Phase 2 Trial to Evaluate the Early EBA, Safety and Tolerability of Amoxicillin/Clavulanate With or Without Meropenem, Ertapenem or Rifampicin in Adults With Newly Diagnosed, Smear-Positive Rifampicin-Susceptible Pulmonary Tuberculosis
Phase: PHASE2
Conditions: Pulmonary Tuberculosis
Sponsor: TASK Applied Science

  
TASK-003_Version 1.2_dated 27 February 2020 
                                                                                   Page 1 of 65        
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
 
Protocol Title: 
A Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of Meropenem 
Administered Intravenously Once or Twice Daily in Combination with Oral Amoxicillin/Clavulanate,  
Ertapenem Administered Once Daily Intravenously or Intramuscularly with Oral 
Amoxicillin/Clavulanate, Oral Amoxicillin/Clavulanate Alone, and Rifampicin with Oral 
Amoxicillin/Clavulanate in Adults with Newly Diagnosed, Smear-Positive Rifampicin-Susceptible 
Pulmonary Tuberculosis 
 
 
                                                  Protocol Number: 
TASK-003 
 
Protocol Version:      
Version 1.2 
 
    Protocol Date:       
27 February 2020 
 
 
 

 
 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
          Page 2 of 65   
Sponsor Protocol Signature Page 
 
Protocol Title: A Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of 
Meropenem Administered Intravenously Once or Twice Daily in Combination with Oral 
Amoxicillin/Clavulanate,  Ertapenem Administered Once Daily Intravenously or 
Intramuscularly with Oral Amoxicillin/Clavulanate, Oral Amoxicillin/Clavulanate Alone, 
and Rifampicin with Oral Amoxicillin/Clavulanate in Adults with Newly Diagnosed, 
Smear-Positive Rifampicin-Susceptible Pulmonary Tuberculosis. 
 
 
Protocol Number: 
TASK-003 
 
Protocol Date:  
27 February 2020 
 
 
Sponsor  
 
I agree to the terms of this study protocol. 
 
 
 
 
____________________________________________ 
 
_______________________________________ 
Signature of Sponsor/Sponsor Representative 
 
Printed Name 
 
 
 
 
____________________________________________ 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
          Page 3 of 65   
Principal Investigator Protocol Signature Page 
 
Protocol Title: A Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of 
Meropenem Administered Intravenously Once or Twice Daily in Combination with Oral 
Amoxicillin/Clavulanate,  Ertapenem Administered Once Daily Intravenously or 
Intramuscularly with Oral Amoxicillin/Clavulanate, Oral Amoxicillin/Clavulanate Alone, 
and Rifampicin with Oral Amoxicillin/Clavulanate in Adults with Newly Diagnosed, 
Smear-Positive Rifampicin-Susceptible Pulmonary Tuberculosis. 
 
 
Protocol Number: 
TASK-003 
 
Protocol Date:  
27 February 2020 
 
 
Principal Investigator 
 
I agree to the terms of this study protocol. 
 
 
 
____________________________________________ 
 
_______________________________________ 
Signature of Principal Investigator 
 
 
 
Printed Name 
 
 
 
____________________________________________ 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
          Page 4 of 65   
Development Phase: 
2 
Sponsor Representative: 
TASK Foundation NPC 
M2, Karl Bremer Hospital 
Mike Pienaar Avenue 
Bellville, 7530 
Cape Town, South Africa 
 
Funding by: 
European Union – Horizon2020 
Medical Monitor: 
Name: Prof Peter Donald 
Address:  
Department of Paediatrics and Child Health  
Faculty of Medicine and Health Sciences  
Stellenbosch University  
South Africa Phone  
Phone:  +27 (21) 554 1124  
Mobile: +27 (82) 603 5355  
Fax:        +27 21 938 9717 
Email:    prd@sun.ac.za 
 
Principal Investigator: 
Name: Andreas Diacon 
Address: TASK Clinical Research Centre 
1 Smal Street,  
Bellville  7531  
Cape Town, South Africa 
Phone:   +27 21 917 1044 
Mobile:  +27 82 420 1677 
Fax:        +27 21 948 2297 
Email:     ahd@sun.ac.za 
 
 

 
 
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Table of Contents 
 
1 
Protocol Synopsis   
 
 
 
 
 
 
 
 
Page 
11 
1.1 Synopsis 
 
 
 
 
 
 
 
 
1.2 Trial Flow Chart  
 
 
 
 
 
 
 
 
1.3 PK Chart   
 
 
 
 
 
 
 
 
 
  
2 
Background Information   
 
 
 
 
 
 
 
Page  21 
2.1 Tuberculosis  
 
 
 
 
 
 
 
  
2.2 Early Bactericidal Activity Clinical Studies  
 
 
 
 
  
2.3 New Biomarkers as Surrogates for Drug Activity  
 
 
 
 
 
2.4 Optimizing the Use of Existing Antibiotics 
2.5 Agents to be Studied 
2.5.1 
Repurposing an Optimised Combination of Beta-lactams for MDR/XDR-TB  
2.5.2 
Preclinical Rationale for Use of ß-lactams for Tuberculosis 
2.5.3 
Clinical Rationale for Use of ß-lactams for Tuberculosis 
2.5.4 
Clinical Rationale for Use of Carbapenems for Tuberculosis 
2.5.5 
Boosting the Activity of Rifampicin 
2.6 Known and Potential Risks and Benefits of the Investigational Product/s and Procedures 
2.6.1 
Beta-lactams 
2.6.2 
Amoxicillin/CA 
2.6.3 
Carbapenems 
2.6.4 
Rifampicin (35mg/kg) 
2.6.5 
Rifafour e275® 
2.6.6 
Blood Draws and Sputum Collection 
2.6.7 
FDG-PET/CT Scans 
2.7 Overall Benefit/Risk Assessment 
 
3 
Study Rationale And Objectives   
 
 
 
 
 
 
Page  30  
3.1  Study Rationale  
3.2 Study Design Rationale  
3.3 Rationale for Selection of Agents and Doses  
3.4 Exploratory Biomarkers 
3.5 Trial Objectives 
3.5.1 
Primary Objectives 
3.5.2 
Secondary Objectives 
  
 
4 
Trial Design  
 
 
 
 
 
 
 
 
 
Page  33 
 
 
4.1 Summary of Trial Design  
 
 
4.2 Treatment Arms 
 
 
4.3 Trial Endpoints 
 
 
 
4.3.1 Primary Endpoints 
 
 
 
4.3.2 Secondary Endpoints  
 
 
 
 
4.2.2.1 Activity  
 
 
 
 
4.2.2.2 Safety and Tolerability  
 
 
 
 
4.2.2.3 Pharmacokinetics  
 
 
 
 
4.2.2.4 Pharmacokinetics – Pharmacodynamics  
 
 
 
 
4.2.2.5 Biomarkers 
 
 
 
 
4.2.2.6 Mycobacteriology Characterization  
 
 
 
 
4.4 Trial Population  
 
 
 
 
 
 
 
 
 
 
 
 
4.4.1 Inclusion Criteria  
 
 
 
4.4.2 Exclusion Criteria  
 
 
4.5 Restrictions 
 
 
 
4.5.1 Foods and Beverages 
 
 
 
4.5.2 Prior and Concomitant Medications 

 
 
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4.5.3 Activity 
 
 
 
 
 
4.6 Treatment Discontinuation and Participant Withdrawal  
 
 
4.7 Treatment Plan: Schedule of Assessments  
 
 
 
4.7.1 Pre-Treatment Period  
 
 
 
 
4.7.1.1 Visit 1/Day -9 to -3 
 
 
 
 
4.7.1.2 Visit 2/Day -2 
 
 
 
 
4.7.1.3 Visit 3/Day -1  
 
 
 4.7.2 Treatment Period  
 
 
 
 
4.7.2.1 Visit 4/Day 1  
 
 
 
 
4.7.2.2 Visit 5 to 16/Days 2 to 13 
 
 
 
 
4.7.2.3 Visit 17/Day 14 
 
 
 
 
4.7.2.4 Visit 18/Day 15 
 
 
 
 
4.7.2.5 Early Withdrawal  
 
 
 
4.7.3 Follow-Up Period  
 
 
 
 
4.7.3.1 Visit 19/Day 28 
 
 
4.8 Stopping Rules  
 
 
4.7 Participant Progress Definition  
 
 
 
 
5.  Investigational Product   
 
 
 
 
 
 
 
Page  43 
 
 
5.1 Trial Treatments  
 
 
5.2 Method of Assigning Participants to Treatment Groups  
 
 
5.3 IP Administration 
 
 
 
5.3.1 Route and Dosage  
 
 
 
5.3.2 Dosing Times  
 
 
 
5.3.3 IP Reconstitution 
 
 
 
5.3.4 Participant Compliance  
  
 
 
5.4 Blinding and Procedures for Breaking the Blind  
 
 
5.5 Packaging  
 
 
5.6 Labelling 
 
 
5.7 Storage  
 
 
5.8 Dispensing and Accountability 
 
 
5.9 Returns and Destruction  
 
 
 
 
6.  Trial Variables and Procedures   
 
 
 
 
 
 
Page  48 
 
 
6.1 Demographic and Baseline Variables and Procedures  
 
 
6.2 FDG-PET/CT Scan  
 
 
6.3 Activity Variables and Procedures  
 
 
6.4 Safety and Tolerability Variables and Procedures  
 
 
6.5 Pharmacokinetic Variables and Procedures  
 
 
6.6 Biomarkers 
 
 
6.7 Mycobacteriology Characterization Variables and Procedures  
 
 
7.  Adverse Events   
 
 
 
 
 
 
 
 
Page  51 
 
 
7.1 Definitions  
 
 
 
7.1.1 Adverse Events 
 
 
 
7.1.2 Serious Adverse Events  
 
 
 
7.1.3 Unlisted (Unexpected) Adverse Event  
 
 
 
7.1.4 Life Threatening  
 
 
 
7.1.5 Associated with the Use of the Drug  
 
 
 
7.1.6 Attribution/Causality  
 
 
 
7.1.7 Severity  
 
 
 
7.1.8 Other AE Definitions  
 
 
7.2 Reporting  
 
 
 
7.2.1 Adverse Event  
 
 
 
7.2.2 Serious Adverse Event  

 
 
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7.2.3 Follow up of Adverse Events  
 
 
 
7.2.4 Post-Trial Adverse Events  
 
 
 
 
7.2.5 Clinical Laboratory Adverse Events  
 
 
 
 
7.2.6 Disease under Study  
 
 
 
7.2.7 Overdose  
 
 
 
7.2.8 Drug Interaction  
 
 
 
7.2.9 Pregnancy  
 
 
7.3 Monitoring and Safety for Specific Toxicities  
 
 
 
7.3.1 Any other Toxicities  
 
 
8. 
Statistical Analysis  
 
 
 
 
 
 
 
 
Page  56 
 
 
8.1 Analysis Population/s  
 
 
8.2 Sample Size  
 
 
8.3 Interim Analyses  
 
 
8.4 Endpoint Analysis  
 
 
 
8.4.1 Primary Endpoint Analysis 
 
 
 
8.4.2 Secondary Endpoints Analysis  
 
 
 
 
8.4.2.1 Activity  
 
 
 
 
8.4.2.2 Safety and Tolerability Analyses  
 
 
 
 
8.4.2.3 Pharmacokinetics Analysis  
 
 
 
 
8.4.2.4 Pharmacokinetic and Pharmacodynamic Analysis  
 
 
 
 
8.4.2.5 Mycobacteriology Characterization  
 
 
9.  Records Management  
 
 
 
 
 
 
 
 
Page  58 
 
 
9.1 Data Collection  
 
 
9.2 Source Documents  
 
 
9.3 File Management at the Trial Site  
 
 
9.4 Records of Retention at the Trial Site  
 
 
10.  Quality Control and Assurance   
 
 
 
 
 
 
Page  59 
 
 
10.1 Site Procedures  
 
 
10.2 Monitoring  
 
 
10.3 Auditing  
 
 
11.  Ethics and Regulatory  
 
 
 
 
 
 
 
 
Page  60 
 
 
11.1 Basic Principles  
 
 
11.2 Independent Ethics Committee/Institutional Review Board Review  
 
 
11.3 Regulatory Authorities  
 
 
11.4 Informed Consent  
 
 
11.5 Confidentiality  
 
 
12.  Incidental Findings  
 
 
 
 
 
 
 
 
Page  61 
13.  Publication Policy  
 
 
 
 
 
 
 
 
Page  61 
14.  Protocol Amendment Policy  
 
 
 
 
 
 
 
Page  61 
15.  Financial Aspects, Insurance and Indemnity  
 
 
 
 
 
Page  62 
16.  References  
 
 
 
 
 
 
 
 
 
Page  63 
 
 
 
 
 
 
 

 
 
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Appendices 
None 
 
 
Tables 
Table 1: 
MICs of Imipenem, Meropenem, and Ertapenem Alone and in the Presence of 
2.5g/ml of Clavulanate (Ca) (Veziris 2011)   
Table 2:   
MICs of Amoxicillin 
Table 3:   
Total Maximum Radiation per Subject per 1 Year (3 PET/CTs and 1 Chest X-ray) 
Table 4:   
Treatment Groups 
Table 5:   
Treatment Groups 
Table 6:  
 Investigational Medicinal Product Details 
Table 7:  
Analyte/s to be Measured per Treatment Arm 
Table 8: 
MIC/s to be measured per Treatment Arm 
Table 9:   
Adverse Events Attribution/Causality Ratings 
Table 10:  
Adverse Event Severity Ratings 
Table 11:   
Expected Standard Errors of Group mean log CFU and confidence intervals 
 
 
Figures 
Figure 1:   
MIC of Meropenem in the Presence of a Fixed Concentration of 2.5mg/l CA before 
and after the Addition of Amoxicillin (Gonzalo 2014) 
Figure 2:   
Intracellular Susceptibility of H37Rv to Carbapenems in Combination with CA (England 
2012) 
Figure 3:  
Estimated log10CFU Counts per Treatment Over Time  
Figure 4: 
Estimated log10CFU Counts per treatment over time for meropenem 6 grams 
once daily over 6 hours 
Figure 5: 
Trial Schematic 
 

 
 
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  List of Abbreviations and Definitions of Terms 
 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine Aminotransferase 
AMX 
Amoxicillin 
AST  
Aspartate Aminotransferase 
AUC  
Area Under the Plasma Concentration Time Curve 
AUC(0-24) 
Area Under the Plasma Concentration Time Curve From Zero to End of Dosing 
Interval  
BD 
Twice Daily 
CA 
Clavulanic Acid 
CFU 
Colony Forming Units 
Cmax  
Maximum Observed Plasma Concentration 
Cmin 
Minimum Observed Plasma Concentration at the End of the Dosing Interval 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DR 
Drug Resistant 
DS 
Drug Sensitive 
EBA 
Early Bactericidal Activity 
EC 
Ethics Committee 
ECG  
Electrocardiogram 
EMB 
Ethambutol 
EWV 
Early Withdrawal Visit 
GCP  
Good Clinical Practice 
GGT 
Gamma-Glutamyltransferase 
HIV  
Human Immunodeficiency Virus 
HRZE 
Isoniazid/Rifampicin/Pyrazinamide/Ethambutol 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IF 
Incidental Findings 
IV 
Intravenous 
IP 
Investigational Product 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
INH 
Isoniazid 
LDH 
Lactate Dehydrogenase 
m  
Meters 
MDR 
Multi Drug Resistant 
MGIT 
Mycobacterial Growth Indicator Tube 
MIC  
Minimum Inhibitory Concentration 
MOXI 
Moxifloxacin 
MTB 
Mycobacterium Tuberculosis 
PCR  
Polymerase Chain Reaction 
PD 
Pharmacodynamic  
PI 
Principal Investigator 

 
 
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          Page 10 of 65   
PK  
Pharmacokinetic 
PR 
Electrocardiographic PR Interval 
PZA 
Pyrazinamide 
QT 
Electrocardiographic QT Interval 
QTc 
Corrected QT Interval 
RIF/RF 
Rifampicin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
t 
Time 
t½ 
Apparent Terminal Elimination Phase Half-Life 
TB 
Tuberculosis 
TEAEs 
Treatment-Emergent Adverse Events 
Tmax 
Time at Which Cmax is Observed 
TMIC 
Time over Minimum Inhibitory Concentrations 
TTP  
Time to Sputum Culture Positivity 
ULN 
Upper Limit of Normal 
WHO  
World Health Organization 
XDR 
Extensively Drug Resistant 
 
  EBA Definitions 
EBA 
 
An agent’s ability to kill mycobacteria originating within pulmonary cavities during 
the first weeks of treatment. 
EBA CFU 
 
Determination of EBA by quantification of solid medium of viable Colony Forming 
Units (CFU) of M. Tuberculosis from an overnight sputum collection.  
EBA TTP 
 
Determination of EBA by measurement in an automated liquid culture system of 
time to positivity (TTP) of M. Tuberculosis from an overnight sputum collection.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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1. Protocol Synopsis 
 
1.1 Synopsis 
 
Name of Sponsor/Company: 
TASK Foundation NPC, funded by the European Union (Horizon 2020) 
Name of Finished Products: 
Meropenem ; Ertapenem; Rifampicin; Amoxicillin/CA  
Protocol Title: 
A Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and 
Tolerability of Meropenem Administered Intravenously Once or Twice 
Daily in Combination with Oral Amoxicillin/Clavulanate,  Ertapenem 
Administered Once Daily Intravenously or Intramuscularly with Oral 
Amoxicillin/Clavulanate, Oral Amoxicillin/Clavulanate Alone, and 
Rifampicin with Oral Amoxicillin/Clavulanate in Adults with Newly 
Diagnosed, 
Smear-Positive 
Rifampicin-Susceptible 
Pulmonary 
Tuberculosis. 
Treatment Indication: 
Pulmonary tuberculosis (TB). 
Trial Objective: 
The overall objective of this study is to evaluate the 2-week 
bactericidal activity and pharmacokinetics of the following beta-
lactam containing combinations with the aim to select the most 
active and implementable solution to be incorporated into a drug-
resistant TB combination regimen: 
 
 
Once or twice daily meropenem administered intravenously in 
combination with once or twice daily oral amoxicillin/clavulanic 
acid; 
 
Once 
daily 
ertapenem 
administered 
intravenously 
and 
intramuscularly 
in 
combination 
with 
twice 
daily 
oral 
amoxicillin/clavulanic acid; 
 
Twice daily oral amoxicillin/clavulanic acid; 
 
Once daily rifampicin administered orally at highest currently 
established dosage of 35mg/kg in combination with twice daily 
oral amoxicillin/clavulanic acid. 
 

 
 
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          Page 12 of 65   
Name of Sponsor/Company: 
TASK Foundation NPC, funded by the European Union (Horizon 2020) 
Name of Finished Products: 
Meropenem ; Ertapenem; Rifampicin; Amoxicillin/CA  
Trial Design: 
 
 
 
A single-center, open-labeled, clinical trial in two groups. The 
treatments are:  
Group 1: 
1. Meropenem 6g intravenously once daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
2. Ertapenem 1g intramuscularly once daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
Group 2: 
3. Meropenem 3g intravenously twice daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
4. Ertapenem 1g intravenously once daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
5. Amoxicillin/CA 2 x 1000mg/62.5mg orally 12-hourly on days  
1-14.  
6. Rifampicin 35 mg/kg once daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
7. Meropenem 6g OR meropenem 4g intravenously once daily; 
plus amoxicillin/CA 2 x 1000mg/62.5mg orally once daily on 
days 1–14. 
 
A total of 4 participants per group will receive standard first line TB 
treatment as per the South African TB guidelines (Rifafour e-275) and 
is included as a control for the EBA quantitative mycobacteriology 
and to evaluate whether HRZE gives similar EBA results to that 
demonstrated 
in 
prior 
studies 
with 
this 
combination. 
The 
mycobacteriology laboratory will remain blinded until closure of the 
EBA results.  Enrollment into group 1 will be completed before 
enrollment into group 2 will start.  After completion of enrollment into 
group 1, there will be an interim analysis while enrollment into group 2 
is ongoing. 
Patient Population: 
A total of 113 male or female participants (7 groups of 15 participants 
receiving IP and 2 groups of 4 participants receiving Rifafour e-275), 
aged between 18 and 65 years (inclusive), with newly diagnosed, 
smear-positive, pulmonary TB. 

 
 
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          Page 13 of 65   
Name of Sponsor/Company: 
TASK Foundation NPC, funded by the European Union (Horizon 2020) 
Name of Finished Products: 
Meropenem ; Ertapenem; Rifampicin; Amoxicillin/CA  
Test Product, Dose and 
Mode of Administration: 
The Investigational Product (IP) will be supplied as: 
 
Meropenem 1g reconstitution vials 
 
Ertapenem 1g reconstitution vials 
 
Amoxicillin/CA 1000/62.5mg tablets 
 
Rifampicin 150mg and 300mg tablets 
 
Treatment will be administered for 14 consecutive days in the following 
dosing schemes:  
1. Meropenem 6g intravenously once daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
2. Ertapenem 1g intramuscularly once daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
3. Meropenem 3g intravenously twice daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
4. Ertapenem 1g intravenously once daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
5. Amoxicillin/CA 2 x 1000mg/62.5mg orally 12-hourly on days  
1-14.  
6. Rifampicin 35 mg/kg once daily; plus amoxicillin/CA  
2 x 1000mg/62.5mg orally 12-hourly on days 1-14.  
7. Meropenem 6g OR 4g intravenously once daily; plus 
amoxicillin/CA 2 x 1000mg/62.5mg orally once daily on days 1 
– 14. 
 
Positive Control Product, 
Dose, and Mode of 
Administration: 
Rifafour e-275 will be supplied as tablets and administered orally once 
daily for 14 days as per South African National TB Treatment Guidelines. 
The daily dose is dependent on the participants’ weight as follows: 40 
- 54kg: 3 tablets; 55 – 70kg: 4 tablets; 71kg and over: 5 tablets. 
Criteria for evaluation: 
Primary Endpoint Analysis 
The EBACFU(0-14) as determined by the rate of change in logCFU per ml sputum over the period day 
0 to day 14 which will be described with at most 3 parameters from a linear, bi-linear or non-linear 
regression of logCFU on time. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
 
Secondary Endpoint Analysis 
Activity: 
 
The EBACFU(0-2) and EBACFU(2-14) as determined by the rate of change of logCFU in sputum over 
the period day 0 to day 2 and day 2 to day 14, which will be described with at most 3 parameters 
from an appropriate function of logCFU on time. 
 
The EBATTP(0-2), EBATTP(0-14), and EBATTP(2-14) in the Mycobacterial Growth Indicator Tube 
(BactecTM MGITTM 960) system as determined by the rate of change in TTP in sputum over the 
periods day 0 to day 2, day 0 to day 14, and will be described with at most 3 parameters from an 
appropriate function of TTP on time. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out.  
 
Safety and Tolerability Analyses 
 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and will be presented by preferred term within each MedDRA System Organ Class (SOC). 
 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the first 
administration of IP and includes those events that started prior to the first administration of IP but 
which worsened after the first intake. Adverse events starting after the last administration of IP until 
the last scheduled visit/assessment/measurement will be regarded as treatment-emergent. 

 
 
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          Page 14 of 65   
Name of Sponsor/Company: 
TASK Foundation NPC, funded by the European Union (Horizon 2020) 
Name of Finished Products: 
Meropenem ; Ertapenem; Rifampicin; Amoxicillin/CA  
 
The incidence of the following events will be summarized by treatment group for further medical 
analysis: 
o 
Incidence of treatment-emergent adverse events (TEAEs);  
o 
Incidence of TEAEs by Severity; 
o 
Incidence of drug related TEAEs; 
o 
Incidence of Serious TEAEs; 
o 
Incidence of TEAEs leading to early withdrawal; 
o 
Incidence of TEAEs leading to death. 
 
Other safety variables: laboratory parameters, physical examination, vital signs, concomitant 
medication. Descriptive summary statistics will be presented. 
 
Pharmacokinetic Analysis 
The maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum 
observed plasma concentration (Cmin) 24 hours following day 14, area under the plasma 
concentration time (t) curve from zero to 24 hours (AUC(0-24)) will be estimated for the following, on 
day 14: 
 
Treatment Arm 
Analyte/s 
Meropenem plus amoxicillin/CA 
Meropenem; amoxicillin; CA  
Ertapenem plus amoxicillin/CA 
Ertapenem;  amoxicillin; CA 
Rifampicin 
Rifampicin; amoxicillin; CA 
Amoxicillin; CA 
Amoxicillin; CA 
Rifafour e275 
None 
No PK analyses will be performed on the Rifafour e275 treatment arm. 
 
The following PK parameters will be estimated from participants’ individual plasma concentrations 
(except in the Rifafour e275® treatment arm) by applying a noncompartmental approach using PK 
software such as WinNonlin Professional. Concentration values reported as below the limit of 
quantitation will be set to zero. Each parameter will be calculated separately using plasma 
concentrations of  meropenem and ertapenem and their respective metabolites, amoxicillin/CA and 
rifampicin.  PK parameters will be estimated for day14 only.  
 
Cmax:          Maximum observed plasma drug concentration. 
 
Tmax:          Time at which Cmax is observed (obtained without interpolation). 
 
Cmin:           Minimum observed plasma drug concentration 24 hours following the last dose. 
 
AUC(0-24): Area under the drug concentration-time curve calculated using linear trapezoidal 
summation from time zero to time 24 hours. 
 
Descriptive statistics including mean, standard deviation, coefficient of variation, median, minimum 
and maximum, geometric mean and geometric mean CV% will be computed for each PK parameter 
by group. Grouping will be by gender.  
In addition, mean and median concentration-versus-time graphs will be provided (with error bars as 
appropriate).  
 
Pharmacokinetic and Pharmacodynamic Analysis 
The EBACFU(0-14), EBACFU(0-2), and EBACFU(2-14) vs. the following PK variables will be presented for 
Meropenem, ertapenem, amoxicillin/CA, and rifampicin:  
 
Cmax;  
 
AUC(0-24); 
 
Time over minimum inhibitory concentrations (TMIC). 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
 
No PK-PD analyses will be performed on the Rifafour e275 treatment arm. 
 
Mycobacteriology Characterization 

 
 
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          Page 15 of 65   
Name of Sponsor/Company: 
TASK Foundation NPC, funded by the European Union (Horizon 2020) 
Name of Finished Products: 
Meropenem ; Ertapenem; Rifampicin; Amoxicillin/CA  
Cultures grown from the overnight sputum collections from Baseline (day -2 or day -1) and the last 
available culture on a treatment day will be assessed as follows: 
 
A culture will be grown from a sputum sample submitted before treatment initiation (baseline) for 
confirming that the infecting organism is M. tuberculosis susceptible to isoniazid and rifampicin 
(GenoType MTBDRplus, Hain, Nehren, Germany). Cultures from baseline and from day 14 sputum 
will be kept for determination of the minimum inhibitory concentration (MIC) of the investigational 
agents that the subject was treated with. If a Day 14 culture is not available the last available 
culture after Day 8 will be kept. MIC tests for beta-lactams are under development and cultures 
might be exported for this purpose.  
Statistical Methods: 
This is a descriptive study with no inferential statistics or hypothesis testing. The planned sample size of 
15 participants per treatment group is in keeping with other phase 2 trials of this type and accounts 
for the possibility of up to 3 drop-outs per arm, which based on previous studies of this type conducted 
at these sites, represents a conservative estimate of the expected drop-out rate. The statistical analysis 
plan (SAP) will be developed before the database is locked. 
Trial Duration: 
37 days (up to 9 days pre-treatment plus 15 days treatment period plus 14 days post-treatment 
follow-up). 
Recruitment period 18 months. Recruitment of additional arm 7 will be 2 months. 

TASK-003_1.1_dated 23 August 2017 
 
     
   
 
 
 
 Page 16 of 65          
1.2 Trial Flow Chart 
 
Period 
Pre-Treatment 
Treatment 
Follow-up 
Visit 
1 
2 
3 
4 
5 to 10 
11 
12 to 16 
17 
18 
Early 
With-
drawal 
19 
Day 
(-9 to -3) 
A 
-2B 
-1 
1 
2 to 7C 
8 
9 to 13C 
14 
15 
28 
Documentation 
of 
Positive 
GeneXpert/TB smear (TB clinic/site of 
initial diagnosis) 
X 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical & Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion/Eligibility 
Assessment 
X 
 
X 
 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
Physical ExaminationD 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs E 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG  
X 
 
 
 
 
 
 
 
 
 
X 
PKF 
 
 
 
 
 
 
 
X 
X 
X 
 
Spot Sputum (confirm TB & adequate 
bacterial load) G 
X 
 
 
 
 
 
 
 
 
 
 
Rifampicin Resistance Test (rapid)G 
X 
 
 
 
 
 
 
 
 
 
 
Haematology, 
Clinical 
Chemistry, 
Urinalysis H 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Urine Drug ScreenI 
X 
XI 
 
 
 
 
 
 
 
 
 
β-HCG Serum Pregnancy (women of 
child bearing potential only) 
X 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy TestQ 
 
X 
X 
 
 
 
 
X 
X 
 
 
HIV Test and CD4 Count 
X 
 
 
 
 
 
 
 
 
 
 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
Page 17 of 
65   
Period 
Pre-Treatment 
Treatment 
Follow-up 
Visit 
1 
2 
3 
4 
5 to 10 
11 
12 to 16 
17 
18 
Early 
With-
drawal 
19 
Day 
(-9 to -3) 
A 
-2B 
-1 
1 
2 to 7C 
8 
9 to 13C 
14 
15 
28 
Urine and Serum BiomarkersJ 
 
 
 
X 
X 
 
 
X 
 
X 
 
FDG-PET/CTK 
 
X 
X 
 
 
 
 
X 
X 
 
 
Hospital Admission 
XB 
XB 
 
 
 
 
 
 
 
 
 
Overnight SputumL 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
RandomizationM 
 
X 
X 
 
 
 
 
 
 
 
 
IP Administration and Compliance 
Check 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Mycobacteriology Assessments N 
 
X 
 
 
 
 
 
X 
 
 
 
Hospital Discharge 
 
 
 
 
 
 
 
 
X 
X 
 
Concomitant Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse EventsO 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Point of Care Blood GlucoseP 
 
X 
X 
 
 
 
 
X 
X 
 
 

TASK-003_1.1_dated 23 August 2017 
 
     
  
 
 
  
 Page 18 of 65          
A: 
The Visit 1 (day -9 to -3) time period will be up to a maximum of 7 days but will be kept as short 
as possible. 
  
B: 
Participants can proceed with the Visit 2 (day -2) assessments as soon as their Visit 1 (day -9 to 
-3) assessments have been completed i.e. Visits 1 and 2 may occur on the same day as long 
as the screening results are available in time for randomization at Visit 3. Participants may be 
hospitalized during the entire pre-treatment period if the Investigator considers it advisable. 
 
C: 
All events listed as occurring on Visit 5 (day 2) to Visit 10 (day 7) and Visit 12 (day 9) to Visit 16 
(day 13) will be conducted each day during these times, unless specified differently elsewhere. 
 
D: 
Height (m) will only be collected once at Visit 1 (day -9 to -3). A full physical examination will 
be performed at Visit 1 (day -9 to -3), with symptom-directed physical examinations at Visit 17 
(day 14), Visit 19 (day 28) and Early Withdrawal.  Symptom directed physical examinations may 
be conducted as required during the study (visits 4 to 16). 
 
E:  
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg), heart rate (beats per 
minute [bpm]), body temperature (axillary; oral) and weight (kg). To be performed within 2 
hours before the first daily dosing on Visit 4 (day 1) through to Visit 17 (day 14) and within 2 
hours before the time dosing would have occurred on Visit 18 (day 15). On days where the 
following assessments are done the order should be: vital signs before blood draws for PK or 
safety assessments. 
 
F: 
PKs will be performed as noted in the PK flow chart. No PK will be performed on the Rifafour 
e275 treatment arms.  At the Early Withdrawal Visit (EWV) a PK will be done pre-dose of the 
time of the planned first daily dosing.  If this is not possible, a random PK sample will be done. 
G:  
Microscopy and molecular rapid test for TB and rifampicin resistance (GeneXpert). If the first 
spot sputum does not show unequivocal results, the tests may be repeated on freshly collected 
spot sputum or overnight sputum and that result used. 
 
H: 
Laboratory assessments: haematology (haemoglobin, haematocrit, red blood cell count, 
white blood cell count with differential, platelet count). Clinical Chemistry (albumin, urea, 
creatinine, direct, indirect and total bilirubin, total protein, alkaline phosphatase, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), 
lactic dehydrogenase (LDH), sodium, potassium, calcium (corrected for albumin), chloride, 
random/fasting glucose). Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, 
ketones, bilirubin, creatinine, nitrite, sodium, urobilinogen, blood, leukocytes, microscopy). To 
be performed within 2 hours before dosing on Visit 4 (day 1) and Visit 11 (day 8) and within 2 
hours before the time dosing would have occurred on Visit 17 (day 14). 
 
I: 
Urine drug screen: cannabinoids, cocaine, met/amphetamines and opiates. Urine drug screen 
can be repeated at Visit 2 (day -2) for participants who were not hospitalized at Visit 1 (day -9 
to -3). 
 
J: 
Urine and blood collected for biomarkers at day 1 before the first IP dosing, days 3, 7, 14 and 
the EWV. 
 
K: 
FDG-PET/CT will be done on day-2 or day -1 visit, or before IP is administered on day 1.  Day 14 
FDG-PET/CT has a +/- day 1 window.  In the event of an FDG-PET/CT not being able to be done 
within the allowed window of +1 day, it should be done within +3 days and the IP should be 
continued until the FDG-PET/CT has been completed. 
 
L: 
Overnight sputum sampling may start at Screening visit (day -9 to -3) or on Visit 2 (day –2) and 
will continue daily until Visit 7 (day 4), Visit 9 (day 6), Visit 11 (day 8), Visit 13 (day 10), Visit 15 
(day 12) and Visit 17 (day 14). Sputum sampling will stop on the morning of Visit 18 (day 15). 
Sputum collection will start in the afternoons around 15h00 and continue for 16 hours +/- 1 hour 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
Page 19 of 65   
overnight. The 16-hour sputum sampling for each of the sampling days must be finished prior 
to the administration of the next day’s IP.  
 
Overnight sputum collection may be collected for a number of screening days if the screening 
results are delayed, or the mycobacterial testing on the first spot sputum shows an 
indeterminate result, in which case the test may be repeated on a freshly collected spot 
sputum or an overnight sputum and that result used. It will not be collected for more than the 
pre-treatment time period. Of the pre-treatment period samples collected only the Visit 2 (day-
2) and Visit 3(day -1) overnight sputum samples will be used for the activity endpoint tests. 
 
The day sputum collection starts reflects the day to which that sample applies. e.g. a sample 
whose collection starts on day 1 and ends on day 2, is designated as the day 1 overnight 
sputum sample (and results).  
 
M: 
Randomization by the pharmacist/registered dispenser may occur once all the screening 
results are available and the Investigator has determined that the participant is eligible for the 
trial.  
 
N: 
A culture will be grown from a sputum sample submitted before treatment initiation (baseline) 
for confirming that the infecting organism is M. tuberculosis susceptible to isoniazid and 
rifampicin (GenoType MTBDRplus, Hain, Nehren, Germany). Cultures from baseline and from 
day 14 sputum will be kept for determination of the minimum inhibitory concentration (MIC) of 
the investigational agents that the subject was treated with. If a Day 14 culture is not available 
the last available culture after Day 8 will be kept. MIC tests for beta-lactams are under 
development and cultures might be exported for this purpose.  
O: 
Adverse events (AE) will be collected by the Investigator from the time a participant receives 
his/her first dose of IP through to the Visit 19 (day 28) Follow up Visit.  
 
P:   
Point of care blood glucose test to coincide with the day of the PET scan and does not have 
to be repeated on the other days. 
 
Q: 
The urine pregnancy test at baseline and day 14 has to coincide with the PET scan day and 
does not have to be repeated on the other days. 
 
 

TASK-003_1.1_dated 23 August 2017 
 
     
   
 
 
 
 Page 20 of 65          
1.3 PK Chart 
 
STUDY VISIT  
Visit 17 
Visit 18 
STUDY DAY 
Day 14 
Day 15 
STUDY HOUR  
0 
0.5 
1 
1.5 
2 
3 
4 
6 
8 
12 
24 
Dose 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
sampling 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PK samplings are to be performed at the specified time points as follows: 
 
Pre-dose (study hour 0):  
0-5 minutes before first daily dose on day 14 (0 hours) 
 
0.5 hour: 
 
 
at 30 minutes post dosing of the first daily dosing on day 14 (+/- 5 min) 
 
1 – 6 hours: 
 
 
at 1, 1.5, 2, 3, 4 and 6 hours post dose of the first daily dosing on day 14 (+/- 10 min) 
 
8 hours: 
 
 
at 8 hours post dose of the first daily dosing on day 14 (+/- 15 min) 
 
12 hours: 
 
 
at 12 hours post dose of the first daily dosing on day 14 (+/- 15 min) 
 
24 hours:  
 
 
at 24 hours post dose of the first daily dosing on day 14 (+/- 30 min) 
 
EW = Early withdrawal. PK sampling to be performed pre-dose of the time of the first daily dosing on preceding days. 
 
No PK sampling will be done on the Rifafour e275® control groups 

TASK-003_1.1_dated 23 August 2017 
 
     
  
 
 
  
 Page 21 of 65          
2. Background Information 
 
2.1 Tuberculosis 
Tuberculosis (TB) remains a concerning health problem, with Mycobacterium tuberculosis (Mtb) now 
causing more deaths than HIV/AIDS. Six countries in Africa and Asia accounted for the majority of the 
10.4 million new TB cases reported in 2018 (WHO 2019). The current long-standing first-line 
antituberculosis agents are relatively ineffective in controlling the TB epidemic in high-burden 
countries. Treatment takes 6 -9 months to complete and is associated with side effects resulting in poor 
compliance which leads to treatment failure and an increased likelihood of developing drug-
resistance.  
 
Drug-resistant TB poses a major threat to control of the TB epidemic. The prevalence of multi drug 
resistant TB (MDR: resistance to at least isoniazid and rifampicin) and extensively drug resistant (XDR: 
MDR plus resistance to at least a fluoroquinolone and an injectable antituberculosis drug) continues 
to increase. In 2018, an estimated 600 000 new cases qualified for MDR-TB treatment and incident 
cases of XDR-TB, approximately 10% of patients with MDR-TB, were reported in more countries, 
including Eastern Europe and India (WHO 2019).  
 
The treatment of DR-TB remains sub-optimal due to constraints such as availability, duration (9-24 
months, of which 6 months is an injectable), and significant toxicities leading to poor compliance and 
an increased risk of developing further drug-resistance. The new 9-month regimen for MDR-TB recently 
proposed by the WHO is optimising the use of currently known substances but only a minority of MDR 
cases are likely to qualify for it (WHO 2016b). Despite the lengthy duration, DR-TB treatment is only 
successful in around half of MDR- and less than a third of XDR-TB cases, further escalating the threat 
to global health.  
 
The development of new drug combinations that are effective against drug-resistant strains of Mtb, 
and that have the potential to shorten the duration of TB treatments seem to be an effective 
approach to tackling the TB pandemic. The addition of promising new drugs such as moxifloxacin, 
bedaquiline (Rustomjee 2008; Diacon 2009; Diacon 2013), delamanid (Diacon 2011b), PA-824 (Diacon 
2010; Diacon 2012) and new oxazolidinone candidates (Wallis 2014; Furin 2016) for M/XDR-TB, could 
help to improve this situation. Questions however remain related to their best possible use in 
combination regimens. At least three different drugs are needed to construct a new treatment 
regimen to which no clinical resistance exists, but potential antagonism in humans between agents 
(Mdluli 2011), for instance PA-824 and bedaquiline, and the additive potential for significant toxicity 
e.g. QTc prolongation of moxifloxacin (Bloomfield 2008), bedaquiline (Matteelli 2010) and possibly 
some others, are narrowing down the number of possible combinations. This highlights the need for 
the development of additional new chemical entities that strike an appropriate balance between 
antituberculosis activity and safety profiles, a balance that will enable new future drug combinations 
that make the best of previously developed entities.  
 
2.2 Early Bactericidal Activity Clinical Studies 
The assessment of the early bactericidal activity (EBA) of antituberculosis agents in sputum over the 
first 2 weeks of treatment is the established method for the early clinical evaluation of new 
antituberculosis agents and regimens (Jindani 1980). The primary endpoint of EBA studies is the daily 
rate of change of colony forming units (CFU) of Mtb in sputum (measured as log10CFU/ml sputum/day) 
or the prolongation of time to positivity (TTP) in liquid culture (measured in hours/day) in untreated 
patients with smear-positive pulmonary tuberculosis (TB). The latter provides an indication whether a 
novel treatment has antituberculosis properties in humans, and gives an early indication of the dosage 
required. Pharmacokinetic analyses offer the opportunity to study the relationship between dosages, 
serum levels, efficacy and other host or pathogen factors related to the compound. Preliminary safety 
and tolerability data can also be collected for the duration of the treatment (Donald 2003; Diacon 
2011a). 
 
 
 
2.3 New Biomarkers as Surrogates for Drug Activity 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
Page 22 of 65   
EBA studies also allow the exploration of new ways of measuring TB treatment activity in short-course 
trials beyond measurement of CFU or TTP. Such novel surrogate markers can be radiological, 
immunological, biochemical, microbiologial or any combination of these.  In addition to more 
traditional biomarkers from urine or blood, an interesting candidate is Positron Emission Tomograpy 
(PET) as a non-invasive approach to evaluate drug action by measuring the activity of inflammation 
in lung tissue. PET with 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) integrated with computed 
tomography (CT) is a non-invasive imaging technique widely used as a clinical diagnostic tool, 
especially in the field of oncology. The [18F]-FDG tracer is taken up by cells with increased metabolic 
activity and a greater need for glycolysis, resulting in increased expression of glucose transport 
proteins and up-regulation of intracellular hexokinase and phosphofructokinase. Once these cells 
take up [18F]-FDG, it is phosphorylated and “trapped” within the cell. The concentration of tracer 
within a particular region of interest can then be quantified (Kaim 2002; Hara 2003; Harkirat 2008).  
Novel biomarkers that reflect the early treatment-induced changes could significantly impact future 
clinical trial design, and shorten clinical development timelines. 
 
2.4 Optimizing the Use of Existing Antibiotics 
There are two approaches that can be taken to develop new treatments for both drug-sensitive TB 
and drug-resistant TB. The first, and ideal, is the development of new chemical entities (e.g. 
bedaquiline and delamanid) with novel mechanisms of antituberculosis activity, but without the 
possibility of cross-resistance to existing antimycobacterials. The second approach to finding new TB 
treatment options is repurposing of existing antibiotics with known pharmaceutical properties that are 
currently approved for other conditions, or boosting efficacy of known TB drugs (e.g. rifampicin) 
through potentiation of its activity by combination with a synergistic partner drug.  
 
2.5 Agents to be Studied 
 
2.5.1 
Repurposing an Optimised Combination of Beta-lactams for MDR/XDR-TB  
The beta (β)-lactams are a broad family of antibiotics that include the penicillin derivatives, 
cephalosporins, monobactams, carbapenems, and the β-lactamase inhibitors. The β-lactams have 
an exceptional track record of clinical safety in humans and has been in widespread use for many 
decades. The β-lactam antibiotics act by inhibiting bacterial cell wall synthesis by binding to and 
inactivating peptidoglycan 43 cross-linking enzymes of classical ᴅ,ᴅ-transpeptidase – the penicillin 
binding proteins (PBPs) (Goffin 1998).  
 
Despite being successful antibiotics, the β-lactams have historically been overlooked as candidates 
for TB treatment. The general perception was that β-lactams are ineffective against Mtb due to rapid 
hydrolyses by Mtb’s chromosomally encoded, broad spectrum β-lactamase, BlaC.  Clavulanic acid 
(CA) functions as a β-lactamase inhibitor by quickly binding to Mtb Blac, stably and irreversibly 
deactivating the enzyme (Hugonnet 2007). CA itself has no significant antimicrobial activity and is 
marketed for human use only in combination with amoxicillin and ticarcillen for the treatment of 
certain bacterial infections. The addition of CA enhances the activity of other β-lactams (Finlay 2003). 
In combination with CA, the in vitro bactericidal activity of amoxicillin against Mtb is improved 
(Cynamon 1983; Chambers 1998).  
 
The carbapenems are the β-lactams with the broadest spectrum of activity and they are poor 
substrates for BlaC, exhibiting rapid acylation followed by slow deacylation, enabling them to also act 
as potent inhibitors of BlaC (Tremblay 2010). This was demonstrated in vitro for the interaction of BlaC 
with meropenem (Hugonnet 2009) and also ertapenem (Tremblay 2010). It has recently been 
demonstrated that the majority of Mtb’s peptidoglycan cross-links are of the 33 type that are 
catalysed by nonclassical ʟ,ᴅ-transpeptidases critical for cell wall biosynthesis. These nonclassical 
transpeptidases are innately resistant to the earlier generation β-lactams, but are efficiently 
inactivated by the carbapenems; by imipenem and ertapenem more rapidly than by meropenem 
and doripenem (Gupta 2010; Dubee 2012; Cordillot 2013; Lun 2014; Kumar 2016). There are five 
genetic variants of ʟ,ᴅ-transpeptidases, designated LdtMt1 to LdtMt5 with both LdtMt1 and LdtMt2 
inactivated by carbapenems in vitro (Tipper 1965; Lavollay 2008). The nonclassically cross-linked 
peptidoglycan has also been reported to predominate in non-replicating Mtb, or persisters, with LdtMt1 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
Page 23 of 65   
thought to play a critical role in peptidoglycan adaptation to the non-replicating state of Mtb 
(Lavollay 2008). The loss of the gene that encodes ʟ,ᴅ-transpeptidases for 33 cross-linking results in 
altered cellular morphology and size of Mtb, loss of virulence and increased susceptibility to 
amoxicillin/CA during the chronic phase of infection, both in vitro and in a mouse model of TB. This 
suggests that a drug that inhibits both ʟ,ᴅ-transpeptidase and β-lactamase could effectively treat 
chronic persisters of Mtb (Gupta 2010), an attractive approach to development of anti-TB drugs. 
 
2.5.2  Preclinical Rationale for Use of ß-lactams for Tuberculosis 
Contrary to the perceived intrinsic resistance of Mtb against β-lactams, there has been longstanding 
proof that amoxicillin, alone and in combination with CA, has in vitro activity against Mtb (Cynamon 
1983; Chambers 1998). When CA was combined with meropenem, potent bactericidal activity 
against laboratory strains of Mtb was achieved. Sterilization of aerobically grown cultures was 
observed within 14 days. Inhibitory activity against anaerobically grown cultures that mimic the 
“persistent” state was seen and the combination also inhibited the growth of 13 extensively drug-
resistant strains of Mtb (Hugonnet 2009). The activity of meropenem is further potentiated by 
amoxicillin/CA. Gonzalo and colleagues confirmed the synergy of meropenem and amoxicillin/CA 
by conducting experiments with 28 Mtb strains (7 susceptible, 2 mono-resistant, 16 MDR and 3 XDR) 
that were tested against different concentrations and combinations of meropenem, CA and 
amoxicillin. All of the strains resistant to high concentrations of amoxicillin increased their susceptibility 
to amoxicillin/CA after the addition of meropenem. The addition of CA to meropenem reduced the 
minimum inhibitory concentration (MIC) of meropenem by an average of over 1.8 dilutions. The 
authors concluded that the combination of amoxicillin/CA plus meropenem is active against Mtb 
strains including MDR/XDR-TB strains in vitro (Gonzalo 2013) (Figure 1). These results were also 
reproduced in a murine model of tuberculosis (Veziris 2011; England 2012). 
 
Figure 1 : MIC of Meropenem in the Presence of a Fixed Concentration of 2.5mg/l CA before and after 
the Addition of Amoxicillin (Gonzalo 2013) 
 
Ertapenem is a newer carbapenem with a longer half-life than imipenem and meropenem. The data 
in support of ertapenem as a promising β-lactam option with clinical anti-TB activity is less than with 
meropenem. Like meropenem, ertapenem is also a slow substrate for Mtb BlaC and acts as an inhibitor 
of BlaC in vitro (Tremblay 2010). In an in vitro peptidoglycan cross-linking assay, ertapenem inactivated 
the LdtMt1 paralogue of Mtb ʟ,ᴅ-transpeptidases more rapidly than meropenem (Cordillot 2013). 
England and colleagues reported on the intracellular susceptibility of Mtb to carbapenems, including 
ertapenem, in combination with 200M CA. Highly significant killing was observed for all carbapenems 
by day 2 with a 1.5 to 2.0 log reduction in CFU compared to untreated controls at day 6 (Figure 2) 
(England 2012). In a murine model of TB, imipenem and meropenem in combination with CA, 
significantly improved survival of mice, but was not bactericidal. The MICs of imipenem, meropenem, 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
Page 24 of 65   
and ertapenem against Mtb in the presence of CA were reduced 4-16 fold (Table 1). The MIC of 
ertapenem/CA did not fall in the range of susceptibility and ertapenem was also less effective at 
preventing mouse mortality. It is, however, important to keep in mind that the half-life of ertapenem 
in mice is shorter than in humans (1 hour in mice versus 4 hours in humans). The antibacterial activity 
of the β-lactams depends on the time above MIC, and the author concluded that the activity of 
ertapenem in the model is probably less than can be expected in humans (Veziris 2011).  
 
Figure 2: Intracellular Susceptibility of H37Rv to Carbapenems in Combination with CA (England 2012) 
●, untreated controls; ■, rifampin; ▲, isoniazid; x, meropenem; ◊, faropenem; +, doripenem;  
    , ertapenem; ○, imipenem. 
 
 
Treatment 
MIC H37v g/ml 
- 
2.5g/ml CA 
EUCAST 
susceptibility 
breakpoints 
Imipenem 
16 
1 
2-8 
Meropenem 
8 
1 
2-8 
Ertapenem 
16 
4 
0.5-1 
 
Table 1 : MICs of Imipenem, Meropenem, and Ertapenem Alone and in the Presence of 2.5g/ml of 
Clavulanate (Ca) (Veziris 2011)    
 
Treatment 
MIC H37v g/ml 
- 
 
2.5g/ml CA 
Amoxicillin (Hugonnet 2009) 
>10 
>10 
 
- 
 
8g/ml CA 
Amoxicillin (Chambers 1998) 
>16 
≤2 
 
Table 2:  MICs of Amoxicillin 
 
The MIC for Mtb of CA alone is >64g/ml (Ramon-Garcia 2016). 
 
Following insights from preclinical testing there was ample reason to believe that the carbapenems 
could be repurposed as therapeutic agents for TB (drug-resistant and drug-sensitive) when enhanced 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
Page 25 of 65   
with other blockers of β-lactamase (Hugonnet 2009). Furthermore, a regimen that contains an inhibitor 
of, both ʟ,ᴅ-transpeptidases and β-lactamase, in combination with a β-lactam may be able to kill 
replicating and non-replicating Mtb bacilli by destroying the peptidoglycan layer. 
 
2.5.3 
Clinical Rationale for Use of ß-lactams for Tuberculosis 
The β-lactam antibiotics have been proposed as antituberculosis agents and tested clinically. 
Amoxicillin/CA has been evaluated in two EBA studies. In the first, 10 pulmonary tuberculosis 
participants from the USA and Turkey received amoxicillin 1g with CA 250mg three times daily for 7 
days and a reasonable 2-day EBA of 0.39 logCFU/ml/day (SD 0.32) was found, although EBA days 2-7 
fell to 0.02 (SD 0.04) (Chambers 1998). A later study from Cape Town enrolling 10 participants to receive 
amoxicillin 3g and CA 750mg in a single dose, found a 2-day EBA of only 0.018 (SD 0.130) that did not 
differ from that found in participants receiving no drug (0.016, SD 0.069) (Donald 2001). The reason for 
these conflicting findings is unclear.   
 
Yew et al. reported in 1995 their experience with 5 participants with MDR-TB in whom amoxcycillin/CA 
was part of the treatment regimen. The contribution of amoxicillin/CA to the overall effectiveness of 
the multidrug regimens described in that report is unknown. Two out of 5 participants eventually 
achieved sustained culture conversion. No gastro-intestinal, biochemical or haematological side 
effects were noted (Yew 1995). 
 
2.5.4 
Clinical Rationale for Use of Carbapenems for Tuberculosis 
Intravenously applied meropenem/CA has repeatedly shown antituberculosis activity in humans. 
Case series have documented positive results with intravenous meropenem with or without CA in 
therapeutically destitute participants with highly drug resistant tuberculosis. Dauby et al reported 
successful treatment of a 14-year old female by adding intravenous meropenem 1.5 g thrice daily, 
and amoxicillin 1g/CA 200mg thrice daily, to a regimen of capreomycin, linezolid, clarithromycin, 
pyrazinamide and cycloserine. No adverse events from the ß-lactam combination were noted (Dauby 
2011). Six Participants aged 14-46 years with XDR TB (1 HIV-positive) were treated with 4-6g of 
meropenem administered intravenously twice or three times daily and with CA given in the form of a 
combination of amoxicillin plus CA (500 mg/125 mg), in addition to individual background regimens 
with other drugs. Dramatic improvement was found in 5 of 6 participants with the majority proceeding 
to cure or successful surgery. No adverse reactions were attributed to meropenem-amoxicillin-CA 
(Payen 2012). In the largest series to date the retrospective efficacy and safety of meropenem/CA 
added to linezolid-containing regimens in the treatment of MDR- and XDR-TB was reported. 
Meropenem/CA (3 g daily dose) was prescribed to 37 cases with MDR-/XDR-TB. Treated cases 
exhibited higher smear- and culture-conversion rates than controls. One case had to withdraw from 
meropenem/CA due to increased transaminase levels. Five (13.5%) participants experienced 
diarrhoea potentially attributed to meropenem–CA but this did not require withdrawal of the drug (De 
Lorenzo 2013).  
 
In a recent successful proof-of-concept study, we found robust 2-week bactericidal activity of 
intravenous meropenem, administered at maximum allowable dosage of 2g thrice daily, in 
combination with oral amoxicillin/CA (500mg/125mg) thrice daily. 15 Participants were randomized to 
receive the meropenem-amoxicillin/CA combination while 15 were randomized to receive a standard 
oral anti-TB regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) once daily. We 
found an average daily fall in CFU of Mtb per ml sputum of 0.11 (95% confidence interval [CI], 0.09 to 
0.13) and 0.17 (95% CI, 0.15 to 0.19) for the meropenem-amoxicillin/CA and HRZE arms respectively 
(p<0.001 for both groups, as compared with no effect; p<0.001 for the comparison between groups) 
(Figure 3). The reduction of CFU during the first 14 days of treatment is comparable to that previously 
reported for rifampicin and pyrazinamide. Adverse events, mostly diarrhoea, were mild and 
infrequent. It was unfortunate that no activity was detected for the orally available alternative 
carbapenem, faropenem sodium, also evaluated in the aforementioned EBA. Faropenem has shown 
efficacy in a murine model of TB when combined with amoxicillin, clavulanate and probenicid (Rullas 
2015), but it is possible that no EBA was detected in the study due to low levels of exposure and limited 
time above the MIC for faropenem (Diacon 2016). 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
Page 26 of 65   
 
Figure 3 : Estimated log10CFU Counts per Treatment Over Time 
 
The figure shows mean log10 CFU counts at each time point as symbols (triangles and circles) and 
superimposed treatment activities as lines, with 95% confidence intervals shown as dashed lines, as 
derived from a linear mixed-effects model (Diacon 2016).  
 
Following the successful POC, we conducted the second EBA study described in this protocol with the 
aim to simplify carbapenem treatment for TB. We evaluated the 14-day EBA of meropenem combined 
with oral amoxicillin/CA in participants with rifampicin susceptible pulmonary TB. Participants received 
meropenem 6g once daily administered intravenously over 6 hours along with two tablets of 
amoxicillin/CA 1000/62.5mg 12 hourly (Group 1, arm 1). In the interim analysis, linear mixed-effects 
modelling was used to estimate the EBA as the daily change in log10CFU per ml sputum. A total of 18 
participants were enrolled in the meropenem group (participants who withdrew were replaced) and 
4 in the HRZE control group. Mero-Amx/CA 6g once daily showed significant EBA with a daily decrease 
of 0.094 (95% CI: 0.075 to 0.115, p-value<0.0001) which was not different from mero-amx/CA 2g 8-
hourly in the POC (Figure 4). The higher dosage of meropenem was well tolerated without toxicity (De 
Jager 2020).  
 
 
 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
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Figure 4 : Estimated log10CFU Counts per treatment over time for meropenem 6 grams once daily 
over 6 hours 
This figure shows the fourteen-day mycobactericidal activity of intravenous meropenem 6 
grams once daily over 6 hours vs. 2 grams 8-hourly, compared to that of ertapenem 1 gram 
once daily intramuscularly and HRZE dosed once daily according to standard weight bands. 
The darker blue lines represent estimated daily on-treatment log10(CFU), adjusted for baseline 
CFU, age, BMI, gender and study. The lighter blue shadows are the associated 95% confidence 
bands. The dark squares represent time point of sputum collection. We employed a single joint 
linear mixed-effects model, taking into account the correlation between observations from 
each participant. 
 
HRZE = isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E). CFU = colony forming 
units. BMI = body mass index. Erta = ertapenem. Mero = meropenem. 
The antituberculosis activity of ertapenem has not yet been formally studied in humans. Tiberi et al. 
were the first to report on ertapenem when used as part of a multi-drug regimen to treat a small 
number of patients with MDR-TB in Italy. Safety, tolerability, and efficacy data of ertapenem was 
retrospectively collected on MDR-TB cases treated between 2008 and 2015. Carbapenems were 
incorporated into regimens when background agents were failing and included meropenem (3g 
thrice daily) and imipenem (500mg 4 times a day) for inpatient treatment. Ertapenem 1g once daily 
was the carbapenem of choice for easier home or day-hospital administration. Three out of 5 patients 
who were treated with an ertapenem-containing regimen were considered cured at end of 
treatment and 1 participant improved clinically, but sputum cultures did not convert to negative. All 
the carbapenems were well tolerated (Tiberi 2016). In The Netherlands 18 patients with drug resistant 
TB were treated with a multi-drug regimen that contained ertapenem. Safety and pharmacokinetic 
data was collected retrospectively. All of the 18 patients who received 1g ertapenem intravenously 
once daily for a mean of 77 (5-210) days had conversion of sputum smears and cultures to negative. 
Fifteen of the 18 participants completed treatment and were considered cured. Ertapenem was well 
tolerated with a favourable pharmacokinetic/ pharmacodynamics profile (Van Rijn 2016). Given the 
fact that ertapenem can be administered once daily intramuscularly and, along with its good safety 
profile, it seems to be a promising β-lactam for MDR-TB treatment that warrants further investigation in 
prospective clinical trials. 
 

 
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From the interim analysis described in this protocol, we found that intramuscular administration 
of Ertapenem 1g daily with two tablets of amoxicillin/CA 1000/62.5mg 12 hourly does not have 
an EBA (Figure 4). The results of the group 2 analysis are pending at the time of writing this 
amendment.  
  
2.5.5 
Boosting the Activity of Rifampicin 
Rifampicin is a key drug in standard TB treatment. Its introduction, together with pyrazinamide, has 
allowed shortening of treatment duration from 18 to 6 months (Fox 1999). The standard 10mg/kg 
(600mg) dose of rifampicin has been used for years and selection of this dose was made based on 
“favourable” pharmacokinetics and concerns about adverse events, but primarily to cut costs (Van 
Ingen 2011). To the contrary, studies with higher than standard doses of rifampicin have consistently 
shown a direct relationship between the dose administered and antituberculosis activity as well as 
safety (Diacon 2007; Steingart 2011). Boeree and colleagues reported on a dose-ranging trial of 
rifampicin in participants with pulmonary TB (PTB). 10 Participants received standard 10mg/kg 
rifampicin and 15 participants per experimental arm were randomized to receive 20, 25, 30, and 
35mg/kg rifampicin, respectively, over 14 days. High-dose rifampicin at 35mg/kg resulted in clinically 
relevant increases in systemic drug exposure and showed a greater estimated fall in bacterial load 
over 2 weeks. The higher dose was also safe and well tolerated (Boeree 2015). In a more recent multi-
arm, multi-stage trial by the PanACEA consortium, rifampicin 35mg/kg was administered to 
participants with PTB in combination with ethambutol, isoniazid and pyrazinamide over a 12-week 
intensive phase treatment period. The higher dose was safe, well tolerated and showed to be more 
efficacious in terms of culture conversion in liquid media than a control arm receiving standard HRZE 
(Boeree 2017). Though the maximum dose of rifampicin has not yet been identified, there are likely 
limits to its oral bioavailability, and exposure levels needed to overcome rifampicin resistance are not 
achievable (Boeree 2015). One alternative to boost rifampicin activity is potentiation by combining it 
with a synergistic partner (Ramόn-García 2011). 
 
The intrinsic resistance of Mtb to most clinically approved antibiotics led Ramόn-García and 
colleagues to test whether certain available antibiotics with limited efficacy against Mtb might be 
repurposed as anti-TB drugs when administered in combination with a synergistic partner drug. A high 
throughput screen (HTSS) was developed and an in-house library of around 600 commercially 
available antibiotics, most with unknown activity against Mtb, was screened for synergistic activity 
with rifampicin. Synergistic activity was validated through checkerboard assays (Ramόn-García 2011). 
A large proportion of cell wall inhibitors, mainly the β-lactams, were identified as hits with rifampicin. 
One possible explanation for the synergy could be that the β-lactams target the peptidoglycan layer 
of the cell wall causing increased permeability and thus intracellular accumulation of rifampicin. In 
combination with amoxicillin, with and without CA, the carbapenems tested had a range of effects 
on rifampicin accumulation. The largest effect was, however, elicited by the amoxicillin/CA 
combination. On average the synergism between the β-lactams and rifampicin allowed up to a 16-
fold reduction in the MIC of rifampicin. Clavulanic acid was found to be a key partner in triple 
synergistic combinations that were effective against rifampicin-resistant strains of Mtb (Ramόn-García 
2016). Promising in vitro synergistic activity of amoxicillin/CA with rifampicin was also reported by 
Pagliotti and colleagues, whose study also demonstrated no antagonism between amoxicillin/CA 
and other first line TB drugs i.e. isoniazid and ethambutol (Pagliotti 2016). The addition of CA could 
therefore further enhance the anti-tuberculosis activity of rifampicin/β-lactam combinations (Ramόn-
García 2016).  
 
2.6 Known and Potential Risks and Benefits of the Investigational Product/s and Procedures 
 
2.6.1   Beta-lactams 
Beta-lactams are widely available, approved for human use and free of QTc-prolongation or potential 
interactions with current antituberculosis drugs and antiretroviral agents, making them suitable 
candidates for use in combination treatment regimens in patients with drug-resistant TB. Meropenem, 
ertapenem as well as amoxicillin/CA are marketed drugs from the β-lactam class that has an 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
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exemplary safety record (Linden 2007). Though not tested in this study all the beta-lactams are 
available in paediatric formulations. Further information is provided in the accompanying 
documentation. 
 
2.6.2 
Amoxicillin/CA 
The most common side effects experienced are diarrhoea, nausea, vomiting, indigestion, abdominal 
pain, skin rashes, urticaria and erythema multiforme, vaginitis, abnormal taste, headache, dizziness, 
tiredness and hot flushes. 
 
2.6.3 
Carbapenems 
To date, the most frequently observed (>2%) side effects from clinical trial of Meropenem IV (as per 
package insert) are categorised into local adverse reactions and systemic adverse reactions. Local 
adverse reactions include inflammation at the injection site, pain at the injection site, oedema at the 
injection site and thrombophlebitis. Systemic adverse events include headache, nausea, constipation, 
diarrhoea, anaemia, vomiting, skin rash pruritis, apnea, sepsis and shock.  
 
The most frequently observed adverse experiences reported in clinical trials of ertapenem (as per 
package insert) were diarrhoea, injection site reactions, nausea, headache, and vaginitis in females. 
These adverse events were described as mild to moderate in severity. 
 
2.6.4 
Rifampicin (35mg/kg) 
Studies have shown that rifampicin used at higher than standard dose were safe and well tolerated. 
In the trials with high-dose rifampicin monotherapy, the most common adverse events reported were 
abdominal pain, vomiting, headache, and pruritis. When used in combination with isoniazid, 
pyrazinamide, and ethambutol additional adverse effects such as hyperuricemia, and pain in the 
extremities occurred in all groups and were not attributable to a specific dose group (Boeree et al. 
2015). 
 
2.6.5 
Rifafour e275® 
Some participants will be treated with standard, intensive phase pulmonary TB treatment as 
recommended in the SA National TB Treatment Guidelines as a positive control to verify that the 
laboratory assays used measure the expected magnitude of activity. This is RHZE 150/75/400/275 mg 
oral daily (Rifafour e-275) (HRZE: H=isoniazid: R=rifampicin: Z=pyrazinamide: E=ethambutol). The 
Rifafour treatment group is included as a control for the EBA quantitative mycobacteriology and to 
evaluate whether HRZE in this population gives similar EBA results to that demonstrated in prior studies 
with this combination. 
 
Please see the Rifafour e-275 Package Insert for its known and potential risks and benefits. 
 
2.6.6    Blood Draws and Sputum Collection 
There are minor risks related to blood drawing, including discomfort, haematoma, and rarely an 
infection.  Sputum collection may also be uncomfortable and sputum induction can cause wheezing 
or a tightness in the airways.  It is generally thought to be a safe procedure. There is a risk, although 
rare, that placing an IV for the administration of IP or for the FDG-PET may result in a hematoma, 
thrombophlebitis, infection, or nerve damage.  
 
2.6.7 
FDG-PET/CT Scans 
There is also risk associated with radiation exposure from imaging. Radiation from CXR is negligible.  
Both PET and CT components of the scan will expose subjects to ionizing radiation.  We have 
considered ways to limit the amount of radiation exposure subjects will receive.  By restricting the CT 
scan to the chest as the area of interest rather than performing a whole body scan (which is customary 
for PET/CT) we will reduce radiation exposure and reduce incidental findings.  Also by limiting the 
number of subjects that receive more than one PET/CT scans we will limit total radiation exposure of 
the cohort.  Subjects will undergo a maximum of 2 PET/CT scan in a calendar year during the course 
of the study.   The expected maximum effective dose a subject will receive from scans and CXR 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
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scheduled as part of the study over one calendar year is 3.14 rem. The breakdown is as follows when 
7 mCi of F-18-FDG is injected per subject for each PET scan: 
 
cScan 
Individual Dose (rem)  
Maximum Number 
of Scans Given on 
Study 
Total 
Dose 
(rem) 
CXR 
0.04 
1 
0.04 
FDG-PET 
0.44 
2 
0.88 
CT 
1.11 
2 
2.22 
TOTAL Maximum ED 
 
 
3.14 
 
Table 3: Total Maximum Radiation per Subject Per 1 Year (3 PET/CTs and 1 Chest X-ray) 
 
This is less than the maximal permissible annual occupational exposure of 5 rem/yr (USNRC 2004) .  
 
2.7   Overall Benefit/Risk Assessment 
Carbapenems have demonstrated substantial in vitro and also recent clinical antituberculosis activity 
against Mtb. It is important to establish whether these agents at optimized dosages and given as 
monotherapy demonstrate promising mycobactericidal activity in the setting of a carefully controlled 
EBA study.  
 
The risks of each of the investigational agents over a 14 day period are expected to be relatively minor 
for this period of dosing. The results of this study will establish whether one or several of the drugs have 
activity, tolerability and safety adequate to take into subsequent studies of longer duration or 
incorporation into a novel regimen to be used as rescue treatment for XDR-TB. 
 
Participants in this study will be given drugs for 14 days that are not proven for the long term treatment 
of pulmonary TB. However these drugs are very likely to have anti-TB activity and a delay of treatment 
with the full standard regimen of 14 days is not expected to have an adverse impact on the ultimate 
cure of TB in these participants. Participants in this study will have their TB infection carefully 
characterized and drug sensitivity profiles established.  Participants will remain under constant medical 
attention and will be housed and monitored in hospital from admission through the duration of the 
treatment period; this will allow a continuous monitoring of the health conditions of each participant, 
any of whom can be withdrawn at any stage of the trial and removed from study treatment should 
his/her condition suggest to the Investigator that this would be in his/her best interest. Multiple blood 
samples will be taken for safety laboratory studies. Upon discharge, the participants will be given the 
initial doses of standard TB treatment and immediately referred to the national TB treatment program 
local TB clinic. The Investigators’ primary responsibility is to ensure participant safety. 
 
3 
Trial Rationale and Objectives 
 
3.1   
Study Rationale 
This trial seeks to establish the antituberculosis effect of the selected agents on serial CFU counts of 
Mtb in sputum over 14 days of therapy. Given the increasing need for novel regimens to treat 
participants with DS TB, it is important to evaluate the antituberculosis activity of promising anti-TB drugs 
in a carefully conducted EBA study to determine their contributions as building blocks for potential 
future studies of new regimens. The results of this study will be used to plan future studies of longer 
duration.  
 
We recently found robust 2-week antituberculosis activity for meropenem and amoxicillin/CA in 
tuberculosis patients in a 14-day EBA study. This was the first formal proof, half a decade after the 
discovery of this drug class, that beta-lactam antibiotics can be used for the treatment of tuberculosis. 
Based on pharmacokinetic/pharmacodynamic modelling derived from these results we now aim to 
refine the application of this treatment. 

 
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In the 2-week EBA study described in this protocol (TASK-003), we were utilizing once daily 6g 
meropenem administered as an intravenous infusion over 6 hours with oral amoxicillin/CA twice daily 
(group 1, arm 1). From the results of the interim analysis following completion of group 1, we now 
have reason to believe that a once daily dosing regimen is possible. Following proof that a once 
daily administration of meropenem with oral amoxicillin/CA has bactericidal activity comparable to 
the 2g intravenous meropenem administered thrice daily in the POC (Diacon 2016), we now aim to 
refine the administration of meropenem further by shortening the infusion time to one hour by 
adding an additional meropenem arm to group 2. We fixed the one hour infusion time as the 
duration and with using either 4g or 6g of meropenem we will have a range of exposures that can 
be used in a pharmacokinetic modelling analysis.  
 
The antituberculosis activity of ertapenem has not yet been formally studied in humans. Ertapenem 
can be administered once daily by intravenous or intramuscular injection, making it a more feasible 
carbapenem option if proven to be successful. 
 
With this study we will evaluate whether the antimycobacterial activity of higher than standard dose 
rifampicin is enhanced when combined with amoxicillin/CA based on the concept of synergistic 
activity.  
 
A once daily dosing regimen would make carbapenem treatment accessible for outpatients and 
hence for the majority of people suffering from drug-resistant tuberculosis in less affluent regions of the 
world. Shortening the meropenem infusion time from 6 hours to 1 hour will make the administration of 
meropenem even more suitable for outpatient use. Also, most clinics are familiar with once daily 
intramuscular injections as part of currently available treatment regimens containing aminoglycosides. 
The use of amoxicillin/CA in synergistic combination with rifampicin could potentially increase the 
efficacy of rifampicin which could lead to a shortened DS-TB regimen and allow the re-introduction 
of rifampicin for MDR-/XDR-TB treatment. 
The 14 day duration of the dosing in this study is generally accepted as the longest period that a new 
drug or regimen may be used in participants with TB in monotherapy. 
 
3.2 
Study Design Rationale  
 
This study will be a standard 14 day EBA design incorporating 2 groups with parallel treatment arms. 
This design allows comparison of the results of this study with similar prior studies of treatments for TB. 
No placebo treatment is included in this study – all participants will be given either active study 
treatment or Rifafour e275® control. Given the availability of effective treatment for TB, and the serious 
consequences of allowing TB to go untreated, inclusion of a placebo treatment arm would be 
unethical. 
 
All participants will remain under constant medical attention and will be housed and monitored in 
hospital from check-in through the duration of the treatment period; this will allow a continuous 
monitoring of the health conditions of each participant, any of whom can be withdrawn at any stage 
of the trial and removed from study treatment should his/her condition suggest to the Investigator that 
this would be in his/her best interest. Upon discharge, the participants will be given initial doses of 
standard TB treatment and immediately referred to the national TB treatment program local TB clinic. 
The Investigators’ primary responsibility is to ensure participant safety. 
 
3.3   Rationale for Selection of Agents and Doses 
The selection of β-lactam agents and drug doses for this study is based on pre-clinical evidence of β-
lactam antimycobacterial activity and the recent demonstrated EBA of a meropenem and 
amoxicillin/CA combination as well as informal evidence of the success of ertapenem, when added 
to MDR-/XDR-TB regimens.  
 
In the 2-week proof-of-concept study we were utilizing maximum allowable doses of thrice daily 2g 
meropenem (short 5 minutes IV infusion leading to high maximum serum concentrations). This 
treatment could be used as part of a rescue regimen in patients with highly resistant TB for whom no 
other options exist. However, this treatment is strictly intravenous and can only be given to patients 

 
TASK-003_Version 1.2_dated 27 February 2020 
 
 
 
 
 
 
 
 
 
 
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admitted to hospitals with advanced nursing care. Such facilities are not frequently found in areas 
where patients with highly resistant TB reside. Based on recent modelling simulations by our group, we 
now hypothesise that prolonging infusion time will allow us to extend dosing intervals of meropenem 
or even achieve sufficient exposure with only one infusion. From the results of the interim analysis of 
once daily meropenem administered as a 6 hour infusion, we now believe that prolonging the infusion 
time, as well as increasing the dose, successfully increases the percentage of the dosing interval that 
free drug concentration remains above the MIC (TMIC). TMIC is the main driver of pharmacodynamics 
correlating with anti-tuberculosis response of β-lactams like meropenem (Macvane 2014). From further 
pharmacokinetic modelling work done by our group, we now propose that infusion of a higher dose 
of meropenem over 60 minutes, might make an even more practical once daily dosing regimen 
possible. Meropenem has been used for outpatient treatment of infective exacerbations of 
bronchiectasis as a 3g once daily dose administered over 30 minutes intravenously (Darley et al. 2000). 
Bulik and colleagues reported on the use of meropenem as a 3g infusion over 3 hours thrice daily for 
the treatment of cystic fibrosis (total daily dose of 9g). This higher dosage was well tolerated without 
toxicity. A concerning but infrequent adverse event of the carbapenems is the development of 
seizures. Meropenem has a low propensity for neurotoxicity and this likelihood can seemingly be 
further reduced by administering a high dosage over a longer infusion time thus avoiding high peak 
concentrations (Bulik et al. 2010). In the POC study conducted by Diacon and colleagues (Diacon 
2016), the 2g meropenem dosage was administered over a 5 minute intravenous push leading to high 
peak serum concentrations. Modelling work performed by our group predicts that the higher dose of 
4g or 6g meropenem to be infused over one hour, as is proposed in this amendment, will not lead to 
higher peak serum concentrations than in the POC study, hence not posing the risk of neurotoxicity ( 
Muliaditan and Della Pasqua, unpublished 2019).  
 
Ertapenem has regulatory approval in South Africa for other non-TB indications. It is used in clinical 
practice at a dosage of 1g intravenously administered over 30 minutes or 1g intramuscularly, and is 
generally well tolerated. Ertapenem has been successful when used clinically at the approved dose 
of 1g daily IV/IM as part of drug-resistant TB regimens.  
 
This protocol tests two beta-lactam treatment options with widely available agents that can 
potentially be given once daily. If they are active, these treatment options may be helpful for patients 
that cannot be admitted as inpatients but for whom outpatient or day-care treatment is possible. 
These two treatments are thus prioritized in this study and will be tested first together with half of the 
positive control subjects.  
 
The dose of amoxicillin/CA (1000mg/62.5mg), 2 tablets twice daily, is registered in South Africa for use 
in non-TB infections. Amoxicillin/CA is used widely in routine clinical practice and has a good safety 
record. In this study it is used primarily for the β-lactamase inhibitory activity of CA because CA is not 
available for human use on its own. However, the addition of amoxicillin to carbapenems and also 
rifampicin has been shown to be synergistic (Gonzalo 2013, Ramόn-García 2016). In the proposed 
amendment, amoxicillin/CA (1000mg/62.5mg), 2 tablets will be administered once daily to coincide 
with the once daily administration of meropenem.  By including an amoxicillin/CA only treatment arm 
we will gain understanding of the individual contribution of high dose amoxicillin/CA in all the 
proposed injectable treatment arms, and we will once and for all settle the question whether 
amoxicillin/CA has early bactericidal activity or not as earlier trials were not conclusive in this respect 
(Chambers 1998, Donald 2001).  
 
The selected dose of rifampicin 35mg/kg to be used in this study is based on recent clinical trials in 
drug-sensitive TB which showed that the higher dose of rifampicin is safe and well tolerated (Boeree 
2015; Boeree 2017). Furthermore, the EBA of rifampicin 35mg/kg measured higher than that of the 
standard 10mg/kg dose (Diacon 2007). 
  
All agents will be sourced locally. Meropenem, ertapenem, and amoxicillin/CA or any of the generic 
products available in South Africa will be used during the trial. This will depend on availability of the 
products. 
 

 
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3.4   Exploratory Biomarkers 
Through PET/CT and the collection of immunological samples, this protocol will explore new ways of 
measuring TB treatment activity beyond the measurement of sputum CFU or TTP. By capturing 
dynamic immunologic markers, in addition to functional and anatomical changes measured by 
PET/CT, our biologic characterization of durable treatment effects within potentially persistent M.tb 
subpopulations may be expanded. PET is subject to the availability of this resource at the time this 
study will be conducted. A second PET scanner is planned to be installed in the near future at an 
academic centre in close proximity to the study site. PET scanning is an exploratory component and 
not essential to this study and might not be conducted if the resource is not available.   
 
3.5   Trial Objectives 
The overall objective of this study is to evaluate the 2-week bactericidal activity and pharmacokinetics 
of the following beta-lactam containing combinations with the aim to select the most active and 
implementable solution to be incorporated into a drug-resistant TB combination regimen: 
 
 
Once or twice daily meropenem administered intravenously in combination with once or twice 
daily oral amoxicillin/clavulanic acid; 
 
Once daily ertapenem administered intravenously and intramuscularly in combination with twice 
daily oral amoxicillin/clavulanic acid; 
 
Twice daily oral amoxicillin/clavulanic acid; 
 
Once daily rifampicin administered orally at highest currently established dosage of 35mg/kg in 
combination with twice daily oral amoxicillin/clavulanic acid. 
 
3.5.1 
 Primary Objectives 
 
Among participants with drug-sensitive pulmonary TB caused by Mycobacterium 
tuberculosis: to estimate the 14 day early bactericidal activity based on colony forming unit 
counts, of the combination of meropenem with amoxicillin/clavulanic acid, ertapenem 
with amoxicillin/clavulanic acid, amoxicillin/clavulanic acid alone, and rifampicin with 
amoxicillin/clavulanic acid; 
 
 
Among participants with drug-sensitive pulmonary TB caused by Mycobacterium 
tuberculosis : to estimate the 14 day early bactericidal activity based on time to positivity in 
liquid culture, of the combination of meropenem with amoxicillin/clavulanic acid, 
ertapenem with amoxicillin/clavulanic acid, amoxicillin/clavulanic acid alone, and 
rifampicin with amoxicillin/clavulanic acid. 
 
3.5.2 
Secondary Objectives 
 
To estimate the 2-day, 7-day, and day 2-14 antimycobacterial activity in terms of colony 
forming units and liquid culture time to positivity; 
 
 
To describe the safety and tolerability of the study regimens administered for 14 days; 
 
 
To determine the steady state pharmacokinetic parameters of meropenem, ertapenem, 
amoxicillin/clavulanic acid and rifampicin (35mg/kg); 
 
 
To determine the pharmacokinetic-pharmacodynamic parameters of meropenem, 
ertapenem, amoxicillin/clavulanic acid, and rifampicin (35mg/kg); 
 
 
To explore the validity of integrating a novel set of surrogate markers of efficacy; 
 
 
To determine the minimum inhibitory concentrations of study drugs, alone and in 
combination, for each participant’s Mycobacterium tuberculosis isolate 
 
4 
Trial Design 
 
4.1  Summary of Trial Design 

 
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This will be a phase 2 single-centre, open-labelled bactericidal activity study of intravenous 
meropenem administered twice and once daily, intravenous/intramuscular ertapenem administered 
once daily, rifampicin (35mg/kg) administered once daily, all in combination with oral 
amoxicillin/clavulanic acid, as well as oral amoxicillin/clavulanic acid alone, over 14 days in 
treatment-naïve, smear positive participants with drug-sensitive pulmonary TB. The study will first enrol 
two arms with once- daily treatment options along with half of the control arm, and will continue 
uninterrupted with the remaining arms and the second half of the control arm. This is done to have 
the results of the treatments that are most likely useful for selected patients in the clinic as soon as 
possible.  
 
The study will enrol 113 participants: 15 participants, which is the standard group size for an exploratory 
EBA study, will be enrolled in each of 7 experimental treatment arms and 8 participants will be 
randomized to receive a control regimen of standard first line TB treatment as per the South African 
TB guidelines (Rifafour® e-275). The study will be randomized, but not blinded. The study endpoints are 
laboratory based and it will be ensured that all microbiology staff is blinded to treatment allocation. 
Subjects will undergo screening procedures within 7 days prior to hospitalization, will be admitted to 
the trial ward on day -2, or from screening if in the interest of the participant as per the investigator’s 
decision and remain in hospital until 1 day after the last dose of investigational drug was given. In the 
case that for logistical reasons the FDG-PET/CT cannot be done on day 14 or 15 as per the allowed 
window, the FDG-PET/CT can be done on days 15, 16 or 17.  In this setting the IP will be extended until 
the FDG-PET/CT has been done.  Before discharge a full course of standard antituberculosis treatment 
will be initiated. 
 
The 14 day duration of the dosing in this study is generally accepted as the longest time period that a 
new drug or regimen may be used in participants with TB as monotherapy. 
 
4.2 Treatment Arms  
The groups will consist of 15 participants per treatment arm with a control arm of 4 participants in each 
group (Table 4). 
 
Treatment 
Group 
Treatment 
arm 
Number 
per arm 
Regimen components 
1 
1 
15 
Meropenem IV 
6 grams once daily 
infused over 6 hours 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
2 
15 
Ertapenem IM 
1 gram once daily 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
Control 
 
4 
Rifafour (HRZE)  
Standard dose 
- 
2 
 
3 
15 
Meropenem IV 
3 gram twice daily each 
dose infused over 60 minutes 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
4 
15 
Ertapenem IV 
1 gram once daily  
infused over 60 minutes 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
5 
15 
- 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
6 
15 
Rifampicin oral 
35mg/kg once daily 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
 
7 
15 
Meropenem IV 4 grams OR  
6 grams once daily 
infused over 60 minutes 
Amx/CA oral 1000/62.5mg  
2 tablets once daily 
Control 
  
4 
Rifafour (HRZE)  
Standard dose 
- 
 

 
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Table 4: Treatment Groups 
 
In each treatment group standard HRZE treatment is included as a control for the EBA quantitative 
mycobacteriology and to evaluate whether HRZE in this population gives similar EBA results to that 
demonstrated in prior studies with this combination. 
 
Figure 5: Trial Schematic 
 
Meropenem plus amoxicillin/CA 
 
 
Ertapenem plus amoxicillin/CA 
 
 
Amoxicillin/CA 
 
 
Rifampicin plus amoxicillin/CA 
 
 
Rifafour e-275® 
 
          Visit    1          2          3          4          5          6           7          8          9         10        11        12        13        14        15        16        17        18        19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         Day  -9 to -3      -2        -1         1          2           3          4          5          6          7          8          9         10        11        12        13       14        15       28 
                                   FDG PET/CT                                                                                                                         FDG PET/CT 
 
 
Pre Treatment 
Treatment 
Follow up 
 
 
 
4.3   Trial Endpoints 
 
4.3.1   Primary Endpoints  
 
The EBACFU(0-14) as determined by the rate of change in logCFU per ml sputum over the period Day 0 
to Day 14 which will be summarised and described with a statistical model as an estimated average 
decrease per day for patients in each group. 
 
The EBATTP(0-14) as determined by the percentage rate of change in TTP per ml sputum over the period 
Day 0 to Day 14, which will be summarised and described with a statistical model as an estimated 
average increase per day for patients in each group. 
 
P-values for the statistical significance of the estimated rates of change (slopes of fitted lines), as well 
as p-values for pair wise differences in rates of change between treatment groups will be given and 
graphically illustrated.  
 
4.3.2 
Secondary Endpoints 
 
4.3.2.1 Activity 
Drug activity with CFU or TTP over different treatment periods such as 0-2 days, 0-7 days, and 2-14 days 
as indicated, for cross-comparison with other published data.   
 
Data will be displayed graphically, together with modelled estimates. 
 

 
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4.3.2.2 Safety and Tolerability 
Incidence of treatment emergent adverse events (TEAEs) will be summarised by severity, IP 
relatedness, and seriousness, leading to early withdrawal and leading to death. Information on all 
adverse events will be collected, but only grade 2 or higher events and those of practical relevance 
i.e. diarrhoea and events related to injections, will be captured in the CRF. 
 
4.3.2.3 Pharmacokinetics (PK) 
The maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum 
observed plasma concentration (Cmin) 24 hours following intake of the first daily dosing on day 14, 
area under the plasma concentration time (t) curve from zero to 24 hours (AUC(0-24)) will be 
estimated for all analytes in all treatment arms.  
 
4.3.2.4 Pharmacokinetics-Pharmacodynamics (PK-PD) 
The EBACFU(0-14), EBACFU(0-2), and EBACFU(2-14) versus the following PK variables will be graphically 
presented for meropenem, ertapenem, amoxycillin/clavulanic acid and rifampicin (35mg/kg): 
 
Cmax; 
 
AUC(0-24); 
 
Time over minimum inhibitory concentration 
(TMIC) 
for 
meropenem, ertapenem, 
amoxicillin/clavulanic acid, and rifampicin (35mg/kg) 
 
4.3.2.5 Biomarkers 
An exploratory component consisting of novel clinical parameters such as positron emission 
tomography (PET) scanning and biomarker sample collection (e.g. blood and urine) for a variety of 
immunological response biomarkers, at specified time points. 
 
4.3.2.6 Mycobacteriology Characterization 
1. The identifying organism will be confirmed as Mycobacterium tuberculosis at least once by 
polymerase chain reaction (PCR) either at screening (GeneXpert or Line Probe) and on a culture 
grown from a sample collected before treatment 
2. Drug susceptibility testing of Mycobacterium tuberculosis for sensitivity to rifampicin with a 
molecular method will be tested at the screening visit (GeneXpert). Susceptibility to INH and RIF 
will be confirmed on a culture grown from a sample collected before treatment either by 
phenotypical testing or line probe.  
3. A culture will be grown from a sputum sample submitted before treatment initiation (baseline) for 
confirming that the infecting organism is M. tuberculosis susceptible to isoniazid and rifampicin 
(GenoType MTBDRplus, Hain, Nehren, Germany). Cultures from baseline and from day 14 sputum 
will be kept for determination of the minimum inhibitory concentration (MIC) of the investigational 
agents that the subject was treated with. If a Day 14 culture is not available the last available 
culture after Day 8 will be kept. MIC tests for beta-lactams are under development and cultures 
might be exported for this purpose. 
 
4.4 Trial Population  
 
4.4.1 
Inclusion Criteria 
Participants are required to meet all of the following criteria in order to be randomized. 
1. Provide written, informed consent prior to all trial-related procedures including HIV testing.  
2. Male or female, aged between 18 and 65 years, inclusive. 
3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive. 
4. Newly diagnosed, previously untreated, rifampicin-susceptible pulmonary TB. 
5. A chest X-ray picture which in the opinion of the Investigator is consistent with TB. 
6. Sputum positive on direct microscopy for acid-fast bacilli on at least one sputum sample (at least 
1+ on the IUATLD/WHO scale). 
7. Ability to produce an adequate volume of sputum as estimated from an overnight sputum 
collection sample (estimated 10 ml or more).  
8. Be of non-childbearing potential or using effective methods of birth control, as defined below: 
Non-childbearing potential: 

 
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(a)  Participant - not heterosexually active or practicing sexual abstinence; or  
(b) Female participant/sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or 
hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive 
months; or  
(c) Male participant/sexual partner - vasectomised or has had a bilateral orchidectomy minimally 
three month prior to screening; 
Effective birth control methods: 
(a) Double barrier method which can include a male condom, diaphragm, cervical cap, or 
female condom (male and female condoms should not be used together); or  
(b) Barrier method combined with hormone-based contraceptives or an intra-uterine device for 
the female partner; and are willing to continue practicing birth control methods throughout 
participation in the study until Visit 19 (day 28).  
(Note: hormone-based contraception alone may not be reliable when taking IP; therefore, 
hormone-based contraceptives alone cannot be used by female participants to prevent 
pregnancy).  
 
4.4.2 
Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria. 
 
1. Evidence of clinically significant conditions or findings, other than the indication being studied, 
particularly epilepsy, that might compromise safety or the interpretation of trial endpoints, per 
discretion of the Investigator.   
2. Poor general condition where any delay in treatment cannot be tolerated per discretion of the 
Investigator. 
3. A history of TB less than 3 years ago.  
4. Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, 
osteoarthritic TB, TB meningitis), as judged by the Investigator. 
5. History of allergy to any of the trial IP/s or related substances i.e. β-lactams and penicillin, as 
confirmed by the clinical judgement of the Investigator. 
6. Known or suspected, current or history of within the past 2 years, alcohol or drug abuse, that is, in 
the opinion of the Investigator, sufficient to compromise the safety or cooperation of the 
participant.  
7. HIV infected participants. 
8. Having participated in other clinical studies with investigational agents within 8 weeks prior to trial 
start. 
9. Female participant who is pregnant, breast-feeding, or planning to conceive a child within the 
anticipated period of participating in the trial. Male participant planning to conceive a child within 
the anticipated period of participating in the trial. 
10. Subjects with diabetes (Type 1 or 2), point of care HbA1c above 6.5, or random glucose over 11.1 
mmol/L. 
11. Hypersensitivity to local anaesthesia of amide type. 
12. Treatment received with any drug active against MTB (including but not limited to isoniazid, 
ethambutol, amikacin, cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, 
kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, 
thioamides, metronidazole), or with immunosuppressive medications such as TNF-alpha inhibitors 
or systemic or inhaled corticosteroids, within 2 weeks prior to screening 
13. Participants with the following toxicities at screening as defined by the enhanced CTCEA toxicity 
table 
a. creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN]); 
b. haemoglobin <7.5 g/dL; 
c. platelets grade 2 or greater (under 50x109 cells/L); 
d. serum potassium grade 2 or greater (<3.0 mEq/L); 
e. aspartate aminotransferase (AST) grade 3 (≥3.0 x ULN)  to be excluded; 
f. 
alanine aminotransferase (ALT) grade 3 (≥3.0 x ULN) to be excluded; 
g. APTT grade 3 
h. INR grade 3 

 
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i. 
Total white cell count grade 3 
 
4.5 Restrictions 
  
4.5.1 
Foods and Beverages 
Consumption of foods and beverages containing the following substances will be prohibited as 
indicated: 
 
Methyl-xanthines/caffeine, poppy seeds, alcohol and grapefruit or grapefruit juice from Visit 1 
(days -9 to -3) until after Visit 18 (day 15) or early withdrawal visit i.e. until discharge from the study 
clinic. Decaffeinated drinks are allowed. 
 
4.5.2 
Prior and Concomitant Medications 
Any medication taken within 30 days prior to IP administration or during the trial until visit 19 (day 28) is 
defined as concomitant medication and is to be reported on the concomitant medication page of 
the case report form (CRF). Reported information will include a description of the type of the drug, 
treatment period, dosing regimen, route of administration, and its indication. Any changes in the 
dosage of concomitant medication must also be reported on the concomitant medication page of 
the CRF. Data on concomitant medication will be collected up to the follow-up visit, even after early 
withdrawal of a participant. 
 
Concomitant treatments should be kept to a minimum during the trial. However, if concomitant 
treatments are considered to be necessary for the participant’s welfare and are unlikely to interfere 
with the investigational product, they may be given at the discretion of the Investigator. For any 
concomitant therapy given as a treatment for a new condition or a worsening of an existing condition 
occurring after signing of the Informed Consent Form (ICF), the condition must be documented on 
the concomitant pages of the CRF. 
 
The prescribing information for all concomitant medication should be consulted and reviewed 
carefully. The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected in order to prevent any potentially serious and/or life-threatening drug 
interactions. 
 
The following medications are prohibited during administration of IP and up to the follow-up visit:  
 
Probenecid 
 
Sodium valproate 
 
Furosemide 
 
 Diuretics that deplete potassium; 
 
 Medicinal products used to treat pulmonary TB:  flouroquinolones (including moxifloxacin,  
 gatifloxacin and levofloxacin), isoniazid, ethambutol, amikacin, cycloserine, rifabutin, rifampicin,  
 streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin,  
 quinolones, thioamides and metronidazole. 
 
4.5.3 
Activity 
Participants will be requested not to undertake vigorous exercise during the period from Visit 1 (days -
9 to -3) until after the follow up Visit 19 (day 28). 
 
4.6 Treatment Discontinuation and Participant Withdrawal  
A participant must immediately discontinue treatment and be prematurely withdrawn from the trial 
for the following reasons: 
 
withdrawal of informed consent; 
 
Investigator considers it for safety reasons in the best interest of the participant that he/she be 
withdrawn; 
 
specific Toxicities as described in section 7.3; 
 
serious adverse event (SAE) if in the opinion of the investigator; 
 
pregnancy; 
 
at the specific request of the Sponsor or termination of the study by the Sponsor. 

 
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A participant who, in the opinion of the Investigator or Sponsor, fails to comply with the protocol will 
be withdrawn.  Participants who withdraw from the study before they have received all 14 days’ of IP, 
will be replaced. 
 
All participants withdrawn/treatment discontinued will be referred to the local community TB clinics 
for standard anti-tuberculosis chemotherapy according to national guidelines. The participants will be 
provided with a referral letter to take with them to the TB clinic. Participants will be provided with 
sufficient TB medication to cover the time period from attending their last visit at the study clinic until 
their scheduled visit at the TB clinic. 
 
4.7 Treatment Plan:  Schedule of Assessments 
The trial consists of three periods, as follows: 
 
Pre-Treatment Period (Visit 1/Day -9 to -3 to Visit 3/Day -1); 
 
Treatment Period (Visit 4/Day 1 to Visit 18/Day 15); 
 
Follow-Up Period (Visit 19/Day 28). 
 
Refer to: 
 
Study Flow Chart (section 1) for the timing of all procedures and laboratory samples to done at 
each visit; 
 
Trial Procedures (section 6) for details regarding specific procedures or laboratory tests. 
 
4.7.1 
Pre-Treatment Period (Visit 1/Days -9 to -3 to Visit 3/Day -1) 
 
4.7.1.1 Visit 1/Day -9 to -3 
Prior to Visit 1, participants must have a positive GeneXpert or TB sputum smear microscopy result from 
their TB clinic or site of initial diagnosis. 
 
The following information will be collected and procedures performed: 
 
Written informed consent; 
 
Demographic data; 
 
Clinically significant medical and treatment history; 
 
Eligibility assessment; 
 
Chest X-ray; 
 
Physical examination including height; 
 
Vital signs including weight; 
 
12-lead ECG; 
 
Spot sputum (rifampicin resistance rapid test, confirmation of MTB, bacterial load, adequate 
sputum production); 
 
Haematology, clotting, clinical chemistry, urinalysis laboratory tests; 
 
Urine drug screen (should be repeated at Visit 2 (day -2) if participant not hospitalized at Visit 1 
(day -9 to -3)); 
 
Serum pregnancy test (women of child bearing potential only, whether they are sexually active or 
not); 
 
HIV test; 
 
Hospital admission (participants may be hospitalized during the entire pre-treatment period if the 
Investigator considers it advisable); 
 
Overnight sputum collection; 
 
Randomization by the pharmacist/registered dispenser may occur once all the screening results 
are available and the Investigator has determined that the participant is eligible for the trial. 
 
Participants may proceed with the Visit 2 (day -2) assessments as soon as their Visit 1 (days -9 to -3) 
assessments have been completed. Visits 1 and 2 may occur on the same day if the screening results 
are available in time for randomization. Overnight sputum collection may be collected for a number 
of more days during the pre-treatment period if the screening results are delayed, or the 
mycobacterial testing on the first spot sputum shows an indeterminate or unfavourable results in which 

 
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case the test may be repeated on a freshly collected spot sputum or an overnight sputum and that 
result used. Of the pre-treatment period samples collected only the Visit 2 (day-2) and Visit 3 (day -1) 
overnight sputum samples will be used for the activity endpoint tests. 
 
4.7.1.2 Visit 2/Day -2 
The following information will be collected and procedures performed: 
 
Vital signs including weight; 
 
Point of care blood glucose (to coincide with the PET scan); 
 
Urine pregnancy test (to coincide with the PET scan); 
 
Hospital admission (Participants to be hospitalized on visit 2 if not hospitalised at visit 1); 
 
Overnight sputum collection (activity variable tests and mycobacterial characterization testing); 
 
Concomitant medication/s; 
 
Urine drug screen (urine drug screen can be repeated at Visit 2 (day -2) for participants who were 
not hospitalized at Visit 1 (day -9 to -3). 
 
FDG-PET/CT (if not to be done at visit 3) 
 
Randomization by the pharmacist/registered dispenser may occur once all the screening results 
are available and the Investigator has determined that the participant is eligible for the trial; 
 
4.7.1.3 Visit 3/Day -1 
The following information will be collected and procedures performed: 
 
Eligibility assessment; 
 
Vital signs including weight; 
 
Point of care blood glucose (to coincide with the PET scan); 
 
Urine pregnancy test (to coincide with the PET scan); 
 
Overnight sputum (activity variable tests); 
 
Randomization by the pharmacist/registered dispenser may occur once all the screening results 
are available and the Investigator has determined that the participant is eligible for the trial; 
 
Concomitant medication/s. 
 
FDG-PET/CT (if not done at visit 2) 
 
 
 
 
4.7.2 
Treatment Period (Visit 4/Day 1 to Visit 18/Day 15) 
 
4.7.2.1 Visit 4/Day 1 
The following information will be collected and procedures performed: 
 
Symptom-directed physical examination, as required; 
 
Vital signs including weight; 
 
Haematology, clinical chemistry, urinalysis laboratory tests; 
 
Urine and blood biomarkers; 
 
Overnight sputum (activity variable tests); 
 
IP administration and compliance check (‘hand-and-mouth’); 
 
Concomitant medication/s; 
 
Adverse events. 
 
4.7.2.2 Visits 5 to 16 (days 2 to 13) 
The following information will be collected and procedures performed: 
 
Daily: 
o 
Symptom-directed physical examination, as required; 
o 
Vital signs including weight; 
o 
Overnight sputum (activity variable tests); 
o 
IP administration and Compliance check (‘hand-and-mouth’); 
o 
Concomitant medication/s; 
o 
Adverse events. 
 

 
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 
Visit 6 (day 3) 
o 
Urine and blood for biomarkers 
 
 
Visit 10 (day 7) 
o 
Urine and blood for biomarkers 
 
 
Visit 11 (day 8) 
o 
Haematology, clinical chemistry, urinalysis laboratory tests; 
 
4.7.2.3 Visit 17/Day 14 
The following information will be collected and procedures performed: 
 
Symptom-directed physical examination; 
 
Vital signs including weight; 
 
Haematology, clinical chemistry, urinalysis laboratory tests; 
 
PK sampling: to be performed at hours 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12  in relationship to the time 
of dosing of the first daily dosing (24 hour post dose PK to be done on day 15); 
 
Urine and blood biomarkers; 
 
Point of care blood glucose (to coincide with the PET scan); 
 
Urine pregnancy test (to coincide with the PET scan); 
 
Overnight sputum (activity variable tests); 
 
IP administration and compliance check (‘hand-and-mouth’); 
 
Concomitant medication/s; 
 
Adverse events. 
 
FDG-PET/CT (if not done at visit 17, to be done within 3 days after visit 17) 
 
4.7.2.4 Visit 18/Day 15 
The following information will be collected and procedures performed: 
 
Symptom-directed physical examination, as required; 
 
Vital signs including weight; 
 
PK sampling: to be performed at 24 hours after time of first dosing on day 14;  
 
Point of care blood glucose (to coincide with the PET scan); 
 
Urine pregnancy test (to coincide with the PET scan); 
 
Overnight sputum (completion of day 14 collection)(activity variable tests); 
 
Concomitant medication/s; 
 
Adverse events; 
 
Discharge from hospital with referral letter to National TB treatment programme. The participants 
on the IP arms will receive their first dose/s of standard TB therapy per SA national TB treatment 
guidelines. The participants in the group receiving standard TB treatment will receive an additional 
dose/s to continue on this treatment. All participants will be referred to the local community TB 
clinics for a full course of standard antituberculosis chemotherapy according to national 
guidelines. The participants will be provided with a referral letter to take with them to the TB clinic. 
Within a week of the participant’s discharge from the study clinic, a follow-up call will be made by 
the study site staff to the TB clinic to determine if the participant attended the clinic. Participants 
will be provided with sufficient TB medication (Rifafour e-275®) to cover the period from attending 
their last visit at the study clinic until their scheduled visit at the TB clinic. 
 
4.7.2.5 Early Withdrawal 
In case of early withdrawal during the treatment period of the study, all efforts shall be made to 
complete the early withdrawal assessments. At the early withdrawal visit the following information will 
be collected and procedures performed: 
 
Symptom-directed physical examination; 
 
Vital signs including weight; 
 
Haematology, clinical chemistry, urinalysis laboratory tests; 
 
Urine and blood biomarkers; 
 
Serum pregnancy test; 
 
PK sampling; 

 
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 
Concomitant medication/s; 
 
Adverse events; 
 
Discharge from hospital with referral letter to National TB treatment programme. The participants 
on the IP arms will receive their first dose/s of standard TB therapy per SA national TB treatment 
guidelines. The participants in the group receiving standard TB treatment will receive an additional 
dose/s to continue on this treatment. All participants will be referred to the local community TB 
clinics for a full course of standard antituberculosis chemotherapy according to national 
guidelines. The participants will be provided with a referral letter to take with them to the TB clinic. 
Within a week from the participant’s discharge from the study clinic, a follow-up call will be made 
by the study site staff to the TB clinic to determine if the participant attended the clinic. Participants 
will be provided with sufficient TB medication (Rifafour e-275®) to cover the period from attending 
their last visit at the study clinic until their scheduled visit at the TB clinic. 
 
All participants who received at least one dose of IP will be requested to return for the safety follow 
up visit, Visit 19 (in the case of and early withdrawal, 14 days ± 2 days after their early withdrawal visit). 
 
4.7.3 
Follow-Up Period (Visit 19/Day 28 ± 3 days) 
 
4.7.3.1 Visit 19/Day 28 ± 3 days 
The following information will be collected and procedures performed: 
 
Physical examination; 
 
Vital signs including weight; 
 
Haematology, clinical chemistry, urinalysis laboratory tests; 
 
Single 12-lead ECG; 
 
Concomitant medication/s; 
 
Adverse events. 
 
4.8 Stopping Rules 
There are no trial specific stopping rules.  
 
The Sponsor has the right to stop the trial or the investigational site at any time, although this should 
only occur after consultation between involved parties. Should this occur the local Ethics 
Committee/Institutional review Board (EC/IRB) and Regulatory Authorities will be informed. Should the 
trial/investigational site be closed prematurely, all trial materials (except documentation that has to 
remain stored at the investigational site) will be destructed as per the site’s SOP, as instructed by the 
Sponsor.  The Investigator will retain all other documents until notification given by the Sponsor for 
destruction. Participants currently on treatment will receive an appropriate regimen and all 
participants will be referred as soon as possible to the national TB programme. 
Criteria for discontinuing IP administration for individual participants are noted in Section 7.3, 
Monitoring and Safety for Specific Toxicities. 
 
4.9 Participant Progress Definitions 
 
 
Screening Failure 
Participants from whom informed consent is obtained and is documented in writing (that is, participant 
signs an informed consent form), but who’s not randomized due to him/her not meeting eligibility 
criteria. 
 
 
Completed Treatment 
Participants who complete their 14 day treatment. 
 
 
Early Withdrawal 
Participants who withdraw/are withdrawn from the study after signing the informed consent but prior 
to the completion of their 14 day treatment. 
 
 
Completed Trial 

 
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Participants who complete the last visit (Visit 19/day 28) of the trial. 
 
 
Lost to Follow-up 
Participants who cannot be contacted up to a month (30 days) after the last visit date (Visit 19/day 
28) of the trial. All attempts to contact the participant must be documented. 
 
5 
Investigational Product (IP) 
 
5.1  Trial Treatments 
IP to be used in this study include meropenem, ertapenem, rifampicin, amoxicillin/CA and an 
approved combination treatment for drug-sensitive TB (Rifafour®e275). Rifampicin and amoxicillin/CA 
will be given orally. Meropenem will be given intravenously, while ertapenem will be administered 
intravenously and intramuscularly. Rifafour®e275 will be given orally as tablets with dose based on 
weight according to local TB control program recommendations.  
 
Drug procurement: investigational products will be sourced locally by the clinical trial site. 
 
Treatment will be administered to the participants for 14 consecutive days. They will be randomized 
to one of the treatment arms in group 1 and once group one plus the 4 control participants has been 
enrolled, randomization into group 2 will start.  Treatment groups are summarized in table 5 below. 
 
Treatment 
Group 
Treatment 
arm 
Number 
per arm 
Regimen components 
1 
1 
15 
Meropenem IV 
6 
grams once daily 
infused over 6 hours 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
2 
15 
Ertapenem IM 
1 gram once daily 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
Control 
 
4 
Rifafour (HRZE)  
Standard dose 
- 
2 
 
3 
15 
Meropenem IV 
3 gram twice daily each 
dose infused over 1 hour 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
4 
15 
Ertapenem IV 
1 gram once daily  
Infused over 1 hour 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
5 
15 
- 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
6 
15 
Rifampicin oral 
35mg/kg once daily 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
 
7 
15 
Meropenem IV 6 
grams OR 4 grams once daily 
infused over 1 hour 
Amx/CA oral 1000/62.5mg  
2 tablets once daily 
Control 
  
4 
Rifafour (HRZE)  
Standard dose 
- 
 
Table 5: Treatment Groups 
 
5.2   Method of Assigning Participants to Treatment Groups 
Eligible participants who have given written, informed consent will be enrolled onto the trial during 
Visit 1 (days -9 to -3) and will be identified by a study generated participant identification code for 
anonymity (participant number). Participants who meet all of the inclusion criteria and none of the 
exclusion criteria will be randomized and assigned a treatment number.  
 

 
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The randomization scheme will be generated by the study statistician/data manager. Randomization 
will be done 1:1:1 in group 1 and the 4 controls first. Once all participants of group 1, as well as the 4 
controls have been fully enrolled, randomization into group 2 and the 4 controls will be done 1:1:1:1:1.  
Consecutively numbered, sealed, opaque envelopes will be prepared and provided to the site. The 
site research pharmacist will maintain the randomization envelopes in a secured location. After being 
notified that a participant is eligible for the trial, the research pharmacist will write the participant's 
number on the next numbered envelope and open it to determine the participant's treatment group. 
The participant number, participant initials, the date and time the envelope was opened, and the 
signature of the person opening the envelope will be recorded on the treatment group card in the 
envelope at the time it is opened. Opened envelopes containing treatment group cards will then be 
filed in the participants’ source file. 
 
Participants withdrawn from the trial before they have received all 14 doses of IP, will be replaced.  
 
Participants will be enrolled into the additional meropenem arm (group 2, arm 7) following completion 
of enrolment into arms 3 to 6. Within arm 7, participants will be randomized 1:1 to either receive 4 
grams or 6 grams of meropenem administered as a 1 hour infusion. 
 
5.3 IP Administration 
 
5.3.1   Route and Dosage 
Meropenem and Amoxicillin/CA Once Daily Treatment Arm 1 
Meropenem will be administered as 6 grams once daily for 14 days, intravenously over 6 hours (+/- 10 
minutes) in total.  Two dilutions of 3 grams meropenem will be prepared and stored as described in 
section 5.3.3.  Each of the 2 dilutions containing 3 grams of meropenem will be infused over 3 hours 
(+/- 5 min), with no more than 5 minutes lapsing while replacing the first dilution (bag) with the second 
dilution with meropenem 3 grams. 
 
Amoxicillin/CA will be administered orally as Amx/CA 1000/62.5mg, 2 tablets twice daily for 14 days 
with 250ml of water each, 15 minutes (+/- 5 min) after the start of the infusion. 
 
Meropenem and Amoxicillin/CA Twice Daily Treatment Arm 3 
Meropenem will be administered as 3 grams twice daily for 14 days, intravenously by bolus infusion 
over 1 hour (+/- 10 minutes). 
 
Amoxicillin/CA will be administered orally as Amx/CA 1000/62.5mg, 2 tablets twice daily for 14 days 
with 250ml of water each, 15 minutes (+/- 5 min) after the start of the infusions. 
 
 
Ertapenem and Amoxicillin/CA Once Daily Intravenous Treatment Arm 4 
Ertapenem will be administered as 1gram daily for 14 days, intravenously by bolus infusion over 1 hour 
(+/- 10 min). 
 
Amoxicillin/CA will be administered orally as Amx/CA 1000/62.5mg, 2 tablets twice daily for 14 days 
with 250ml of water each, 15 minutes (+/- 5 min) after the start of the infusion. 
 
Ertapenem and Amoxicillin/CA Once Daily Intramuscular Treatment Arm 2 
Ertapenem will be administered as 1gram daily for 14 days, intramuscularly. 
 
Amoxicillin/CA will be administered orally as Amx/CA  1000/62.5mg, 2 tablets twice daily for 14 days 
with 250ml of water each, 15 minutes (+/- 5 min) after the IM injection was given. 
 
Rifampicin and Amoxicillin/CA Once Daily Treatment Arm 6 
Rifampicin will be administered at a dose of 35mg/kg once daily for 14 days with a full glass of water 
(250ml) 1 hour (+/- 5 min) before the start, or 2 hours (+/- 5min) after the completion of a meal.  The 
dosage of the Rifampicin will be rounded off to the closest available tablet size. 

 
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Amoxicillin/CA will be administered orally as Amx/CA  1000/62.5mg, 2 tablets twice daily for 14 days 
with 250ml of water each,15 minutes (+/- 5 min) after the IP was taken orally. 
 
Amoxicillin/CA Twice Daily Treatment Arm 5 
Amoxicillin/CA will be administered orally as Amx/CA  1000/62.5mg, 2 tablets twice daily for 14 days 
with 250ml of water each. 
 
Meropenem and Amoxicillin/CA Once Daily Treatment Arm 7 
Meropenem will be administered as 6 grams or 4 grams once daily for 14 days, intravenously over 1 
hour (+10 minutes) in total.  One dilution of either 6 grams or one dilution of 4 grams of meropenem 
will be prepared and stored as described in section 5.3.3. The  dilution containing either 6 grams or 4 
grams of meropenem will be infused over 1 hour.  
 
Amoxicillin/CA will be administered orally as Amx/CA 1000/62.5mg, 2 tablets once daily for 14 days 
with 250ml of water each, 15 minutes (+/- 5 min) after the start of the infusion. 
 
Rifafour e275® Treatment Arms 
The Rifafour e-275 will be administered once daily for 14 days with a full glass of water (250ml) 1 hour 
before the start, or 2 hours after the completion of a meal (as per the package insert).  Pyridoxine 
25mg daily will be given to all participants receiving Rifafour e275®. 
 
Rifafour e275® will be administered according to the South African National TB Treatment Guidelines. 
The daily dose is dependent on the participants’ weight as follows: 40 - 54kg: 3 tablets; 55 – 70kg: 4 
tablets; 71kg and over: 5 tablets. 
 
5.3.2    Dosing Times 
Dosing of the IP will be for 14 days.  The first daily dose will be done between 06h00 and 11h00, at a 
specific time point as identified by the site.  This first daily dosing time will remain the same for the 14 
days. 
 
Morning dosing time of the meropenem, ertapenem and rifampicin (treatment arms 1, 2, 3, 4, 6 and 
7) will be recorded as the first dosing time of the day.  The second dose’s time, applicable for 
treatment arm 3, (12 hours later) will be calculated from the start time of the first dose of the day.   
 
Dosing time of the first amoxicillin/CA (treatment arms 1, 2, 3, 4, 6 and 7) will be calculated from the 
dosing time of first morning dose and the second dose amoxicillin/CA dose will be calculated 12 hours 
from the first morning dose of amoxicillin/CA (applicable for treatment arms 1, 2, 3, 4, and 6). 
 
For treatment arms 5, the first amoxicillin/CA will be dosed in the morning and the second dose will be 
12 hours from the amoxicillin/CA first morning dose.   
 
5.3.3 
IP Reconstitution 
Meropenem IV infusion will be provided in reconstitution vials containing 1g of meropenem each. 
Each vial will be reconstituted with 10ml sodium chloride 9 mg/mL (0.9 %) for IV administration. 
Constitute the vial with 10ml of sodium chloride 9 mg/mL (0.9 %), shake to dissolve and let stand until 
clear.  An approximate volume of 10ml will be withdrawn from each of the vials into a syringe.  
 
For the 3 gram twice daily treatment arm, the contents of 3 x 1g reconstituted vials should be added 
to 50 ml of sodium chloride 9 mg/mL (0.9 %).   This should be an approximate average concentration 
of 40mg/ml.   
 
For the 6 gram daily treatment arm 1, 2 dilutions containing 3 gram meropenem each, will be 
prepared.  The contents of 3 x 1 gram reconstituted vials should be added to 50ml of sodium chloride 
9 mg/mL (0.9 %) (diluted).  This dilution will be an approximate average concentration of 40mg/ml.   
 

 
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For the 6 gram daily treatment arm 7, 1 dilution containing 6 gram meropenem, will be prepared.  The 
contents of 6 x 1 gram reconstituted vials should be added to 40ml of sodium chloride 9 mg/mL (0.9 
%) (diluted). 
 
For the 4 gram daily treatment arm 7, 1 dilution containing 4 gram meropenem, will be prepared.  The 
contents of 4 x 1 gram reconstituted vials should be added to 60ml of sodium chloride 9 mg/mL (0.9 
%) (diluted).   
 
The dilution may be stored for up to 4 hours at room temperature (15⁰ – 25⁰ C) or for up to 24 hours 
between 2⁰ – 8⁰C.  If stored between 2⁰ – 8⁰C, the dilution must reach room temperature (taken out of 
the fridge between 30 minutes and 1 hour before administration) before IV administration and should 
be administered within 4 hours after taken from the fridge.  Care will be taken not to freeze solutions 
of meropenem.  The IV line should be flushed with at least 5 ml of sterile water for injection after 
completion of the administration of the meropenem. 
 
Ertapenem IV will be supplied in packs of 1 or 10 vials, with each vial containing 1 gram of ertapenem. 
The contents of a 1 g vial of ertapenem will be reconstituted with 10 mL of water for injection or sodium 
chloride 9 mg/mL (0.9 %) solution to yield a reconstituted solution of approximately 100 mg/ml. It will 
be shaken well to dissolve. For IV administration, reconstituted ertapenem must be diluted 
immediately.  We will add reconstituted 1g ertapenem to 50 mL of sodium chloride 9 mg/mL (0.9 %) 
solution. Diluted solutions for intravenous use are physically and chemically stable for 6 hours at room 
temperature (15 - 25°C) or for 24 hours between 2⁰C to 8°C, after time of reconstitution.  If stored 
between 2⁰ – 8⁰C, the diluted ertapenem must reach room temperature (taken out of the fridge 
between 30 minutes and 1 hour before administration) before IV administration.  Dilutions should be 
used within 4 hours of their removal from the refrigerator. Care will be taken not to freeze solutions of 
ertapenem.  The IV line should be flushed with at least 5 ml of sterile water for injection after completion 
of the administration of the ertapenem. 
 
Ertapenem IM will be supplied in packs of 1 or 10 vials, with each vial containing 1 gram of ertapenem.  
Reconstitute the contents of a 1 g vial of ertapenem with 3.2 mL of 1.0% lidocaine HCl 
injection (without adrenalin).  Shake vial thoroughly to form solution.  Withdraw the contents of the vial 
and administer by deep intramuscular injection into a large muscle mass (such as the gluteal muscles 
or lateral part of the thigh).  The reconstituted IM solution should be used within 1 hour after 
preparation. The reconstituted IM solution should not be administered intravenously.   
 
5.3.4   Participant Compliance 
The IP will be administered by the investigator/designated site personnel. The date, time, number of 
tablets or dosage of intravenous and intramuscular IP, will be recorded in the participant’s CRF and in 
the source documents. All oral IP will be administered with water. Participants will be checked for IP 
compliance by the Investigators or trial personnel via the hand-and-mouth procedure. Both the hand 
and mouth of the participant will be checked to ensure that the participant has swallowed the IP. All 
syringes and vials will be checked to ensure complete administration. 
 
5.4 Blinding and Procedures for Breaking the Blind 
This is an open label study and there is therefore no need for blinding or procedures to break the blind. 
However the mycobacteriology laboratory will remain blinded until closure of the EBA results.  
The complete formulations of the meropenem, ertapenem, amoxicillin/CA, rifampicin and Rifafour 
e275 are found in the applicable Package Inserts. 
 
5.5 Packaging 
Trial medication will be supplied as follows: 
 
Rifafour e275®, meropenem, ertapenem, rifampicin and amoxicillin/CA will be sourced locally and 
labelled appropriately.  Oral IP will be stored and dispensed into labelled containers to each 
participant at randomisation.  Intravenous and intramuscular IP will be prepared as per the instructions 
provided in the registered package inserts. 

 
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Participants will receive the following trial medication, depending on which group they are 
randomized to (Table 6). 
 
Treatment 
Group 
Treatment 
arm 
Number 
per arm 
Regimen components 
1 
1 
15 
Meropenem IV 
6 
grams once daily  
infused over 6 hours 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
2 
15 
Ertapenem IM 
1 gram once daily  
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
Control 
 
4 
Rifafour (HRZE)  
Standard dose 
- 
2 
 
3 
15 
Meropenem IV 
3 gram twice daily each 
dose infused over 1 hour 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
4 
15 
Ertapenem IV 
1 gram once daily infused 
over 1 hour 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
5 
15 
- 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
6 
15 
Rifampicin oral 
35mg/kg once daily 
Amx/CA oral 1000/62.5mg  
2 tablets twice daily 
 
7 
15 
Meropenem IV 6 
grams OR 4 grams once daily 
infused over 1 hour 
Amx/CA oral 1000/62.5mg  
2 tablets once daily 
Control 
  
4 
Rifafour (HRZE)  
Standard dose 
- 
 
Table 6: Investigational Medicinal Product Details 
 
5.6 Labelling 
The meropenem, ertapenem, rifampicin, amoxicillin/CA and Rifafour e-275®, will be sourced locally.  
 
After dispensing the daily containers/vials of each treatment, the outer container will be labelled with, 
at a minimum, the following information: 
 
Protocol number and name of Sponsor; 
 
Name of medication; 
 
Dosage, quantity and method of administration; 
 
Batch number; 
 
Investigational product name; 
 
Directions for use; 
 
Storage conditions; 
 
The statement “For Clinical Trial Use Only”; 
 
Name of Investigator and site details; 
 
Participant details. 
 
5.7 Storage 
All investigational products will be kept securely stored by the site pharmacist/registered dispenser in 
a secured area with limited access to designated site personnel only. Only qualified personnel will 
undertake the preparation, handling and safe disposal of investigational products. Logs will be kept 
for drug accountability (chain of custody) and temperature.  
 
Meropenem (powder form) will be stored in the original packaging (thereby protected from light and 
moisture), between 15 to 25⁰C. Once diluted it can be stored up to 4 hours at room temperature (15⁰ 

 
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– 25⁰C) or for up to 24 hours between 2⁰ – 8⁰C. Solutions of intravenous meropenem IV should not be 
frozen.   
 
Ertapenem will be stored in the original packaging (thereby protected from light and moisture) below 
25⁰C .  Diluted solutions for intravenous use are physically and chemically stable for 6 hours at room 
temperature (15⁰C - 25°C) or for 24 hours between 2 - 8°C. Solutions should be used within 4 hours of 
their removal from the refrigerator. Do not freeze solutions of ertapenem.  The reconstituted solution 
for intramuscular use, should be used within 1 hour after preparation. 
 
Amoxicillin/CA should be stored at a temperature below 25⁰C, protected from moisture and light. 
 
Rifampicin should be stored below 25 °C and protected from light and moisture. 
 
Rifafour e-275® will be stored between 15 - 25⁰C, in the tightly closed container that it is supplied in, 
protected from light. 
 
5.8 Dispensing and Accountability 
The site pharmacist/delegated dispenser will be responsible for dispensing the IP.  Accurate 
accountability records will be kept by the site to assure that the IP will not be dispensed to any person 
who is not a participant under the terms and conditions set forth in this protocol i.e. delivery to site, 
inventory at site, use by participant, destruction etc. The Investigator/designee will immediately inform 
the Sponsor of any quality issues arising with respect to the trial medication. The Sponsor will take 
whatever action is required should such a situation arise. 
The Investigator undertakes to use the trial medication only as indicated in this protocol. 
 
5.9  Returns and Destruction  
Upon completion or termination of the trial, all unused and/or partially used IP will be destructed by 
the site according to their standard operational procedure, or returned to the consortium partners (or 
designated contractor) and destructed according to their standard operational procedure. If no 
supplies remain, this fact will be indicated in the drug accountability section of the final report. 
 
6 
Trial Variables and Procedures 
 
6.1 Demographic and Baseline Variables and Procedures 
The following demographic and background variables will be collected at the time points described 
in the trial flow chart: 
 
 
Written informed consent; 
 
Demographic data:  date of birth, race, gender; 
 
Clinically significant medical and treatment history; 
 
Eligibility criteria; 
 
Chest X-ray: A PA-CXR will be taken according to local SOP. Abnormalities which will be 
considered to parallel a diagnosis of active tuberculosis, according to CDC criteria from the 
Tuberculosis component of Technical Instructions for the medical examination of Aliens in the USA 
May 2008 [76], are outlined below: 
1) Infiltrate or consolidation–Opacification of airspaces within the lung parenchyma. 
Dense or patchy with irregular, ill-defined, or hazy borders.  
2) Any cavitary lesion.  
3) Nodule with poorly defined margins–Round opacity within the lung parenchyma, 
with margins that are indistinct or poorly defined.  
4) Pleural effusion–Presence of a significant amount of fluid within the pleural space.  
5) Hilar or mediastinal lymphadenopathy–Enlargement of lymph nodes in one or both 
hila and/or within the mediastinum. 
6) Miliary Tuberculosis–nodules that are uniform in size, measuring 1 to 2 mm (millet size), 
distributed throughout the parenchyma. 

 
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 
Laboratory parameters: the safety and mycobacteriology laboratory sampling methodology and 
requirements will be described in a separate document, the laboratory manual/s, which will be 
provided prior to the trial start. The following analyses will be performed: 
o 
Urine: 
 
Urine drug screen. 
o 
Serum: 
 
βHCG pregnancy test: women of child-bearing potential only, whether they are 
sexually active or not. 
o 
Serology: 
 
HIV  
Approval for this to be performed will be obtained from participants during the 
written informed consent process. Prior to HIV testing and on receipt of the results, 
participants will be counselled on HIV by the PI, Sub-Investigator or trained 
counsellors. 
o 
Spot sputum: 
 
Rapid test for rifampicin resistance; 
 
Confirmation of MTB prior to randomization; 
 
Adequate bacterial load; 
 
Estimate of adequate sputum production. 
 
Concomitant medications; 
 
Height (meters (m)); 
 
Method of birth control: male and female participants; 
 
Restrictions: restricted food and beverages, restricted activity, prohibited medication; 
 
Post-trial treatment TB programme attendance: attendance at the local TB clinic, inclusion onto 
the national TB programme; 
 
Hospitalization. 
 
6.2    FDG-PET/CT Scan 
The FDG-PET/CT scan will be performed at a facility local to the study site in South Africa.  Participants 
will consent to receive a maximum of 2 FDG-PET/CT scans during the study.  The FDG-PET/CT scans will 
be performed on a Philips Gemini TF Big Bore or similar scanner (preferably the same scanner will be 
used for subjects receiving subsequent scans as was used on their first scan). Maximum effective dose 
associated with scans over a calendar year will be approximately 2.4 rem. Participants will be fully 
briefed with regard to what to expect and any precautions highlighted.  Participants will be asked not 
to eat for approximately 6 hours prior to the scan but to drink plenty of water. Additional dietary 
regimens will be coordinated with dietary restrictions of the treatment so that no conflicting instructions 
exist on PET/CT days. Prior to the FDG-PET/CT scan, subjects will have point of care assessment of blood 
sugar. Following the blood test, a venous cannula will be inserted and 28 MBq/kg of radiolabeled18F-
FDG, minimum total dose of 175 MBq and maximum of 260, administered.  After about 50 minutes, 
subjects will void urine and at about 60 minutes after injection, the subjects will undergo a FDG-PET/CT 
scan of the chest (120 kV, 200 mA, 1 mm slice thickness). The subject will be oriented face up on the 
scanner bed with his or her hands above the head.  
 
For clinical purposes, the scans will be reviewed by a trained radiologist.  For research purposes, PET/CT 
scans will be scored by two or more independent observers blinded to the treatment arm. Our 
experience with over 100 scans indicates that observer concordance is excellent when consensus is 
first achieved on which lesions are simple vs. complex and which to include in the analysis. Simple 
lesions are composed of only a single lesion type whereas complex lesions are contiguous lesions 
composed of two or more lesion types. Based on this method, the readers will first agree by consensus 
on the PET/CT lesions to include in the analysis. The PET/CT scans will then be scored based on this 
consensus. Lesions will be stratified by simple vs. complex with measurements made of cavitary air 
volume (mL), hard lesion volume (Hounsfield unit -100 to 200; mL), soft lesion volume (Hounsfield unit -
500 to -100; mL), and total glycolytic activity (TGA; total SUV*body weight). These measurements will 
be made at baseline and at two weeks to determine the resultant changes. 
 

 
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The PET/CT results can be made available, upon request, to the patient’s physician(s) upon the 
patient’s transfer to standard of care therapy.   
 
6.3 Activity Variables and Procedures 
The following activity variables will be collected at the time points, and as described, in the trial flow 
chart: 
 
 
Overnight Sputum: the mycobacteriology sampling methodology and requirements will be 
described in a separate document, the laboratory manual, which will be provided prior to the trial 
start. The following analyses will be performed: 
o 
Number of CFU per ml sputum; 
o 
TTP.  
 
Using these observed variables the following derived variables will be assessed for evaluation of 
the activity endpoints: 
o 
The rate of change over timeframes in number of sputum CFU of MTB on solid media 
(change in logCFU per day); 
o 
The rate of change over timeframes in TTP in liquid media (the MGIT system) (change in TTP 
per day). 
 
6.4 Safety and Tolerability Variables and Procedures 
The following safety and tolerability variables will be collected at the time points described in the trial 
flow chart and assessed for evaluation of the safety endpoints: 
 
 
Laboratory parameters:  the safety laboratory sampling methodology and requirements will be 
described in a separate document, the laboratory manual, which will be provided prior to the trial 
start. The following analyses will be performed: 
o 
Haematology: haemoglobin, haematocrit, red blood cell count, white blood cell count 
with differential, platelet count; 
o 
Clinical chemistry: albumin, urea, creatinine, direct, indirect and total bilirubin, total 
protein, 
alkaline 
phosphatase, 
aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase (ALT), gamma-glutamyl transferase (GGT), lactic dehydrogenase (LDH), 
sodium, potassium, calcium (corrected for albumin), chloride, random/fasting glucose; 
o 
Urinalysis: pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes, microscopy; 
 
12-lead electrocardiogram (ECG): 
o 
Investigator assessment: Normal, Abnormal; 
o 
Methodology: 
 
Timing and registration technique for ECGs should be standardized for all 
participants (done according to the site SOP); 
 
Participants should be lying down (recumbent) for at least 5 minutes prior to each 
12-lead ECG evaluation; 
 
ECGs are to be recorded for 10 seconds; 
 
Physical Examination.  Height is measured at screening only; 
 
Vital signs: supine systolic and diastolic blood pressure (SBP and DBP), heart rate, axillary/tympanic 
body temperature (it is preferable to choose one method throughout the study), weight. Using the 
observed variables weight and height; 
 
Adverse events; 
 
Concomitant Medication. 
 
6.5 Pharmacokinetic Variables and Procedures  
The following pharmacokinetics variables will be collected at the time points described in the trial flow 
chart: 
 
 
Plasma concentrations. The PK laboratory sampling methodology and requirements will be 
described in a separate document, the laboratory manual, which will be provided prior to the trial 
start. Analyte/s measured are dependent on treatment arm (Table 7). 

 
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Treatment arm 
Treatment 
MIC 
 
Group 1 
Group 1 
1 
Meropenem/ Amoxicillin/ CA 
Meropenem/ Amoxicillin/ CA 
2 
Ertapenem/ Amoxicillin/ CA 
Ertapenem/ Amoxicillin/ CA 
 
Group 2 
Group 2 
3 
Meropenem/ Amoxicillin/ CA 
Meropenem/ Amoxicillin/ CA 
4 
Ertapenem/ Amoxicillin/ CA 
Ertapenem/ Amoxicillin/ CA 
5 
Amoxicillin/ CA 
Amoxicillin/ CA 
6 
Rifampicin/ Amoxicillin/ CA 
Rifampicin/ Amoxicillin/ CA 
7 
Meropenem/ Amoxicillin/ CA 
Meropenem / Amoxicillin/ CA 
 
Table 7: Analyte/s to be Measured per Treatment Arm 
 
Using these observed variables the following derived variables will be measured/estimated for 
evaluation of the PK endpoints for Day 14: 
o 
Maximum observed plasma concentration (Cmax); 
o 
Time to reach Cmax (Tmax); 
o 
Minimum observed plasma concentration (Cmin) 24 hours following the last dose; 
o 
Area under the plasma concentration time (t) curve from zero to 24 hours (AUC(0-24)). 
 
No PK variables will be collected or derived on the Rifafour e275 treatment arm. 
 
6.6 Biomarkers 
Additional blood and urine samples will be collected at baseline (day 1), day 3, day 7, day 14 and 
early withdrawal. The sampling methodology and requirements will be described in a separate 
document, the Biomarker Manual, which will be provided prior to the trial start. The volumes of samples 
that will be collected at each time point are: urine approximately 50ml and blood up to 27ml.  These 
samples will be stored at the clinic site from where it will be shipped for storage at a laboratory outside 
of South Africa. The samples will be stored for potential future analysis of biomarkers related to 
tuberculosis and its treatment and will not be used for human DNA genetic testing. 
 
6.7   Mycobacteriology Characterization Variables and Procedures 
The mycobacteriology characteristics of the Participants’ MTB strains will be assessed at the time points 
described in the trial flow chart. The mycobacteriology laboratory sampling methodology and 
requirements will be described in a separate document, the laboratory manual, which will be 
provided prior to the trial start. The following characteristics will be measured: 
 
GeneXpert at screening for presence of MTB and INH and Rif susceptibility 
 
MIC/s  to be done on Visit 2 (day -2) or Visit 3 (day -2) and the last available culture if day 8 or later. 
MIC/s measured are dependent on treatment arm (Table 8). 
 
A culture will be grown from a sputum sample submitted before treatment initiation (baseline) for 
confirming that the infecting organism is M. tuberculosis susceptible to isoniazid and rifampicin 
(GenoType MTBDRplus, Hain, Nehren, Germany). Cultures from baseline and from day 14 sputum 
will be kept for determination of the minimum inhibitory concentration (MIC) of the investigational 
agents that the subject was treated with. If a Day 14 culture is not available the last available 
culture after Day 8 will be kept. MIC tests for beta-lactams are under development and cultures 
might be exported for this purpose.  
7 
Adverse Events 
The Investigators are responsible for eliciting adverse events by observing the participant and 
recording all adverse events observed by him/her or reported by the participant during the trial. 
 
7.1 Definitions 
 

 
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7.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not related to the medicinal product. 
 
7.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
 
Results in death; 
 
Is life threatening (any event in which the participant was at risk of death at the time of the event; 
it does not refer to an event, which hypothetically might have caused death if it were more 
severe); 
 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
 
Results in persistent or significant disability/incapacity;  
 
Is a congenital anomaly/birth defect; or 
 
Is a medically important event. 
 
Note: Medical and scientific judgment should be exercised in deciding whether an AE is a medically 
important event that may not be immediately life-threatening or result in death or hospitalization, but 
may jeopardize the participant or may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or the development of drug dependency or drug abuse.  A “suspected transmission of infectious 
agent by a medicinal product” is also considered a serious adverse event under the SAE criterion 
“Other medically important condition”.  
 
7.1.3 
Unlisted (Unexpected) Adverse Event 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). 
 
7.1.4 
Life threatening 
Any event in which the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death had it been more severe. 
 
7.1.5 
Associated with the Use of the Drug 
An adverse event is considered associated with the use of the drug (Adverse Drug Reaction) if the 
attribution is possible, probable or very likely. 
 
7.1.6 
Attribution/Causality 
The definitions for rating attribution/causality will be as described in Table 9. 
 
Table 9: Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug. An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive. The relationship in time is reasonable; 
therefore the causal relationship cannot be excluded. 

 
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Probable 
An adverse event, which might be due to the use of the drug. The 
relationship in time is suggestive, e.g., confirmed by dechallenge. An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).  
 
7.1.7 
Severity 
Severity rating is to be made per the CTCAE Toxicity Table Version 4.04 dated 14 June 2010 (Appendix 
1). For abnormalities NOT found elsewhere in the Toxicity Tables the scale described in Table 10 is to 
be used to estimate grade of severity: 
 
Table 10: Adverse Event Severity Ratings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may 
be 
needed; 
no 
or 
minimal 
medical 
intervention/therapy required. 
GRADE 3 
Severe  
Marked limitation in activity, some assistance usually 
required; 
medical 
intervention/therapy 
required, 
hospitalizations possible. 
GRADE 4 
Potentially 
Life-
threatening 
Extreme limitation in activity, significant assistance 
required; 
significant 
medical 
intervention/therapy 
required, hospitalization or hospice care probable. 
 
7.1.8 
Other AE Definitions 
The following definitions will be used for Adverse Event Reporting: 
 
Action Taken with IP 
 
IP unchanged; 
 
IP interrupted; 
 
IP stopped; 
 
Not applicable (Follow-up period). 
Other Action Taken 
 
None; 
 
Medication given; 
 
Hospitalisation or prolongation of hospitalisation; 
 
Therapeutic or diagnostic procedure. 
Outcome 
 
Resolved; 
 
Improved; 
 
Unchanged; 
 
Worse; 
 
Fatal; 
 
Unknown. 
Occurrence  
 
Once; 
 
Intermittent;  
 
Continuous. 
 
7.2 Reporting 
 
7.2.1 
Adverse Event (AE) 

 
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Adverse events will be collected by the Investigator from the time a participant receives his/her first 
dose of study medication (visit 3) through to the day 28 Follow up Visit. Any clinically significant event 
noted between Visit 1 and Visit 4, will be recorded as medical history. Not clinically significant events 
will be noted in the source. 
 
Any AE (serious or non-serious), grade 2 or higher, observed by the Investigator or reported by the 
participant will be recorded on the adverse event case report form. The Investigator will review each 
AE and assess its relationship to drug treatment based on all available information at the time of the 
completion of the case report form. The following information will be recorded for each adverse event 
reported (definitions section 7.1): 
 
 
Diagnosis of the AE, if possible. In the case where an overall diagnosis cannot be made, each 
specific sign and/or symptom will be recorded as individual AEs; 
 
Date of onset; 
 
Stop date (duration) if applicable; 
 
Severity;   
 
Action taken with IP; 
 
Other action taken; 
 
Outcome; 
 
Relationship to IP; 
 
Occurrence; 
 
Seriousness. 
 
7.2.2 
Serious Adverse Events (SAE) 
Any AE that occurs which is serious must be reported by the Investigator to the Sponsor, study monitor 
and Medical Monitor within 24 hours of the site first being aware of the SAE, whether or not the serious 
event is deemed associated with the use of the drug.  
 
In addition, the Investigator will provide a detailed, signed, written, and complete SAE report form that 
addresses the Investigator’s estimates of the attribution/causality of the AE to the IP and the 
seriousness of the AE in question to the study monitor and Medical Monitor within 24 hours of becoming 
aware of the SAE. 
 
The study monitor will confirm receipt of the SAE form with the Investigator and review the initial 
information on the SAE for diagnosis, consistency and completeness of data.  
 
For submission of updated or additional information on a previously reported SAE, the Investigator will 
provide the study monitor and medical monitor with a newly completed serious adverse event form, 
designated as a follow-up report. This will be submitted to the study monitor and medical monitor 
within 24 hours of the Investigator receiving the information. 
 
The study monitor will query for additional information from the Investigator, if necessary, to complete 
the profile of the SAE reported. 
 
The Sponsor/Investigator/designee will inform Regulatory Authorities and/or EC of all SAEs in 
accordance with local requirements and ICH guidelines for GCP. 
 
7.2.3 
Follow up of Adverse Events 
All AEs will be followed until: 
 
Satisfactory clinical resolution or stabilization; or 
 
Until the end of the follow-up period; and  
 
Until all queries on these AEs have been resolved.  
 
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In these 
cases follow-up will be the responsibility of the treating physician/referral clinic. However, this will have 
to be agreed upon with the Sponsor.  

 
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7.2.4 
Post-Trial Adverse Events 
Any new SAEs reported by the participant to the Investigator that occur up to 30 days after the last 
scheduled contact should be reported to the Sponsor on an expedited basis. Any additional new 
SAEs beyond this period that are determined by the Investigator to be possible, probable or very likely 
related to the use of the IP will be reported to the Sponsor, IEC/IRB and regulatory authorities on an 
expedited basis as required in accordance with local requirements and ICH guidelines for GCP. 
 
7.2.5 
Clinical Laboratory Adverse Events 
Changes in the results of the clinical laboratory assessment results which the Investigator feels are 
clinically significant will be reported as adverse events. It is the Investigators’ responsibility to review 
the results of all laboratory tests as they become available. This review must be documented by the 
Investigators’ dated signature on the laboratory report. For each abnormal laboratory test result, the 
Investigator needs to ascertain and document if this is a clinically significant change from baseline for 
that individual participant. This determination, however, does not necessarily need to be made the 
first time an abnormal value is observed. The Investigator may repeat the laboratory test or request 
additional tests to verify the results of the original laboratory tests. If this laboratory value is determined 
by the Investigator to be a clinically significant change from baseline for that participant, it is 
considered to be an adverse event. 
 
7.2.6 
Disease under Study 
Symptoms of the disease under study (pulmonary tuberculosis) experienced by the participant while 
on the study will be assessed by the Investigator. If the symptom has: 
 
Worsened while the participant is in the study; and  
 
The Investigator assesses it as clinically significant; 
It will be recorded as an adverse event.  
 
If there is: 
 
No change; and  
 
The Investigator assesses the symptom as due to the participant’s TB; and  
 
Not clinically significant; 
It will not be recorded as an AE and this will be noted in the participant’s source documentation.  
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
 
7.2.7 
Overdose 
Overdose of IP experienced by the participant while on the study, will be assessed by the Investigator 
to determine whether the overdose led to an adverse event, including if the taking of the suspect 
medicine led to suicidal intention and subsequent overdose of the suspect medicine, or other 
medication. In this case it will be recorded as an adverse event. If it does not lead to an adverse event 
it will not be recorded as an AE and this will be noted in the participant’s source documentation.  
 
7.2.8 
Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which has 
resulted in an adverse event, it will be recorded as an adverse event.  
 
7.2.9 
Pregnancy 
If pregnancy is suspected while the participant is receiving IP, the IP will be withheld immediately until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IP will be permanently 
discontinued in an appropriate manner and the participant withdrawn from the trial. Protocol-
required procedures for trial discontinuation and follow-up will be performed unless contraindicated 
by the pregnancy. 
 
Pregnancy reporting will follow the same time lines and reporting structures as for a SAE (see above). 
SAE reporting will also occur if the pregnancy outcome is a congenital anomaly. This will follow the 
reporting procedures described above for SAE reporting plus an additional clinical report compiled 
by the applicable company.  

 
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7.3 Monitoring and Safety for Specific Toxicities 
AEs that are still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization, or until the end of the follow-up period and until all queries on these AEs have 
been resolved. Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization. 
Note: For grade 3 or 4 laboratory toxicities, participants should have a confirmatory measurement 
within 48 hours where possible. This management scheme is for confirmed lab abnormalities and not 
for isolated events. 
 
Monitoring for specific toxicities is based upon target organs defined in preclinical toxicity studies (see 
package inserts). 
 
7.3.1 
Any other toxicities  
Grade 1 or 2 
Participants who develop grade 1 or 2 AE or laboratory toxicity may continue intake of IP. 
 
Grade 3 or 4 
Participants who develop grade 3 or 4 AE or laboratory toxicity (see Appendix 2 for specifics) will be 
carefully evaluated by the Investigator. Participants may continue intake of IP or be withdrawn from 
the trial if, in the opinion of the Investigator, the AE or laboratory toxicity poses a significant risk for the 
participant in case of continued participation in the trial. Participants should be followed as 
appropriate until resolution of the AE or toxicity. 
 
8 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this section, will 
be written and signed off prior to clinical database lock.  
 
8.1 Analysis Population/s 
All randomised participants who receive at least one dose of IP, will be included in the analyses. 
 
8.2 Sample Size 
The planned sample size of 15 participants per treatment group is in keeping with other phase 2 trials 
of this type and accounts for the possibility of up to 3 drop-outs per arm, which based on previous 
studies of this type conducted at these sites, represents a conservative estimate of the expected drop-
out rate. Previous EBA studies indicate that the between participant standard deviation of logCFU can 
be approximately 0.2. Therefore, assuming similar variability in the new trial the expected standard 
errors of group mean EBA and corresponding width of 95% confidence intervals are described in the 
Table 11.  
 
Table 11: Expected Standard Errors of Group mean log CFU and confidence intervals 
Group Size 
Standard Error 
Width of 95%CI 
15 
0.052 
0.101 
10 
0.063 
0.124 
 
8.3 Interim Analyses 
When the first group (treatment arms 1 and 2) is completed, an interim analysis will be conducted 
without interrupting recruitment into group 2. Should the interim results indicate that one or both of 
these once-daily treatment options might be clinically useful we will disseminate these interim results.  
The final analysis will be done when all data is collected.  
 
8.4 Endpoint Analysis 
 
8.4.1   Primary Endpoint Analysis 

 
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The EBACFU(0-14) as determined by the rate of change in logCFU per ml sputum over the period day 0 
to day 14 which will be described with at most 3 parameters from a linear, bi-linear or non-linear 
regression of logCFU on time. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
 
8.4.2 
Secondary Endpoint Analysis 
 
8.4.2.1  Activity 
 
The EBACFU(0-2) and EBACFU(2-14) as determined by the rate of change of logCFU in sputum over 
the period day 0 to day 2 and day 2 to day 14, which will be described with at most 3 parameters 
from an appropriate function of logCFU on time. 
 
The EBATTP(0-2), EBATTP(0-14), and EBATTP(2-14) in the Mycobacterial Growth Indicator Tube 
(BactecTM MGITTM 960) system as determined by the rate of change in TTP in sputum over the 
periods day 0 to day 2, day 0 to day 14, and will be described with at most 3 parameters from an 
appropriate function of TTP on time. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out.  
 
8.4.2.2 Safety and Tolerability Analyses 
 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and will be presented by preferred term within each MedDRA System Organ Class (SOC). 
 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the first 
administration of IP and includes those events started prior to the first administration of IP but which 
worsened after the first intake. Adverse events starting after the last administration of IP until the 
last scheduled visit/assessment/measurement will be regarded as treatment-emergent. 
 
The incidence of the following events will be summarized by treatment group for further medical 
analysis: 
o 
Incidence of treatment-emergent adverse events (TEAEs);  
o 
Incidence of TEAEs by Severity; 
o 
Incidence of drug related TEAEs; 
o 
Incidence of Serious TEAEs; 
o 
Incidence of TEAEs leading to early withdrawal; 
o 
Incidence of TEAEs leading to death. 
 
Other safety variables: laboratory parameters, physical examination, vital signs, concomitant 
medication. Descriptive summary statistics will be presented. 
 
8.4.2.3 Pharmacokinetic Analysis 
The maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum 
observed plasma concentration (Cmin) 24 hours following day 14, area under the plasma 
concentration time (t) curve from zero to 24 hours (AUC(0-24)) will be estimated for the following, on 
day 14: 
 
Treatment Arm 
Analyte/s 
Meropenem plus amoxicillin/CA 
Meropenem; amoxicillin; CA  
Ertapenem plus amoxicillin/CA 
Ertapenem;  amoxicillin; CA 
Rifampicin 
Rifampicin; amoxicillin; CA 
Amoxicillin/CA 
Amoxicillin; CA 
Rifafour e275 
None 
 
No PK analyses will be performed on the Rifafour e275 treatment arm. 
The following PK parameters will be estimated from participants’ individual plasma concentrations 
(except in the Rifafour e275® treatment arm) by applying a noncompartmental approach using PK 
software such as WinNonlin Professional. Concentration values reported as below the limit of 

 
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quantitation will be set to zero. Each parameter will be calculated separately using plasma 
concentrations of  meropenem and ertapenem and their respective metabolites, amoxicillin/CA and 
rifampicin.  PK parameters will be estimated for day14 only.  
 
Cmax:          Maximum observed plasma drug concentration. 
 
Tmax:          Time at which Cmax is observed (obtained without interpolation). 
 
Cmin:           Minimum observed plasma drug concentration 24 hours following the last dose. 
 
AUC(0-24): Area under the drug concentration-time curve calculated using linear trapezoidal 
summation from time zero to time 24 hours. 
 
Descriptive statistics including mean, standard deviation, coefficient of variation, median, minimum 
and maximum, geometric mean and geometric mean CV% will be computed for each PK parameter 
by group. Grouping will be by gender.  
In addition, mean and median concentration-versus-time graphs will be provided (with error bars as 
appropriate).  
 
8.4.2.4 Pharmacokinetic and Pharmacodynamic Analysis 
The EBACFU(0-14), EBACFU(0-2), and EBACFU(2-14) vs. the following PK variables will be presented for 
Meropenem, ertapenem, amoxicillin/CA, and rifampicin:  
 
Cmax;  
 
AUC(0-24); 
 
Time over minimum inhibitory concentrations (TMIC). 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
No PK-PD analyses will be performed on the Rifafour e275 treatment arm. 
 
8.4.2.5 Mycobacteriology Characterization 
Cultures grown from the overnight sputum collections from Baseline (day -2 or day -1) and the last 
available culture on a treatment day will be assessed as follows: 
 
A culture will be grown from a sputum sample submitted before treatment initiation (baseline) for 
confirming that the infecting organism is M. tuberculosis susceptible to isoniazid and rifampicin 
(GenoType MTBDRplus, Hain, Nehren, Germany). Cultures from baseline and from day 14 sputum 
will be kept for determination of the minimum inhibitory concentration (MIC) of the investigational 
agents that the subject was treated with. If a Day 14 culture is not available the last available 
culture after Day 8 will be kept. MIC tests for beta-lactams are under development and cultures 
might be exported for this purpose. 
 
9 
Records Management 
 
9.1  Data Collection 
All CRF pages will be completed for each participant who receives any amount of IP. For screening 
failure participants a screening failure CRF will be completed. For participants who are prematurely 
withdrawn, the visits up to withdrawal plus the withdrawal and follow-up visits need to be completed. 
 
9.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source documents will include, but are not limited to, 
progress notes, electronic data, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators. The Investigator 
has to permit trial related monitoring, audits, Independent Ethics Committee/Institutional Review 
Board (IEC/IRB) review and regulatory inspections providing authorized persons direct access to 
source documents. 
 
9.3 File Management at the Trial Site 

 
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It is the responsibility of the Investigators to ensure that the trial site’s files are maintained in accordance 
with South African Good Clinical Practice Guidelines and the ethical principles that have their origin 
in the Declaration of Helsinki. 
 
9.4 Records Retention at the Trial Site 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection subsequent to trial completion. The essential documents should be retained for not 
less than 5 years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications or at least 5 years have elapsed since the formal 
discontinuation of clinical development of the.  
 
The Sponsor will make financial provisions for the Investigator to deposit the documents at an external 
site for safekeeping for as long as required by regulations and the Sponsor.  
 
10. Quality Control and Assurance 
 
10.1 
Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, South African 
GCP, and the ethical principles that have their origin in the Declaration of Helsinki.  
 
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a timely, 
accurate and legible manner. CRF entries will be verifiable to source documentation other than the 
CRF. 
 
Site standard operating procedures will be adhered to for all clinical and bio analytical activities 
relevant to the quality of the study. Participant compliance will be monitored throughout the study. 
The Investigator will sign and date any analysis results (e.g. laboratory, ECG, etc.) to verify that the 
results have been reviewed. 
 
The Principal Investigator may appoint other Sub-Investigators to assist with the study. However the 
Principal Investigator maintains responsibility for the study and will supervise the Sub-Investigators. 
Written IEC/IRB approval will be obtained prior to involvement in the study. 
 
The Investigator will ensure that all site personnel are adequately trained in SA-GCP, the protocol, IB 
and all study procedures and requirements. 
 
10.2 
Monitoring 
The Investigator is responsible for the validity of all data collected at the trial site and must accept the 
various monitoring procedures employed by the Sponsor. The purpose of monitoring is to verify that 
the rights and well-being of human participants are protected; that trial data are accurate, complete 
and verifiable with source data; and that the trial is conducted in compliance with the protocol, 
International GCP, the ethical principles that have their origin in the Declaration of Helsinki and the 
applicable regulatory requirements.  
 
Monitors assigned by the Sponsor will conduct regular site visits for the purpose of monitoring various 
aspects of the study. Visits will take place usually within a predetermined interval, but this may vary 
during the course of the study. The Investigator and site staff will allow the study monitor and 
authorized representatives of the Sponsor to (1) inspect all CRFs, written informed consent documents 
and corresponding source documents (e.g. original medical records), participant records and 
laboratory raw data, and (2) access clinical supplies, dispensing and storage areas. The Investigator 
and site staff should also (1) agree to assist with monitoring activities if requested and (2) provide 
adequate time and space for monitoring visits. The monitor will query any missing, confusing, spurious, 
or otherwise ambiguous data with the Investigator. All queries should be resolved in a timely manner. 
A monitoring log will be maintained recording each visit, the reason for the visit, the monitor’s signature 
and Investigator or designee’s confirmation signature. 
 

 
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10.3 
Auditing 
For the purpose of compliance with International GCP and regulatory agency guidelines, it may be 
necessary for sponsor-authorized quality assurance personnel and/or authorized personnel from an 
external regulatory agency to conduct an audit or inspection of the investigational site. The purpose 
of an audit is to assess the quality of data with regard to accuracy, adequacy and consistency, and 
to assure that studies are in accordance with the guidelines. Having the highest quality data from 
studies is an essential aspect of drug development.  
 
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will usually 
last between one and two days and may be conducted at any stage during the study. The audit will 
involve the review of all study-related documentation required by GCP to be maintained by each 
site; drug storage, dispensing and return; all study-related supplies; and source documents against the 
CRFs to assure the adequacy and accuracy of the information which has been recorded, including 
the verification of any AEs which have occurred.  
 
In the event of the site being notified of a regulatory inspection, the Sponsor will help with preparation. 
It is essential that the Sponsor be notified of the inspection as soon as possible.  
 
11 Ethics and Regulatory 
 
11.1 
Basic Principles 
This research will be carried out in accordance with South African GCP, the ethical principles that 
have their origin in the Declaration of Helsinki and the applicable regulatory requirements.  
 
11.2 
Independent Ethics Committee Review 
The protocol and required study related documents will be reviewed by the site’s EC. The study will 
not start until the EC has approved the protocol, written informed consent, any written information to 
be provided to the participant or any modification thereof, plus any other study related documents 
required for review. The IEC/IRB shall be constituted and shall operate in accordance with South 
African GCP, the ethical principles that have their origin in the Declaration of Helsinki. The Investigator 
will maintain an accurate and complete record of all submissions made to the EC. The records should 
be filed in the Investigator’s Study File, and copies will be sent to the Sponsor. 
 
11.3 
Regulatory Authorities 
The regulatory authorities will receive the protocol, amendments, reports on SAEs, and the integrated 
clinical trial report according to national regulations. As required by local legislation, written approval 
will be obtained from the regulatory authorities prior to commencement of the trial and 
implementation of e.g. amendments as applicable. 
 
11.4 
Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable representative) 
before any trial-related procedures (including any screening or pre-treatment procedures) are 
performed. Investigators may discuss the availability of the trial and the opportunity for entry with a 
potential participant without first obtaining consent. However, informed consent must be obtained 
and documented prior to initiation of any procedures that are performed solely for the purpose of 
determining eligibility for research, including withdrawal from current medication(s). When this is done 
in anticipation of, or in preparation for, the research, it is considered to be part of the research. 
 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol. This shall be documented 
on a written informed consent form that shall be approved by the same EC responsible for approval 
of this protocol. Each informed consent form shall include the elements required by the international 
GCP and must adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
 
Once the appropriate essential information has been provided to the participant and fully explained 
by the Investigators (or qualified designees) and it is felt that the participant understands the 

 
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implications of participating, the EC approved written informed consent form will be signed and dated 
by both the participant and the person obtaining consent (Investigators or designees), and by any 
other parties required by the EC. 
 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant. Another copy of the signed informed 
consent form and a source document identifying the trial and recording the dates of participation will 
be placed in the participant’s medical record. 
 
The monitor will inspect the original completed consent form(s) for all participants. 
 
11.5 
Confidentiality 
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of all 
participants taking part in the study, in accordance with South African GCP, applicable local 
legislation/regulations, volunteer to the requirement for source data verification by the study 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained. Only participant study number and initials will be used on the CRF and in all study 
correspondence, as permitted. No material bearing a participant’s name will be kept on file by the 
Sponsor. The written informed consent will contain a clause granting permission for review of the 
participants’ source data. 
 
12 Incidental Findings 
Incidental findings (IFs) in clinical research are findings with potential health or reproductive 
importance that are discovered in the course of conducting the research, but are beyond the aims 
of the study. IFs in this study may arise from the collecting and analyzing of research images i.e. CXR 
or PET/CT or in the tests or information collected to determine eligibility criteria i.e. abnormal vital signs, 
safety bloods, or ECG. 
The Principal Investigator is responsible for handling an IF responsibly and promptly and members of 
the research team will promptly report a suspected IF. If an IF is discovered the PI will inform the 
participant and exercise his/her judgment on a case by case basis to determine the way forward that 
is in the best interest of the participant. The PI will make sure that all the necessary documentation for 
the referral of the participant is put together free of cost to the participant. 
 
13 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from this 
study.  
 
Results of this research will be submitted for publication as soon as feasible upon completion of the 
study in the form of a joint publication(s) between Sponsor and Investigator(s), including site clinical 
and laboratory investigators, as appropriate. 
 
14 Protocol Amendment Policy 
Any change to the protocol will be effected by means of a protocol amendment. Any changes which 
affect participant safety or welfare will be submitted to the EC and Regulatory Authorities prior to 
implementation. The Investigator, EC and Sponsor must agree on all amendments. No amendment 
will be implemented until approved by the relevant authorities and/or EC and signed by all required 
parties. Exceptions to this are when the Investigator considers that the participant’s safety is 
compromised.  
 
Protocol amendments detailing minor administrative changes should be submitted by the Investigator 
to the EC and regulatory authorities, either for notification purposes or approval as appropriate.  
 
 
 
 

 
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15 Financial Aspects, Insurance and Indemnity 
The study Sponsor is the TASK Foundation NPC, funded by the European Union, Horizon 2020. 
 
The participants will not receive any incentives for their involvement in the study. The Sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and from 
the study site and other miscellaneous costs as a result of their study participation. 
 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an associated 
certificate upon request. The insurance does not relieve the Investigators of the obligation to maintain 
their own liability insurance as required by applicable law. The Sponsor does not assume any 
obligation for the medical treatment of other injuries and illnesses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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moxifloxacin on QTc and implications for the design of thorough QT studies. Clin Pharmacol 
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2. Boeree MJ, Diacon AH, Dawson R, Narunsky K, Du Bois J, Venter A, et al. A dose-ranging trial 
to optimize the dose of rifampin in the treatment of tuberculosis. Am J Resp Crit Care Med. 
2015; 91(9): 1058-1065 
3. Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, et al. High-dose rifampicin, 
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controlled trial. The Lancet Infect Dis. 2017 Jan 31;17(1):39-49. 
4. Bulik CC, Quintilani R, Pope JS, Kuti JL, Nicolau DP. Pharmacodynamics and tolerability of high-
dose, prolonged infusion carbapenems in adults with cystic fibrosis – A review of 3 cases. Respir 
Med CME. 2010; 3(3): 146-9 
5. Chambers HF, Kogacöz T, Sipit T, Turner J, Hopewell PC. Activity of amoxicillin/clavulanate in 
patients with tuberculosis. Clin Infect Dis 1998;26:874–877 
6. Cordillot M, Dubeé V, Tribulet S, Dubost L, Marie A, et al. In vitro cross-linking of Mycobacterium 
tuberculosis peptidoglycan by L,D-transpeptidases and inactivation of these enzymes by 
carbapenems. Antimicrob Agents Chemother. 2013; 57(12): 5940-5  
7. Cynamon MH, Palmer GS. In vitro activity of amoxicillin in combination with clavulanic acid 
against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1983 Sep 1;24(3):429-31. 
8. Darley ESR, Bowker KE, Lovering AM, Harvey JE, MacGowan AP. Use of meropenem 3g once 
daily for outpatient treatment of infective exacerbations of bronchiectasis. J Antimicrob 
Chemother. 2000; 45: 247-250 
9. de Jager VR, Vanker N, van der Merwe L, van Brakel E, Lelievre J, Muliaditan M, Barros- 
Aguirre D, Diacon AH. Optimising β-lactams Against Tuberculosis. American Journal of 
Respiratory and Critical Care Medicine. 2020 Jan 10(ja) 
10. Dauby N, Muylle I, Mouchet F, Sergysels R, Payen MC. Meropenem/clavulanate and linezolid 
treatment for extensively drug-resistant tuberculosis. Pediatr Infect Dis J. 2011;30:812-3. 
11. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S, et al. Efficacy and safety 
of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-
/XDR-TB. Eur Respir J 2013 Jun;41(6):1386-92. 
12. Diacon A, Maritz JS, Donald P. Early bactericidal activity of antituberculosis agents. In: Donald 
PR, Van Helden PD, eds. Antituberculosis Chemotherapy. Basel: Karger 2011a:213-19. 
13. Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, et al. Early bactericidal 
activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob 
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