 
14-24 
(2 
monthly) 
End 
TB 
Treat6 
Recur
rence 
Termi
nation 
Time 
of 
IRIS 
Time of 
serocon
version 
Inclusion & Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV test  (performed monthly 
for HIV negative participants) 
X1 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical , Medication and TB 
History & Physical Exam 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals (including Pregnancy 
test ) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception confirmation 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
GeneXpert  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum Smear 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Culture : INTERVENTION 
ARM: until 6 months  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
Culture: CONTROL ARM: 
until 6 months  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
Susceptibility  
 
X 
 
 
 
X 
 
 
 
X* 
 
X
* 
 
 
 
X 
X 
 
 
 
PAXgene for SHIP Study 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
Urine (Lam Testing) 
 
X 
 
 
 
X 
 
 
X 
 X 
 
 
 
 
 
X 
 
 
 
 
Chest radiograph 
 
X2 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
ECG ** 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Vision testing (Snellen and 
Ishihara) Control Arm only  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PI: Dr N Padayatchi 
Site: CAPRISA   
Study No: CAP 011 
Page 55 of 58 
 
Version 4.0, 11 May 2015 
Procedures 
 
Scree
ning 
 
Base
line 
 
Week 
Study Months  
2 
4 
6 
2 
3 
4 
5 
6 
7 
8 
10 
12 
14-24 
(2 
monthly) 
End 
TB 
Treat6 
Recur
rence 
Termi
nation 
Time 
of 
IRIS 
Time of 
serocon
version 
AST, ALT, Bilirubin, Hb, 
platelets, & Full blood count, 
Creatinine clearance, 
potassium, total protein, 
alkaline phosphatase 
X 
X2 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
CD4 Count (HIV Infected 
patients only) 
X 
 
 
 
 
As per SA HIV guidelines  
 
 
 
X 
 
Viral Load (HIV Infected 
patients only) 
X 
 
 
 
 
 
 
X 
 
X 
 
HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
PK Samples (Intervention 
Arm) 
 
 
 
X 
 
X
3 
 
 
 
X 
X
4 
 
 
 
 
 
 
 
 
 
PK Samples (Control Arm) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen Storage 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PBMCs*** 
 
X5 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
1: HIV Testing is required at screening for all potential participants. Thereafter, monthly HIV testing will be required for HIV negative participants only.  
2: A Chest Radiograph/ Bloods will be repeated if they are more than 14 days old 
3: PK blood samples, in the intervention arm only, will be taken once during the intensive phase of TB treatment at either Week 4 OR Month 2 (PK bloods may be repeated at Month 2 if these were 
not taken, incorrectly done or incomplete at Week 4 OR at the discretion of the investigator), and at the end of TB treatment (Month 6)  
4: Additional PK samples will be taken at M7 (or the first visit after if Month 7 is missed) in Intervention Arm before and after the ingestion of the single additional dose of Moxifloxacin. This 
additional PK sample may be deferred to month after TB treatment completion on participants who have TB treatment extended beyond 6 months 
5: If PBMCs are not collected at baseline samples may be taken at Week 4or Month 2 
6.  End of TB Treatment visit will be conducted with 7 days of completion of TB treatment. 
* Samples will be collected and stored for future susceptibility testing,  
**ECG’s will be done at baseline, Month 2, Month 4 and Month 6. ECG’s will be performed 2 monthly during treatment with Moxifloxacin 
***Additional PBMC’s will be collected at IRIS and at the time of seroconversion 
 


PI: Dr N Padayatchi 
Site: CAPRISA   
Study No: CAP 011 
Page 56 of 58  
Version 4.0, 11 May 2015 
ATTACHMENT B - Study Drug Side Effects 
Drug  
Common Side Effects 
Any  
Changes in body shape, such as: 
• increase in fat around the waist and stomach  
• increase in fat on the back of the neck 
• thinning of the face, legs, and arms 
      breast enlargement 
Isoniazid  
 
• changes in vision  
• clumsiness or unsteadiness  
• changes in the colour of urine  
• loose or watery stools  
• loss of appetite, weight loss, nausea (feeling sick to the stomach) and 
vomiting  
• pain in upper abdomen  
• skin rash 
• stools lighter in colour  
• fever  
• tingling and numbness in the hands and feet, especially if extra vitamin 
B6 is not taken with INH; this risk is increased in malnourished 
individuals and pregnant women. 
• weakness and fatigue  
• yellowing of eyes or skin   
 
In general, these side effects are temporary.  There may also be an increase 
in some liver function tests indicating that there may be some damage to 
the liver.  
Pyrazinamide  
 
• Markedly reduced appetite 
• Nausea 
• Flushing 
• liver inflammation  
• vomiting 
• joint pain 
• elevated levels of uric acid in the blood which may lead to gout  
     drug rash 
 
Rarely  
• gout 
• sensitivity to light 
Rifampicin 
 
Rifampicin is commonly prescribed in the United States and worldwide to 
treat TB, and is generally well tolerated.  
 
Rifampicin turns urine, sweat, sputum, and tears a red-orange color. The 
red-orange color in urine may stain undergarments. Soft contact lenses 
may be permanently stained by Rifampicin.  
 
Less common side effects include: 
 
• Hepatitis (inflammation of the liver). This has caused deaths in 
patients who already had liver disease or who were taking other drugs 
that were toxic to the liver. 


PI: Dr N Padayatchi 
Site: CAPRISA   
Study No: CAP 011 
Page 57 of 58  
Version 4.0, 11 May 2015 
• increases in liver function tests  
• increased bilirubin, which may be associated with yellowing of the 
eyes 
• upset stomach, vomiting, and diarrhoea 
• abdominal pain  
• reduced levels of some of your body's hormones  
• reduced levels of calcium and phosphate in blood 
• decreased effectiveness of hormonal contraceptives and many other 
medications 
• reduced blood cell counts  
• headache 
• rash and itching 
• fever 
      kidney failure 
4-drug 
Combination  
The most common side effects of standard therapy with INH, Rifampicin, 
Ethambutol and Pyrazinamide are similar to those that people have with 
the individual drugs.  
• nausea  
• vomiting  
• fever  
• rash  
• joint pain  
• liver toxicity 
• elevated uric acid levels in blood, which rarely lead to gout 
• tingling and numbness in the hands and feet unless extra vitamin B6 is 
taken; this risk is higher in malnourished individuals and pregnant 
women.   
• changes in vision  
 
Rarely 
gout 
Ethambutol 
 
• Inflammation of nerves in the eyes 
• Joint pain 
 
 
Rarely  
• liver inflammation 
• rash 
• elevation of uric acid in the blood, which may lead to gout 
Moxifloxacin 
 
• nausea 
• diarrhoea 
• pain in the belly 
• headache  
• dizziness 
• mild increase in liver enzymes 
 
Rarely 
• inflammation (swelling/tenderness/redness/pain) of the gut 
• allergic reaction 
• loss of smell and mental/mood changes 


PI: Dr N Padayatchi 
Site: CAPRISA   
Study No: CAP 011 
Page 58 of 58  
Version 4.0, 11 May 2015 
 
Very Rarely 
• irregular heartbeats 
• fits 
• severe allergic reaction 
• tendon inflammation 
• arthritis 
• kidney failure 
• myasthenia (weakness of ye and other muscles 
 
Life threatening 
• Liver inflammation leading to liver failure  
• severe skin rash with blistering and peeling 
 
 
 
 
 

SAP_001.pdf: