Conditions: MDR-TB
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 588
Healthy volunteers: no

Brief summary:
Tuberculosis (TB) is a common, infectious, bacterial disease that is spread when an infected person transmits their saliva through the air by coughing or sneezing. Despite the availability and effectiveness of affordable six-month treatments for tuberculosis (TB), the worldwide control of this disease is currently being impacted by the emergence of multidrug resistant TB (MDR-TB). MDR-TB refers to TB that is resistant to at least isoniazid and rifampicin. These are the two most powerful first-line drugs used to treat pulmonary TB. MDR-TB usually develops while a person is taking TB treatment due to either inappropriate treatment or failure of patients to comply with their treatment. This strain of drug-resistant bacteria can also be spread to other people through the air. With the incident rate of MDR-TB on the rise, there is a need to investigate optimal treatment regimens using effective drugs.

Detailed description:
The STREAM study is an international, multi-centre, parallel-group, open-label, randomised, controlled trial in patients with multi-drug resistant tuberculosis (MDR-TB) including patients with rifampicin-resistant and isoniazid-sensitive TB.

Background and Rationale:

In 2011, World Health Organisation (WHO) guidelines for the treatment for MDR-TB recommended an intensive phase of treatment based on at least four drugs known to be effective and given for a minimum of 20 months; this is referred to as the WHO 2011 long regimen. Outcomes with this approach are generally poor. In the most recent WHO TB surveillance report only 50% of MDR-TB patients were successfully treated and a recent meta-analysis reported on average 62% successful outcome and a mortality of 11%.

In 2010, Van Deun et al (2010) reported excellent long-term outcomes in a cohort of over 200 patients in Bangladesh with MDR-TB who were treated with a regimen given for only nine to 11 months. Such a regimen, if successful, would represent a considerable advance over current practice. Evaluation of this regimen is the objective of Stage 1 of STREAM.

In 2016, following review of the available data, the WHO MDR TB treatment guidelines were modified to recommend a 9-12 month shortened regimen under specific conditions similar to Regimen B used in STREAM Stage 1 (referred to as the WHO 2016 short regimen).

Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity. In a phase II trial of patients with MDR-TB time to culture conversion was significantly less in patients receiving bedaquiline compared to those receiving an optimised background regimen only (Diacon et al (2012). In December 2012 the US Food and Drug Administration (FDA) approved bedaquiline as part of the treatment regimen for MDR-TB when other agents are unavailable. Stage 2 of STREAM was designed to investigate ways in which Regimen B could be improved either by removing the second-line injectable, which is associated with severe drug toxicity, or by shortening the regimen to 6 months.

Treatments that are evaluated within the STREAM trial include:

Regimen A The locally-used MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment guidelines.

Regimen B is based on the regimen described by Van Deun 2010. At the start of STREAM this consisted of clofazimine, ethambutol, moxifloxacin, and pyrazinamide given for 40 weeks, supplemented by isoniazid, kanamycin, and prothionamide in the first 16 weeks (intensive phase). ); this combination is referred to as Regimen Bmox. With Version 8.0 of the protocol Regimen B is modified by replacement of moxifloxacin with levofloxacin (referred to as Regimen Blev). Regimen B without specification of which fluoroquinolone is in the regimen refers to either (Bmox or Blev).

Regimen C is a 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for the first 16 weeks (intensive phase).

Regimen D is a 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks (intensive phase).

The primary objectives of the STREAM2 trial are:

To assess whether the proportion of participants with a favourable efficacy outcome at week 76 on Regimen C is non-inferior to that on Regimen B

Study Population: Stage 2 will aim to randomise at least 200 patients to each of Regimens B and C.

All patients will be followed up to Week 132. The primary analysis will be based on the data accrued to Week 76 and is based on the proportion of patients with a favourable outcome at that time point ; the data accrued to Week 132 will be used in secondary analyses.

Although the STREAM study is an open-label study, wherever possible it will be conducted masked to treatment allocation.

Arms:
arm 1: Regimen A locally-used WHO-approved MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment guidelines. arm 2: Regimen B is based on the regimen described by Van Deun 2010. With Version 8.0 of the protocol Regimen B (Regimen Bmox) is modified by replacement of moxifloxacin with levofloxacin (Regimen Blev). Regimen B without specification of which fluoroquinolone is in the regimen refers to either (Bmox or Blev).

Product and dose for \[\<33 kg, 33-50kg, \>50 kg\] respectively:

Moxifloxacin \[400mg, 600mg, 800mg\] OR Levofloxacin \[750mg, 750mg,1000mg\]; Clofazimine \[50mg,100mg,100mg\]; Ethambutol \[800mg,800mg,1200mg\]; Pyrazinamide \[1000mg,1500mg, 2000mg\]; Isoniazid 300mg, 400mg, 600mg\]; Prothionamide \[250mg,500mg,750mg\]; Kanamycin \[15mg per kilogram body weight (maximum 1g)\]. arm 3: Regimen C is a 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for the first 16 weeks (intensive phase).

Product and dose for \[\<33kg, 33-50kg, \>50 kg\] respectively:

Bedaquiline 400mg once daily for first 14 days/200 mg thrice weekly thereafter; Levofloxacin \[750mg, 750mg,1000mg\]; Clofazimine \[50mg, 100mg, 100mg\]; Ethambutol \[800mg, 800mg, 1200mg\]; Pyrazinamide \[1000mg,1500mg, 2000mg\]; Isoniazid \[300mg, 400mg, 600mg\]; Prothionamide \[250mg, 500mg,750mg\]. arm 4: Regimen D is a 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks (intensive phase).

Product and dose for \[\<33kg, 33 to\<40kg, 40-50kg, \>50-60 kg, \>60 kg\] respectively:

Bedaquiline 400mg once daily for first 14 days/200mg thrice weekly thereafter; Levofloxacin \[750mg, 750mg, 750mg, 1000mg, 1000mg\]; Clofazimine \[50mg, 100mg, 100mg, 100mg, 100mg\]; Pyrazinamide \[1000mg,1500mg, 1500mg, 2000mg, 2000mg\]; Isoniazid \[400mg, 500mg, 600mg, 800mg, 900mg\]; Kanamycin \[15 mg per kilogram body weight (maximum 1g)\].

Interventions: intervention 1: Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline) intervention 2: Moxifloxacin intervention 3: Clofazimine intervention 4: Ethambutol intervention 5: Pyrazinamide intervention 6: Isoniazid intervention 7: Prothionamide intervention 8: Kanamycin intervention 9: Levofloxacin intervention 10: Bedaquiline
Intervention descriptions: intervention 1: Drug: Locally-used WHO-approved MDR-TB regimen intervention 2: Moxifloxacin is an 8-methoxy quinolone, and an anti-bacterial fluoroquinolone intervention 3: Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-isopropyliminophenazine. intervention 4: Ethambutol is a bacteriostatic that acts against virtually all strains of Mycobacterium tuberculosis and M. bovis and is also active against other mycobacteria such as M. Kansasii. intervention 5: Pyrazinamide is bactericidal against intracellular mycobacterium tuberculosis. It is a prodrug that is converted into its active form, pyrazinoic acid, by a mycobacterial enzyme, pyrazinamidase, as well as through hepatic metabolism. intervention 6: Isoniazid is a bactericidal in vitro and in vivo against actively dividing tubercle bacilli. Its primary action is to inhibit the synthesis of long-chain mycolic acids, which are unique constituents of mycobacterial cell wall. intervention 7: Prothionamide has a bacteriostatic action. intervention 8: Kanamycin is a bactericidal antibiotic from the group of aminoglycosides. intervention 9: Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class that acts on the DNA-DNA-gyrase complex and topoisomerase IV. It is the S (-) enantiomer of the racemic active substance ofloxacin. intervention 10: Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
1 
 
?dr 
The 
  
STREAM 
The evaluation of a standard treatment regimen  
of anti-tuberculosis drugs for patients with MDR-TB 
 
ISRCTN 78372190 (Stage 1) 
ISRCTN 18148631 (Stage 2) 
 
 
PROTOCOL  
VERSION 11.0 
15 December 2020 (Based on MRC CTU template protocol version 
3.15)      
Authorised by: 
 
Name:     
Prof. Andrew Nunn 
Role: 
Co-Chief Investigator 
Signature: 
Date: 
 
 
Name:     
Prof. Sarah Meredith 
Role: 
Co-Chief Investigator 
Signature: 
Date: 
  


 
 
 
 
 
 
 
 
 
  
SIGNATURE PAGE 
 
Principal Investigator Signature: 
 
The signature below confirms agreement by the individual at the clinical site responsible for 
signing the clinical trial agreement, that this is the trial protocol, STREAM (Version 11.0) dated 
15 Dec 2020. The trial will be conducted in accordance with this protocol, with the principles of 
Good Clinical Practice (GCP) as laid down by the ICH topic E6 (Note for Guidance on GCP), and 
the applicable regulatory requirements. 
 
I agree to conduct the trial according to these regulations and guidelines and to appropriately 
direct and assist the staff under my control, who will be involved in the trial, and ensure that 
all staff members are aware of their clinical trial responsibilities. 
 
Any amendments to this protocol that have a direct influence on the participants in the trial will 
be approved by the relevant ethics committees, regulatory authorities and the sponsor before 
implementation. 
 
 
Principal investigator’s name: 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
This STREAM trial is made possible by the generous support of the American people through 
the United States Agency for International Development (USAID). The contents of this protocol 
are the responsibility of Vital Strategies and MRC CTU at UCL and do not necessarily reflect the 
views of USAID or the United States Government. 


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STREAM Protocol V111 15 Dec 2020 
 
4 
GENERAL INFORMATION 
This document describes the STREAM trial and provides information about procedures for entering 
patients into it. The protocol should not be used as an aide-memoire or guide for the treatment of 
other patients; every care was taken in its drafting, but corrections or amendments may be necessary. 
These will be circulated to site principal investigators in the trial by MRC Clinical Trials Unit at UCL 
(MRC CTU), London. Clinical problems relating to this trial should be referred to the co-Chief 
Investigator(s).  
 
Compliance: 
The trial will be conducted in accordance with this protocol, with the principles of Good Clinical 
Practice (GCP) as laid down by the ICH topic E6 (Note for Guidance on GCP), and the applicable 
regulatory requirements. 
Sponsor: 
Vital Strategies, f/k/a The International Union Against Tuberculosis and Lung Disease, Inc. 
100 Broadway, Fourth floor   
New York, NY  
10005 USA 
Tel (main): +1 212 500 5720   
Fax: +1 212 480 6040 
Email: STREAM@vitalstrategies.org 
 
Funders: 
The United States Agency for International Development (USAID) 
 
UK Medical Research Council (MRC) / Department for International Development (DFID) 
 
Janssen Research & Development, LLC 
 
Main Contacts:       
Co-Chief Investigator 
 
Prof. Andrew Nunn 
MRC Clinical Trials Unit at UCL 
Institute of Clinical Trials and Methodology 
90 High Holborn, 2nd Floor 
London,WC1V 6LJ 
 
Tel: +44 (0)20 7670 4703 
 
Email: a.nunn@ucl.ac.uk  
 
Co-Chief Investigator 
Prof. Sarah Meredith 
MRC Clinical Trials Unit at UCL 
Institute of Clinical Trials and Methodology 
90 High Holborn, 2nd Floor 
London,WC1V 6LJ 
 
Tel: +44 (0)20 7670 4787 
 
Email: s.meredith@ucl.ac.uk 
 
 
 
 
 


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STREAM Protocol V111 15 Dec 2020 
 
5 
Trial coordination 
MRC Clinical Trials Unit at UCL 
Institute of Clinical Trials and Methodology 
90 High Holborn, 2nd Floor 
London,WC1V 6LJ 
 
Tel: +44 (0)20 7670 4738 
Email: mrcctu.trial-stream@ucl.ac.uk   
 
Reference laboratory 
Institute of Tropical Medicine,  
Nationalestraat 155,  
B-2000 Antwerp, Belgium 
Tel: +32 3 2476548 
Fax: +32 3 2476333 
 
 
  
 
 
 
 
Trial Statistician 
 
Dr. Ruth Goodall 
MRC Clinical Trials Unit at UCL 
Institute of Clinical Trials and Methodology 
90 High Holborn, 2nd Floor 
London,WC1V 6LJ 
 
     Tel: +44 (0)20 7670 4728 
 
Email: r.goodall@ucl.ac.uk  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAE/NE NOTIFICATION  
Within one working day of becoming aware of an  SAE/NE, please email a completed 
SAE/NE form to the MRC Clinical Trials Unit on: 
 
Email: mrcctu.streamdata@ucl.ac.uk 
 
 
 


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6 
 


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7 
CONTENTS 
1 
Summary ............................................................................... 12 
1.1 
Abstract and summary of trial design ............................................................ 12 
2 
Background ........................................................................... 19 
2.1 
Introduction ................................................................................................ 19 
2.2 Rationale .............................................................................................................. 23 
3 
Objectives and outcomes ...................................................... 28 
3.1 
Stage 1 objectives ....................................................................................... 28 
3.2 Stage 2 objectives ................................................................................................. 28 
3.3 
Outcome measures ...................................................................................... 30 
4 
Selection of sites ................................................................... 32 
4.1 
Site inclusion criteria .................................................................................... 32 
5 
Selection of patients ............................................................. 33 
5.1 
Patient inclusion criteria ............................................................................... 33 
5.2 
Patient exclusion criteria .............................................................................. 34 
5.3 
Number and source of patients ..................................................................... 35 
5.4 
Screening procedures .................................................................................. 35 
5.5 
Late identification of drug-resistance or drug-sensitivity .................................. 37 
6 
Randomisation procedure ..................................................... 38 
6.1 
Evaluations at the randomisation visit ............................................................ 38 
6.2 
Allocation of treatment (following randomisation) ........................................... 39 
7 
Treatment of patients ........................................................... 40 
7.1 
Introduction ................................................................................................ 40 
7.2 
Trial interventions ........................................................................................ 40 
7.3 
Treatment procedures .................................................................................. 43 
7.4 
HIV ............................................................................................................ 48 
7.5 Other non-trial treatment ....................................................................................... 49 
8. Assessments and follow-up ......................................................... 50 
8.1.1 Assessment schedule .......................................................................................... 50 
8.2 
Blood tests for Stage 2 ................................................................................. 55 
8.3 
Procedures for assessing safety .................................................................... 57 
8.4 
Post-treatment schedule .............................................................................. 58 
8.5 
Changes to treatment or follow-up ................................................................ 58 
8.6 
Trial closure ................................................................................................ 60 
8.7 
Bacteriology ................................................................................................ 61 
8.8 
Health economic assessment ........................................................................ 62 
9 Discontinuation from treatment................................................... 64 
9.1 
Discontinuation of allocated regimen ............................................................. 64 
9.2 
Salvage regimens ........................................................................................ 65 
9.3 
Patient transfers .......................................................................................... 65 
9.4 
Early stopping of follow-up ........................................................................... 66 
10 Data management ...................................................................... 67 
10.1 
Blinding of data ........................................................................................... 67 
11 Statistical considerations ........................................................... 68 
11.1 Analysis population definitions .............................................................................. 68 
11.2 
Outcome measures ...................................................................................... 68 
11.3 
Sample size: Stage 1 ................................................................................... 72 


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8 
11.4 Sample size: Stage 2 ........................................................................................... 74 
11.5 
Interim monitoring and analyses ................................................................... 76 
11.6 
Preliminary analysis plan .............................................................................. 76 
11.7 IDMC review of Stage 1 results ............................................................................. 78 
11.8 IDMC review of recruitment to Regimen A in Stage 2 ............................................. 78 
11.9 Pharmacokinetic Analysis ..................................................................................... 78 
12 Trial monitoring .......................................................................... 80 
12.1 
Risk assessment .......................................................................................... 80 
12.2 
Monitoring plan ........................................................................................... 80 
12.3 
Clinical site monitoring ................................................................................. 80 
12.4 
Central monitoring ....................................................................................... 82 
13 Safety reporting .......................................................................... 83 
13.1 
Definitions .................................................................................................. 83 
13.2 
Institution/investigator responsibilities ........................................................... 85 
13.3 
MRC CTU responsibilities .............................................................................. 87 
13.4 Product quality complaint handling ....................................................................... 88 
14 Ethical considerations and approval ........................................... 89 
14.1 
Ethical considerations .................................................................................. 89 
14.2 
Protocol deviations ...................................................................................... 91 
14.3 
Ethical approval ........................................................................................... 91 
15 Regulatory issues ........................................................................ 93 
16 Indemnity ................................................................................... 93 
17 Ancillary studies .......................................................................... 93 
18 Finance ........................................................................................ 93 
19 Trial committees ......................................................................... 94 
19.1 
Trial Management Group (TMG) .................................................................... 94 
19.2 
Trial Steering Committee (TSC) .................................................................... 94 
19.3 
Independent Data Monitoring Committee (IDMC) ........................................... 94 
20 Publication .................................................................................. 96 
20.1 
Publication .................................................................................................. 96 
20.2 
Dissemination of results to trial participants ................................................... 96 
21 Appendices .................................................................................. 97 
Appendix 1: High-dose moxifloxacin safety summary ..................................................... 97 
Appendix 2: Levofloxacin Safety Summary .................................................................. 100 
22 References ................................................................................ 103 
 
 


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LIST OF TABLES 
Table 1: Regimen Bmox doses (for patients randomised under versions of the protocol prior to 
Version 8.0) ............................................................................................................ 40 
Table 2: Regimen Blev doses (for patients randomised under Version 8.0 of the protocol onwards)
 ............................................................................................................................. 41 
Table 3: Regimen C doses, given daily unless otherwise stated .......................................... 42 
Table 4: Regimen D doses, given daily unless otherwise stated ......................................... 42 
Table 5: Assessment schedule – for all patients recruited in Stage 1 .................................. 51 
Table 6: Assessment schedule – for all patients recruited in Stage 2 .................................. 53 
Table 7: PK Sample Collection Timings ............................................................................ 56 
Table 8: Power to demonstrate non-inferiority in the primary efficacy outcome ................... 73 
Table 9: Power to demonstrate non-inferiority in the primary safety outcome ..................... 74 
Table 10: Power to demonstrate non-inferiority in the primary efficacy outcome (Regimens B and C 
only) ...................................................................................................................... 75 
Table 11: Safety reporting definitions .............................................................................. 83 
Table 12: Definitions of causality ..................................................................................... 86 
Table 13: MIC values for fluoroquinolones ..................................................................... 100 
Table 14: Relapse* after Treatment Completion 45 .......................................................... 101 
 
 
LIST OF FIGURES 
Figure 1: Trial recruitment stages.................................................................................... 14 
Figure 2: Stage 1  Trial Design ........................................................................................ 17 
Figure 3: Stage 2 Trial Design ......................................................................................... 18 
Figure 4: Regimen A* & Regimen Bmox ............................................................................. 20 
Figure 5: Modified Regimen B - Regimen Blev (Protocol Version 8.0 onwards) ...................... 21 
Figure 6: Regimen C (all oral) ......................................................................................... 21 
Figure 7: Regimen D (28-week regimen) ......................................................................... 21 
Figure 8: Treatment phases of investigational regimens .................................................... 22 
Figure 9: Transition from intensive to continuation phase for patients on Regimen B and Regimen C
 ............................................................................................................................. 45 
Figure 10 Transition from intensive to continuation phase for patients on Regimen D .......... 46 
Figure 11: Safety reporting flowchart .............................................................................. 87 
 


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10 
ABBREVIATIONS AND GLOSSARY 
 
 
AE 
AFB 
Adverse Event 
Acid Fast Bacilli 
AR 
Adverse Reaction 
AST 
Aspartate aminotransferase 
ALT 
BDQ 
Alanine aminotransferase 
Bedaquiline 
ICF 
Informed Consent Form 
CI 
CFZ 
Chief Investigator 
Clofazimine 
CRF 
Case Report Form 
CTA 
Clinical Trials Authorisation 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DCF 
Data Clarification Form 
DOT 
Directly Observed Treatment 
DST 
Drug Susceptibility Test 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
EMB 
Ethambutol 
EQA 
External Quality Assurance 
 
FDA 
Fluorescein diacetate staining 
US FDA 
United States Food and Drug Administration  
GCP 
Good Clinical Practice 
GLC 
Green Light Committee 
HE 
Health Economics 
HIV 
Human Immunodeficiency Virus 
IDMC 
Independent Data Monitoring Committee 
IRB 
Institutional Review Board 
ISRCTN 
International Standard Randomised Controlled Trial Number 
ITM 
Institute of Tropical Medicine 
ITT 
IUATLD 
KM 
Intention To Treat 
International Union Against Tuberculosis & Lung Disease 
Kanamycin 
INH 
Isoniazid 
LFX 
Levofloxacin 
LPA 
Line Probe Assay 
LQAS 
Lot Quality Assurance Sampling 
M2 
Metabolite 2 
MDR 
MFX 
Multi-Drug Resistant 
Moxifloxacin 
Genotype 
MTBDRPlus 
Rapid test for M. tuberculosis Complex and its resistance to Rifampicin and/or 
Isoniazid 
Genotype  
MTBDRsl 
Rapid test for M. tuberculosis Complex and its resistance to fluoroquinolones 
and/or second-line injectables/cyclic peptides and/or ethambutol 
MIC 
Minimal Inhibitory Concentration 


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MIRU-VNTR Mycobacterial Interspersed Repetitive Units–Variable Number of Tandem Repeats 
MRC CTU 
Medical Research Council Clinical Trials Unit 
NE 
Notable Event 
NTP 
National Tuberculosis Programme 
PK 
Pharmacokinetics  
PI 
Principal Investigator 
PIS 
PTO 
PZA 
Patient Information Sheet 
Prothionamide 
Pyrazinamide 
QA 
Quality Assurance 
QT Interval 
 
QTc 
QTcF 
A measure of time between the start of the Q wave and the end of the T wave in 
the ECG complex 
QT interval corrected for heart rate 
QT interval corrected for heart rate using the Fridericia correction 
REC 
Research Ethics Committee 
RMP 
Rifampicin 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedures 
SPC 
Summary of Product Characteristics 
SSA 
SSG 
Site Specific Assessment 
Statistical Support Group 
STREAM 
The Evaluation of a Standardised Treatment Regimen of Anti-Tuberculosis Drugs 
for Patients with MDR-TB 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
The Union 
TM 
International Union Against Tuberculosis & Lung Disease 
Trial Manager 
TMG 
Trial Management Group 
TMT 
Trial Management Team 
TREAT TB 
Technology, Research, Education, and Technical Assistance for Tuberculosis 
TSC 
Trial Steering Committee 
UAR 
ULN 
Unexpected Adverse Reaction 
Upper limit of normal 
USAID 
United States Agency For International Development 
WHO 
World Health Organisation 
XDR 
Extensively Drug Resistant 
ZN 
Ziehl-Neelsen 
 
 
Note. In this protocol time (in weeks) refers to the time from randomisation, e.g. Week 76 refers 
to 76 weeks from randomisation. 


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1 SUMMARY 
1.1 Abstract and summary of trial design 
1.1.1 Type of design 
The STREAM study is an international, multi-centre, parallel-group, open-label, randomised, 
controlled trial.  
1.1.2 Disease/patients studied 
Patients with multi-drug resistance tuberculosis (MDR-TB) including patients with rifampicin-
resistant and isoniazid-sensitive TB.  
1.1.3 Trial interventions 
Treatments that are evaluated within the STREAM trial include: 
 
Regimen A  
The locally-used MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment guidelines.1  
 
Regimen B  
Regimen B is based on the regimen described by Van Deun 20102. At the start of STREAM this 
consisted of clofazimine, ethambutol, moxifloxacin, and pyrazinamide given for 40 weeks, 
supplemented by isoniazid, kanamycin, and prothionamide in the first 16 weeks (intensive phase); 
this combination is referred to as Regimen Bmox. With Version 8.0 of the protocol Regimen B is 
modified by replacement of moxifloxacin with levofloxacin (referred to as Regimen Blev).  Regimen B 
without specification of which fluoroquinolone is in the regimen refers to either (Bmox or Blev). With 
Version 10.0 of the protocol, Regimen B is further modified to replace kanamycin with amikacin in 
sites where:   
 
the national TB program has replaced kanamycin with amikacin in line with revised WHO 
guidance14 and  
 
amikacin is available for the trial.  
Kanamycin will continue to be used until the transition takes place within each country programme. 
 
Regimen C  
Regimen C is a 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol, 
levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for 
the first 16 weeks (intensive phase).    
 
Regimen D  
Regimen D is a 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and 
pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks 
(intensive phase).   
 
 
 
 
 


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1.1.4 Trial Stages 
The STREAM trial consists of 2 stages. 
 
Stage 1 
Stage 1 of the trial involves a comparison between two treatment arms: Regimen A and Regimen B 
(as described in section 1.1.3).  During this stage Regimen A acts as the control arm to the 
investigational treatment arm, Regimen B. 
 
Stage 2  
Stage 2 of the trial involves the addition of two further treatment arms: Regimen C and Regimen D.  
During this stage Regimen B acts as the control arm for the primary comparison with the new 
investigational treatment arm, Regimen C and for secondary comparisons with Regimen D.  With 
Version 8.0 of the protocol randomisation to Regimens A and D will end and patients will be 
randomised to Regimen B or Regimen C in a ratio 1:1. 
 
The 2016 WHO MDR-TB treatment guidelines3, including the short course regimen, have already 
been implemented in some participating countries and most of the remaining countries have plans 
to start during the course of 2018. Since patients eligible for the trial would be treated with a short 
regimen in routine practice outside the trial, continued randomisation to Regimen A (the long WHO 
regimen as recommended by the 2011 WHO MDR-TB guidelines) will not be feasible and therefore 
will be dropped from the randomisation options.  
 
With version 8.0 of the protocol patients will no longer be randomised to Regimen D and 
comparisons involving Regimen D are no longer primary objectives. The rationale for this is two-
fold. Firstly, there have been many important developments since the design of Stage 2 and fully 
oral 6-month regimens are being evaluated in ongoing Phase 3 trials. The elimination of the 
injectable from MDR-TB regimens, rather than just reducing the duration, has become a priority to 
clinicians and patients and as such, Regimen D is a less attractive treatment option and a less 
valuable research question. Even if Regimen D could be shown to be safe with non-inferior efficacy 
in STREAM, it is unlikely that it would ever be adopted as a treatment for MDR-TB. Secondly, 
enrolment to Stage 2 has been slower than expected and the continuation of recruitment to 
Regimen D will hamper the ability to make the primary comparison of Regimens B and C. 
 
Patients already randomised to Regimens A and D will complete their course of treatment and 
continue in follow-up according to the protocol. 
 
The start of Stage 2  
Figure 1 presents an overview of the recruitment stages in the STREAM trial.  However, sites may 
begin Stage 2 at different times, depending upon gaining country-specific approval.  Additionally, 
some sites may only be participating in Stage 1 and others only in Stage 2.  
 
 
 
 
 
 
 


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14 
Figure 1: Trial recruitment stages  
 
 
1.1.5 Trial objectives 
 
Primary trial objectives of Stage 1 
The primary objectives of Stage 1 of the STREAM trial are: 
1. 
To assess whether the proportion of participants with a favourable efficacy outcome at Week 
132 on Regimen B is non-inferior to that on Regimen A (WHO 2011 long MDR-TB regimen) 
2. 
To compare the proportion of participants who experience grade 3 or greater adverse events, 
during treatment or follow-up, on Regimen B as compared to Regimen A. 
 
The secondary objectives of Stage 1 of the STREAM trial are listed in section 3.1.2. 
 
Primary trial objective of Stage 2  
The primary objective of Stage 2 of the STREAM trial is: 
To assess whether the proportion of participants with a favourable efficacy outcome at Week 76 on 
Regimen C is non- inferior to that on Regimen B. 
 
Secondary objectives, including safety objectives, of Stage 2 of the STREAM trial are listed in 
section 3.2.2. 
 
1.1.6 Duration of follow-up 
All patients in Stage 1 of the study will be followed up to Week 132. The primary analysis will be 
based on the data accrued to Week 132.  
 
All patients in Stage 2 of the study will also be followed up to Week 132, 56 weeks beyond the primary 
analysis point at Week 76. The main purpose of this extended follow-up is to monitor safety 
outcomes, particularly deaths.  Recruitment to Stage 2 was slower than initially expected, as several 
sites closed to recruitment early due to their NTP adopting a fully oral regimen in line with changing 
WHO Guidelines.  Given the urgent need for evidence to contribute to global guidelines on all-oral 
treatment regimens, with Version 11 of the protocol the end of follow-up for efficacy has been brought 
forward, although follow-up for safety is unchanged; follow-up for efficacy will end when the last 
patient recruited is projected to have reached Week 96. This will allow microbiology results  to be 


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complete by the end of the trial, facilitating rapid analysis and reporting of Stage 2 results. The impact 
of shortening the follow up period for efficacy is minimal, and outweighed by the benefits of earlier 
availability of long-term trial results. The majority of patients (approximately 75% on Regimens B 
and C) will still have efficacy outcomes at Week 132, but for a proportion of patients (those 
randomised towards the end of the recruitment phase) efficacy follow-up will be censored between 
96 and 132 weeks. The reduction in the total person-years of follow-up for the efficacy analysis is 
small, only 3% in Regimens B & C. 
 
In summary, in Stage 2 the primary analysis will be based on the data accrued to Week 76; the data 
accrued to the date when the last patient is projected to have reached Week 96 will be used for the 
secondary long-term efficacy analysis and all data to the end of trial at Week 132 will be used for the 
long-term safety analyses. 
 
1.1.7 Primary outcome measures 
 
Stage 1 
The primary efficacy outcome of the Stage 1 comparison is status at the end of follow-up i.e. the 
proportion of patients with a favourable outcome at Week 132 (as defined in section 11).  
 
The primary safety outcome is the proportion of patients experiencing a grade 3 or greater adverse 
event during treatment or follow-up.  
 
Stage 2 
The primary efficacy outcome of the Stage 2 comparison is status at Week 76 i.e. the proportion of 
patients with a favourable outcome at Week 76 (as defined in section 11).  
 
1.1.8 Sample Size 
 
Stage 1 
A minimum of 400 participants from sites in four or five countries will be randomised to either 
Regimen A or Regimen B in the ratio 1:2 (i.e. 133 allocated to Regimen A, and 267 allocated to 
Regimen B). 
 
Stage 2 
Stage 2 will aim to randomise at least 200 patients to each of Regimens B and C. This revised sample 
size was determined based on the assumption that the proportion of patients with a favourable 
efficacy outcome at Week 76 is 80% for Regimen B (estimated based on preliminary Stage 1 results) 
and 82% for Regimen C (based on an anticipated minimum benefit in efficacy of using 40 weeks 
treatment with bedaquiline compared to 16 weeks treatment with kanamycin). Using a non-inferiority 
margin of 10% and a one-sided significance level of 2.5%, 180 evaluable patients will be required in 
each of the two regimens to demonstrate non-inferiority of Regimen C to Regimen B with 82% power. 
To account for 10% of patients excluded from the primary efficacy analysis population, a total of 
400 patients would be required across the 2 regimens.  
 
An interim analysis will be performed for the purpose of determining the final sample size needed to 
achieve adequate power for testing the Stage 2 primary hypothesis of non-inferiority. The sample 


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size re-estimation will be performed by an independent Statistical Support Group (SSG) and if 
necessary the sample size will be increased, to a maximum of 330 patients in each of regimens B and 
C (the original sample size).  
 
 
 
 
 
 
 


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Figure 2: Stage 1  Trial Design 
 
 
Note. This figure applies to all sites during Stage 1 (i.e. before commencement of Stage 2), and to 
those sites only participating in Stage 1. 
 
 
 


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Figure 3: Stage 2 Trial Design  
 
Note. With Version 8.0 of the protocol recruitment to Regimens A and D will be terminated; this is indicated by the red cross 
over those regimens in the diagram. 
1.1.9 Blinding 
Although the STREAM study is an open-label study, wherever possible it will be conducted masked 
to treatment allocation. The patient and treating clinician will be aware of treatment allocation, 
however, all laboratory assessments will be performed blind. See Section 10.1 for further details 
relating to blinding within the trial. 
 
 


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2 BACKGROUND 
2.1 Introduction 
Despite the availability of an efficacious and affordable six-month chemotherapy regimen for drug-
sensitive TB and the definition of an efficient strategy to deliver treatment under direct observation 
to the majority of TB patients, TB control worldwide is impeded by two major issues: (i) the 
emergence of multidrug resistance (MDR) and (ii) co-existent HIV infection. The former hampers 
dramatically the efficacy of widely implemented standard short-course chemotherapy, thus limiting 
the success of efforts to fight against tuberculosis worldwide3,4, and since 2002, at least one case of 
extensively drug-resistant tuberculosis (XDR-TB) has been reported from 45 countries5.  
 
2.1.1 Relevant studies/trials 
In 2011, World Health Organisation (WHO) guidelines for the treatment for MDR-TB recommended 
an intensive phase of treatment based on at least four drugs known to be effective and given for a 
minimum of 20 months;6 this is referred to below as the WHO 2011 long regimen. Outcomes with 
this approach are generally poor. In the most recent WHO TB surveillance report only 50% of MDR-
TB patients were successfully treated.7  and a recent meta-analysis reported on average 62% 
successful outcome and a mortality of 11%8. 
 
In 2010, Van Deun et al (2010)2 reported excellent long-term outcomes in a cohort of over 200 
patients in Bangladesh with MDR-TB who were treated with a regimen given for only nine to 11 
months.  Such a regimen, if successful, would represent a considerable advance over current practice.  
Evaluation of this regimen is the objective of Stage 1 of STREAM. In an updated analysis of over 500 
patients in this cohort there was a relapse-free cure rate of 84.4% (95% confidence interval 81.3% 
- 87.6%).9 These results were further supported by data from two West African cohorts with 89% 
cure rates seen in both the Niger and Cameroon cohorts of 65 and 150 patients respectively.10,11 Both 
cohorts used a regimen similar to that studied in Bangladesh but of 12 months duration. Other 
prospective cohort studies of similar shortened regimens have also been implemented in Uzbekistan 
and several countries in West Africa. 
 
In 2016, following review of the available data, the WHO MDR TB treatment guidelines were modified 
to recommend a 9-12 month shortened regimen under specific conditions similar to Regimen B used 
in STREAM Stage 1 (referred to below as the WHO 2016 short regimen).12  This was a conditional 
recommendation based on very low certainty in the evidence. 12 
 
Final analysis of STREAM Stage 1, presented at the Union Conference in October 2018, found that 
78.8% of participants on Regimen B, the short regimen, had a favourable outcome at 132 weeks 
from randomisation compared to 79.8% on Regimen A, the 20-24 month long regimen. After 
adjustment for the randomisation stratification factors of HIV status and centre, the difference in 
efficacy between the regimens was 1.0%, (95% CI -7.5 to 9.5%) meeting the pre-specified 10% 
non-inferiority margin.  The primary safety outcome of the trial, the proportions of patients who 
experienced a Grade 3 or greater adverse event at any time during treatment and follow-up, was 
also similar on the two regimens (48.2% on the shorter regimen compared to 45.4% on the longer 
regimen).   
 


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Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity. In a phase II trial of patients 
with MDR-TB time to culture conversion was significantly less in patients receiving bedaquiline 
compared to those receiving an optimised background regimen only.13 In December 2012 the US 
Food and Drug Administration (FDA) approved bedaquiline as part of the treatment regimen for MDR-
TB when other agents are unavailable. Stage 2 of STREAM was designed to investigate ways in which 
Regimen B could be improved either by removing the second-line injectable, which is associated with 
severe drug toxicity, or by shortening the regimen to 6 months. 
 
In December 2018, the WHO issued revised guidelines for treatment of MDR TB following review of 
a meta-analysis of available trial and observational data.14  This included a re-classification of drugs 
for longer MDR-TB treatment regimens, with moxifloxacin or levofloxacin, bedaquiline and linezolid 
all listed in Group A (medicines that should be used in the regimen); it was also recommended that 
when an injectable agent is required, amikacin should be used rather than kanamycin or capreomycin.  
2.1.2 Population 
The STREAM study population consists of patients diagnosed with MDR-TB who fulfil the 
inclusion/exclusion criteria outlined in sections 5.1 and 5.2.  
2.1.3 Investigational regimens 
 
Stage 1 
The investigational regimen in Stage 1 of the STREAM trial is Regimen Bmox.  This regimen consists 
of clofazimine, ethambutol, moxifloxacin, and pyrazinamide given for 40 weeks, supplemented by 
isoniazid, kanamycin, and prothionamide in the first 16 weeks, as illustrated in Figure 4. This is 
compared with Regimen A, the locally-used WHO 2011 long regimen. 
 
Figure 4: Regimen A* & Regimen Bmox 
 
 
*WHO 2011 long regimen 
 
The only change in Regimen B from the regimen described by Van Deun2 is that gatifloxacin has been 
replaced by moxifloxacin because gatifloxacin was withdrawn by the original marketing authorisation 
holder and generic sources investigated did not meet WHO requirements for quality, safety and 
efficacy.  
 
Stage 2 
Stage 2 involves Regimen A and Regimen B as described in Stage 1 above, with the addition of two 
investigational regimens: Regimen C and Regimen D. These two regimens are modifications of 
Regimen B, both of which include the drug bedaquiline. In Stage 2 Regimen B is the control regimen 
for Regimen C and Regimen D. 


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With Version 8.0 of the protocol, Regimen B is modified by replacement of moxifloxacin with 
levofloxacin.   With Version 10.0 of the protocol, Regimen B is further modified to replace 
kanamycin with amikacin in sites where: 
 
the national TB programme is using amikacin as the preferred injectable in line with revised 
WHO guidance,14and  
 
amikacin is available for the trial.  
 
Kanamycin will continue to be used until the transition takes place within each country programme. 
 
Participants randomised to Regimen B should be treated with the fluoroquinolone and injectable 
allocated at the start of treatment unless there is a clinical or operational reason to make a change. 
 
Figure 5: Modified Regimen B - Regimen Blev (Protocol Version 8.0 onwards) 
 
 
 
Regimen C is a 40-week, fully-oral regimen consisting of bedaquiline, clofazimine, ethambutol, 
levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for 
the first 16 weeks (intensive phase).  This is a modification of Regimen B, as illustrated in Figure 6, 
in which kanamycin is replaced with bedaquiline, and moxifloxacin is replaced with an alternative 
fluoroquinolone, levofloxacin, which has a better profile with respect to the potential for QT 
prolongation. 
 
Figure 6: Regimen C (all oral) 
 
 
Regimen D is a 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and 
pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks 
(intensive phase). This regimen is a modification of Regimen B, as illustrated in Figure 7, in which 
bedaquiline is given throughout, and moxifloxacin is replaced with an alternative fluoroquinolone, 
levofloxacin, and the total duration is reduced to 28 weeks.  
 
Figure 7: Regimen D (28-week regimen) 


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Figure 8 presents the phases of treatments across the four arms of the trial. 
 
Figure 8: Treatment phases of investigational regimens 
 
* Following implementation of protocol Version 8.0 recruitment to Regimen A and Regimen D was 
discontinued and in Regimen B moxifloxacin was replaced by levofloxacin. 
Following implementation of protocol version 10.0, either kanamycin or amikacin will be used in 
Regimen B, depending on availability. 
 
2.1.4 Ending randomisation to Regimen A 
According to Version 7.0 of the Stage 2 protocol, patients may be randomised to Regimen A unless 
the participating country has adopted or has imminent plans to adopt a short MDR-TB regimen, in 
keeping with the WHO 2016 guidelines. This is because patients eligible for STREAM would also 
meet the WHO criteria for a shortened regimen and it is very unlikely that patients would accept 
the possibility of randomisation to a 20- to 24-month treatment regimen when under routine care 
they would be treated with a 9-month regimen.  In addition, patients already enrolled in the trial 
and allocated to Regimen A would be more likely to subsequently withdraw from the trial, thus 
reducing the scientific value of the results.   
 
With Version 8.0 of the protocol, randomisation to Regimen A will cease completely because several 
of the countries participating in STREAM have already implemented or have plans to implement a 
shortened regimen.  As a result Regimen A would not have sufficient concurrently randomised 
patients for comparison and therefore continuation is considered futile. In addition, Stage 1 of 


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STREAM provides a good estimate of the performance of Regimen A under trial conditions. Patients 
already enrolled and allocated to Regimen A will continue on that treatment. 
 
2.1.5 Ending randomisation to Regimen D 
Patients will no longer be randomised to Regimen D from the point of implementation of Version 
8.0 of the protocol and comparisons involving Regimen D will no longer be primary objectives. The 
rationale for this is two-fold. Firstly, there have been many important developments since the 
design of Stage 2 and fully oral 6-month regimens are being evaluated in several ongoing Phase 3 
trials. The elimination of the injectable from MDR-TB regimens, rather than just reducing the 
duration, has become a priority to clinicians and patients and as such, Regimen D is a less 
attractive treatment option and a less valuable research question. Even if Regimen D was shown to 
be safe with non-inferior efficacy in STREAM, it is unlikely that it would be adopted as a treatment 
for MDR-TB. Secondly, enrolment to Stage 2 has been slower than expected and the continuation 
of recruitment to Regimen D will hamper the ability to make the primary comparison of Regimens B 
and C. 
 
Patients already randomised to Regimen D will complete their course of treatment and continue in 
follow-up according to the protocol. 
2.2 Rationale 
 
Given the urgent need to increase access to treatment for MDR-TB, careful evaluation of treatment 
strategies is vital to ensure the most effective and feasible approaches are implemented, particularly 
in low-income settings where most cases of MDR-TB are found. New drugs with novel mechanisms 
of action for the treatment of MDR-TB are being evaluated. In addition, the optimisation of existing 
drugs is essential for the protection of new compounds for use in alternative regimens; clinical trials 
utilising these new compounds in treatment regimens are warranted.  
 
The primary objective of Stage 1 of the STREAM trial is to assess whether Regimen B, which is based 
on the regimen used in Bangladesh,2 is non-inferior to Regimen A, the locally-used WHO 2011 long 
MDR-TB regimen. Its practical, programme-based study design will also ensure that if the results are 
favourable, they will be generalisable to routine programme settings. 
 
In addition, health system and patient costs associated with implementation will be documented.  
These will be analysed in association with the clinical outcomes of the trial using the TREAT TB Impact 
Assessment Framework15 in order to provide as much information as possible for subsequent policy 
and practice decision-making. 
 
It was necessary to substitute moxifloxacin for gatifloxacin in Regimen B because the original 
manufacturer of gatifloxacin withdrew their product from the market due to reports of associated 
dysglycaemia, and it was not possible to identify a generic source of gatifloxacin that met WHO 
manufacturing norms and standards for quality, safety and efficacy. If Regimen B was found to be 
inferior to Regimen A, one possible explanation could be that moxifloxacin is less effective than 
gatifloxacin. However, moxifloxacin and gatifloxacin have similar bactericidal activity16 and the trial 
will therefore test the regimen closest to the standardised regimen developed by Van Deun2  that is 
available in routine programme settings.   
 


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Stage 2 of the STREAM trial will involve the investigation of two alternative regimens, both variations 
on Regimen B, incorporating the drug bedaquiline. The first of these investigational regimens, 
Regimen C, involves the removal of the injectable, kanamycin, in order to avoid the associated risks 
of ototoxicity and renal toxicity.  The second investigational regimen, Regimen D, investigates the 
possibility of treatment being further shortened to 28 weeks, with a shorter duration of kanamycin 
and isoniazid and also whether ethambutol, which is of questionable efficacy, and prothionamide, 
commonly associated with severe gastric symptoms, can be removed.  
 
The primary objective of Stage 2 is to assess whether Regimen C is non-inferior to Regimen B.  
 
As the final results of STREAM Stage 1 would not be available until late in enrolment for Stage 2, 
and due to the urgent public health and clinical need to improve treatment of MDR-TB, Stage 2 was 
started without randomised controlled trial evidence that Regimen B is non-inferior to Regimen A.  
Regimen B was selected as the control arm for Stage 2 after careful consideration. 
 
The final analysis of STREAM Stage 1 made public at The Union Conference in October 2018 found 
that 78.8% of participants on Regimen B had a favourable outcome at 132 weeks from 
randomisation compared to 79.8% on Regimen A. After adjustment for the randomisation 
stratification factors of HIV status and centre, the difference in efficacy between the regimens was 
1.0%, 95% CI (-7.5 to 9.5%). The upper bound of the confidence interval met the pre-specified 
10% non-inferiority margin. The proportions of patients who experienced a Grade 3 or greater 
adverse event at any time during treatment and follow-up, the primary safety outcome, was also 
similar on the two regimens (48.2% on the shorter regimen compared to 45.4% on the longer 
regimen).  
 
From a preliminary review by the sponsor of the Stage 1 safety data it was apparent that regular 
ECG monitoring was of value throughout treatment.  Although this is manageable in the context of 
a clinical trial, it would be a challenge for programmatic implementation, particularly in resource-
limited settings. Because a key objective of STREAM is to evaluate effective and feasible 
approaches to MDR-TB treatment suitable for the settings in which the disease is most common, in 
Version 8.0 of the protocol Regimen B will be modified and moxifloxacin replaced by levofloxacin to 
assess whether this reduces the safety monitoring requirements of the regimen, given that the 
effect on the QT interval may be lower for levofloxacin than for moxifloxacin. The primary 
comparisons will be of Regimen C with Regimen B, whether it contains moxifloxacin or levofloxacin. 
Comparison of Regimen C with modified Regimen B (Regimen Blev) alone will be added as 
secondary objectives of the trial. 
 
In the light of the revised WHO recommendations for the treatment of MDR-TB in 2018, Regimen B 
was modified to allow either amikacin or kanamycin to be used in the intensive phase.  
 
As described in sections 2.1.4 and 2.1.5, from the point of implementation of Version 8.0 of the 
protocol, patients will no longer be randomised to Regimens A or D. Comparisons involving 
Regimen D will no longer be primary objectives. 
 
2.2.1 Risks and benefits 
Regimens B, C and D are substantially shorter than regimens recommended by the 2011 WHO 
guidelines6 and could therefore increase the risk of treatment failure or relapse, and the acquisition 


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of additional drug resistance.  However, this has not been observed in settings where variations of 
Regimen B have been used.9-11  
 
Additional data from Stage 2 will enable a more precise comparison of the true difference between 
Regimen B and A to be made.    
 
Regimen D may carry greater risk of failure or relapse compared with Regimen B because it is shorter 
and because of the removal of prothionamide and ethambutol. Although unlikely, regimen C may also 
carry a risk of failure or relapse compared to regimen B. There may also be greater risk of acquisition 
of additional drug resistance in regimens C and D. However, this risk is believed to be small given 
that, in stage 2 of the bedaquiline C208 trial, no subject in the bedaquiline arm developed extensively 
drug-resistant (XDR) or pre-XDR infection with 24 weeks of dosing of bedaquiline compared to six 
participants in the control arm;17 this is comparable with 9% reported from a recent follow-up of over 
800 patients treated with the WHO 2011 long regimen.18  
 
Restriction of the second-line injectables and prothionamide to the intensive phase may explain why 
no acquired resistance to these drugs was observed in the failure or relapse cases in the Van Deun2 
study. Although used with only one second-line drug in the continuation phase, acquired 
fluoroquinolone resistance did not occur, probably due to the relatively high fluoroquinolone dose 
used; baseline resistance to ofloxacin rarely resulted in an adverse bacteriological outcome. Moreover, 
study criteria limiting inclusion to cases with no LPA evidence of resistance to either fluoroquinolones 
or kanamycin is expected to almost certainly prevent amplification of resistance leading to extensively 
drug-resistant tuberculosis.  
 
Most second-line drugs are associated with unpleasant and sometimes serious toxicities.  The removal 
of prothionamide from Regimen D will avoid the gastric side effects which some patients find 
intolerable. The reduced duration of kanamycin in the 28-week regimen, Regimen D, and its removal 
from the fully oral 40-week regimen, Regimen C, will reduce the risk of kanamycin toxicity (renal 
damage and deafness).  
 
Isoniazid is included in Regimen B, Regimen C, and Regimen D at higher doses than is usual.  
Similarly, the fluoroquinolone doses, moxifloxacin in Regimen Bmox and levofloxacin in regimens Blev, 
C and D, for patients in the higher weight bands are greater than the standard doses.  However, the 
regimen given in Bangladesh was well-tolerated and it is possible that the shorter duration of 
chemotherapy in Regimen B, Regimen C, and Regimen D may result in fewer severe adverse drug 
reactions than in Regimen A.   
 
A summary of the safety information on the higher dose of moxifloxacin is provided in Appendix 1. 
The potential for QT prolongation is of particular concern and regular ECG monitoring is specified in 
the protocol (see Section 8.3.1). 
 
Bedaquiline given in addition to a standardised background regimen has been shown to greatly 
reduce the time to culture conversion in MDR-TB (median 83 days compared to 125 days, HR 2.44, 
95%CI (1.57 - 3.80)).  However, there is less clinical experience with bedaquiline than with the 
other drugs in the study regimens, and although generally well tolerated, a number of potential 
risks have been identified from preclinical and clinical studies and the findings from the C208 trial; 
these are outlined below and will be carefully monitored in the course of this study. 


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Mortality 
In Stage 2 of the bedaquiline C208 trial, a difference in the number of deaths was observed 
between the bedaquiline group (10/79, 12.7%) and the placebo group (3/81, 3.7%), despite better 
microbiological outcomes in the former. This imbalance remained in the pooled analysis of C208 
Stage 1 and Stage 2. The reason for the increased overall mortality is as yet unclear; the causes of 
death were varied (the only cause of death reported more than once was death due to TB), and 
there was a wide range in time to death since last intake of bedaquiline/placebo (2-911 days). In 
addition, none of the deaths in the bedaquiline arm were considered related to study drug by the 
investigator. Mortality will be thoroughly evaluated in this study, which includes follow-up to 132 
weeks for all participants.  
 
Liver toxicity 
In the bedaquiline C208 trial, the most frequently observed laboratory abnormalities that were 
more frequent in the bedaquiline than the placebo arm were increases in aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT). There were two cases (one in a 
subject in the bedaquiline arm in C208 and one in a subject in the bedaquiline arm in C209) where 
the transaminase increases were accompanied by increased total bilirubin such that both subjects 
met laboratory criteria for Hy’s law.  There were no cases of severe hepatotoxicity attributed to 
bedaquiline by the investigators in the clinical studies, however in view of the relatively small study 
populations and the combination with other potentially hepatotoxic drugs in the STREAM regimens, 
it will be important to monitor this closely. 
 
Pancreatic toxicity 
Pancreatic changes were observed in mice and dogs receiving bedaquiline that correlated with 
increases in pancreatic amylase and lipase, without trypsin-like immunoreactivity increase. Although 
there is no clear evidence of an increased risk in the clinical studies, patients with a pancreatic 
amylase more than twice the upper limit of normal will be excluded from Stage 2 of the trial and 
pancreatic function will be monitored closely.  
 
Cardiac effects 
Based on the observation of cardiac myocyte degeneration and QT prolongation in dogs that 
received exposures in excess of the clinical exposure in toxicology studies, cardiac muscle effects 
are monitored in the current study by creatine kinase-MB and safety ECGs.  However, no increases 
in these laboratory tests suggesting bedaquiline cardiac toxicity were noted in either stage of the 
bedaquiline C208 trial.  QT prolongation has been observed with bedaquiline: 
1. The largest mean increase in QTcF in Janssen's C208 Stage 2 trial at a predose time point in the 
Any BDQ group during the first 24 weeks was 15.4 ms (at Week 24) and 7.7 ms in the Any placebo 
group (at Week 20). 
2. In addition and pertinent to Stream Stage 2, in Janssen's C209 trial a maximal increase mean 
change from reference in QTcF at Week 24 was 12.2 ms over 24 months and in those patients also 
taking clofazimine (n=17) the mean increase change from reference was 32ms.19   
 
In Stage 2 of STREAM, patients with a QTcF greater than or equal to 450 ms at screening will not 
be eligible and there will be regular ECG monitoring (see Section 8.3.1). As a consequence of the 
risk of QT prolongation with bedaquiline, moxifloxacin is contraindicated and has been replaced by 


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levofloxacin (see Appendix 2 for levofloxacin safety summary) in the two bedaquiline-containing 
experimental regimens: Regimen C and Regimen D.  
 
Musculoskeletal effects 
In some animal studies elevations of myoglobin and CK were observed, consistent with the known 
ability of cationic amphiphilic drugs to cause myopathies, which tend to occur only after prolonged 
dosing in humans or at high dose administration and are usually reversible after treatment 
cessation. No myopathies were reported in the clinical studies, but this will be kept under review in 
STREAM. 
 
Reproduction 
Since the effects of bedaquiline on foetal development are unknown, the use of effective 
contraception is required for both male and female participants (see Section 5.1). 
 
2.2.2 Safety in the ongoing STREAM trial 
The Independent Data Monitoring Committee (see Section 19.3) for STREAM have reviewed the 
safety data approximately 6-monthly since recruitment to Stage 1 started. The committee have not 
identified any safety concerns that required amendment of the protocol. 
 
 
 
 


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3 OBJECTIVES AND OUTCOMES 
3.1 Stage 1 objectives  
3.1.1 Stage 1 primary objectives 
The primary objectives of the Stage 1 comparison of the STREAM trial are: 
 
1. To assess whether the proportion of participants with a favourable efficacy outcome on 
Regimen B is non-inferior to that on Regimen A (WHO 2011 long MDR-TB regimen), the 
control regimen for Stage 1, at Week 132, using a 10% margin of non-inferiority. 
2. To compare the proportion of participants who experience grade 3 or greater adverse events 
during treatment or follow-up in Regimen B as compared to Regimen A. 
3.1.2 Stage 1 secondary objectives 
The secondary objectives of the Stage 1 comparison of the STREAM trial are: 
 
1. To determine the proportion of participants with a favourable efficacy outcome on Regimen 
B in each country setting 
2. To compare the economic costs incurred by patients and by the health system during 
treatment on Regimen B as compared to Regimen A. 
 
3.2 Stage 2 objectives  
3.2.1 Stage 2 primary objective: 
The primary objective of the Stage 2 comparisons of the STREAM trial is: 
 
1. To assess whether the proportion of participants with a favourable efficacy outcome on 
Regimen C, the fully oral regimen, is non-inferior to that on Regimen B (with moxifloxacin or 
levofloxacin) at Week 76, using a 10% margin of non-inferiority 
 
3.2.2 Stage 2 secondary objectives: 
 
The secondary objectives of the Stage 2 comparison of the STREAM trial are: 
 
1. To assess whether Regimen C is superior to Regimen B with regards to the proportion of 
participants with a favourable efficacy outcome at Week 76 and Week 132 (if non-
inferiority is demonstrated at either time-point) 
2. To assess whether Regimen C is non-inferior to Regimen B with regards to the proportion 
of participants with a favourable efficacy outcome at Week 132 
3. To compare the efficacy of 40 weeks of bedaquiline in combination with the other drugs 
of Regimen C with Regimen B during treatment and follow-up 
4. To compare the efficacy of 28 weeks of bedaquiline in combination with the other drugs 
of Regimen D with Regimen B during treatment and follow-up 
5. To compare the safety, including the effect on mortality and tolerability, of 40 weeks of 
bedaquiline in combination with the other drugs of Regimen C with Regimen B during 
treatment and follow-up. 


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6. To compare the proportion of participants who experience grade 3 or greater adverse 
events during treatment or follow-up in Regimen C as compared to Regimen B  
7. To estimate the difference between Regimen C and Regimen Bmox in the proportion of 
participants with a favourable efficacy outcome at Week 76 and Week 132 
8. To estimate the difference between Regimen C and Regimen Blev in the proportion of 
participants with a favourable efficacy outcome at Week 76 and Week 132  
9. To estimate the difference between Regimen C and Regimen A in the proportion of 
participants with a favourable efficacy outcome at Week 132 
10. To estimate the difference between Regimen B and Regimen A in the proportion of 
participants with a favourable efficacy outcome at Week 132 
11. To estimate the difference between Regimen D and Regimen B in the proportion of 
participants with a favourable efficacy outcome at Week 76 and Week 132  
12. To estimate the difference between Regimen D and Regimen A in the proportion of 
participants with a favourable efficacy outcome at Week 132  
13. To investigate the safety, including the effect on mortality and tolerability of 28 weeks of 
bedaquiline in combination with the other drugs of Regimen D compared to Regimen B 
during treatment and follow-up. 
14. To compare the proportion of participants who experience grade 3 or greater adverse 
events during treatment or follow-up in Regimen B as compared to Regimen A 
15. To compare the proportion of participants who experience grade 3 or greater adverse 
events during treatment or follow-up in Regimen C as compared to Regimen Bmox 
16. To compare the proportion of participants who experience grade 3 or greater adverse 
events during treatment or follow-up in Regimen C as compared to Regimen Blev 
17. To compare the proportion of participants who experience grade 3 or greater adverse 
events during treatment or follow-up in Regimen D as compared to Regimen B  
18. To investigate the safety, including the effect on mortality and tolerability, of bedaquiline-
containing regimens compared to Regimen B during treatment and follow-up. 
19. To investigate the effect on mortality of bedaquiline-containing regimens compared to 
non-bedaquiline containing regimens. 
20. To evaluate the pharmacokinetics of bedaquiline and M2 in all participants randomised to 
Regimen C or Regimen D at sites selected for the PK study and assess 
pharmacokinetic/pharmacodynamics relationships of bedaquiline for safety and efficacy 
21. To evaluate the pharmacokinetics of bedaquiline and M2 in a subset of HIV co-infected 
participants on Regimen C or Regimen D receiving antiretroviral treatment 
22. To evaluate the 4β-hydroxycholesterol/cholesterol ratio as a measure of cytochrome P450 
3A (CYP3A) activity in Regimen C and Regimen D as compared to Regimen B. 
23. To compare the economic costs incurred during treatment by patients (transport and food 
costs for attending DOTs and patient assessment visits, food supplements costs and 
income loss) and by the health system (inpatient stay, laboratory tests, medication, staff, 
consumables and serious adverse events costs) in Regimen B and C. To calculate 
economic costs associated with regimen D, and compare these with regimen B, for those 
sites where this is possible. 
24. To compare the proportions of participants having undergone lung surgery (resection or 
pneumonectomy) by Week 76 and Week 132 in Regimen C and Regimen D as compared 
to Regimen B. 


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25. To compare the development of resistance to background drugs, especially resistance 
leading to the development of pre-XDR or XDR strains of TB in Regimen C and Regimen D 
as compared to Regimen B. 
26. To investigate the development of increased MIC to bedaquiline in regimens C and D. 
 
3.3 Outcome measures 
 
3.3.1 Stage 1 
The primary efficacy outcome measure of the Stage 1 comparison is the proportion of patients with 
a favourable outcome at Week 132 as defined in section 11, Statistical Considerations.   
 
For the Stage 1 comparison, the primary safety outcome measure is the proportion of patients 
experiencing a grade 3 or greater adverse event, as defined by the DAIDS criteria20, during treatment 
and follow-up. 
 
Secondary outcome measures for the Stage 1 comparison include:  
 
Time to sputum smear conversion 
 
Time to sputum culture conversion 
 
All-cause mortality during treatment or follow-up 
 
Change of regimen for adverse drug reactions 
 
Number of serious adverse reactions occurring on treatment and during the follow-up period 
 
Adherence to treatment. 
 
Additional exploratory outcome measures for the Stage 1 comparison include:  
 
Time to unfavourable efficacy outcome  
 
Time to cessation of clinical symptoms based on PI assessment 
 
In selected sites, costs and acceptability of Regimens A and B to stakeholders will be analysed in 
terms of: 
 
Costs to the health system 
 
Household costs 
 
Patient treatment and support experiences 
 
Health worker experiences. 
 
3.3.2 Stage 2 
The primary efficacy outcome measure of the Stage 2 comparisons is the proportion of patients with 
a favourable outcome at Week 76 as defined in section 11, Statistical Considerations.   
 
There will be two sensitivity analyses of the primary outcome: 
 
Proportion of patients with a favourable outcome at Week 76 as defined in section 11, 
Statistical Considerations, but ignoring substitutions of levofloxacin for moxifloxacin and vice 
versa as treatment changes. 
 
Proportion of patients with a favourable outcome at Week 76 as defined in section 11, 
Statistical Considerations of protocol v10.0 or earlier i.e. not counting starting linezolid alone 
as unfavourable. 


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Secondary outcome measures of the Stage 2 comparisons include:  
 
Time to failure or relapse   
 
Time to sputum culture conversion 
 
Time to sputum smear conversion 
 
Time to unfavourable efficacy outcome 
 
Efficacy status (unfavourable outcome) at week 132 
 
All-cause mortality during treatment or follow-up 
 
Proportion of patients experiencing a grade 3 or greater adverse event, as defined by the 
DAIDS criteria, during treatment and follow-up  
 
Change of regimen for adverse drug reactions 
 
Number of adverse events occurring on treatment and during the follow-up period  
 
Pharmacokinetic outcomes 
 
Adherence to treatment 
 
Additional exploratory outcome measures of the Stage 2 comparisons include:  
 
The proportion of participants in each category who meet the WHO classification of outcome 
as applicable at the time of analysis  
 
Proportion of participants with a successful TB outcome at Week 132, irrespective of treatment 
changes 
 
Time to cessation of clinical symptoms based on PI assessment 
 
In selected sites, the regimens will be analysed in terms of: 
 
Costs to the health system 
 
Patient direct and indirect costs 
 
 


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4 SELECTION OF SITES 
Country selection is based on background disease burden of TB, MDR-TB, and TB-HIV co-infection. 
Sites within countries are selected to ensure sufficient numbers of MDR-TB cases to meet recruitment 
targets.  Site suitability, based on the listed criteria in Section 4.1, will be evaluated during pre-trial 
and feasibility assessments. 
 
4.1 Site inclusion criteria 
 
Participating sites are required to meet the following criteria: 
 
 
Experience in treating MDR-TB patients 
 
Support from the Tuberculosis Control Programme at national or regional level 
 
A local Principal Investigator (PI) who is a TB specialist and experienced in the treatment of 
MDR-TB who will oversee the patients throughout the trial (there may be more than one PI 
per country) 
 
Suitable treatment site staff and facilities 
 
Treatment site staff willing to recruit all eligible patients into the trial (site would ideally 
function as a single coordinating/recruiting facility and work with satellite sites for treatment 
and follow-up) 
 
Acceptable plans for close supervision of patients in treatment and follow-up 
 
Willing to offer HIV testing to all patients wishing to participate in the trial and routinely 
available HIV clinical management services (including provision of antiretroviral therapy (ART) 
 
A network of well-functioning AFB smear microscopy laboratories and a reference laboratory 
already performing cultures, with a system of quality assurance 
 
Ability to export sputum culture for testing to ITM, Antwerp, if required 
 
Ability to get authorisation of importation for the medicines which will be procured and 
delivered by The Union/Vital Strategies. 
 
Agreement to use specified standardised bacteriological methods 
 
Availability of rapid genotypic line-probe drug susceptibility testing (LPA DST) for rifampicin, 
second-line injectables and fluoroquinolones of the required quality (or ability to quickly build 
capacity for this testing) 
 
Acceptable infection control procedures consistent with WHO guidance. 
 
 
 


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5 SELECTION OF PATIENTS 
Patients will be recruited into the trial from tuberculosis clinics in the catchment area of the main site. 
The target population is patients with pulmonary TB and evidence of resistance to at least rifampicin21 
(including patients sensitive to isoniazid).  
  
5.1 Patient inclusion criteria 
A patient will be eligible for randomisation into the study (Stage 1 or Stage 2) if he/she: 
1. Consent 
1.1 Is willing and able to give informed consent to participate in the trial treatment and follow-
up (signed or witnessed consent if the patient is illiterate). If the patient is below the age 
of consent (according to local regulations), the parent/caregiver should be able and willing 
to give consent, and the patient be informed about the study and asked to give positive 
assent, if feasible  
2. Age 
2.1 Is aged 18 years or older (Stage 1) or 15 years or older (Stage 2)  
3. AFB or GeneXpert results 
3.1 Has a positive AFB sputum smear result at screening (at least scanty), or a positive 
GeneXpert result (with a cycle threshold (Ct) value of 25 or lower) from a test performed 
at screening or from a test performed within the four weeks prior to screening 
4. Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype22), 
GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at 
screening or from a test performed within the four weeks prior to screening 
5. Is willing to have an HIV test and, if positive, is willing to be treated with ART in 
accordance with the national policies but excluding ART contraindicated for use with 
bedaquiline 
6. Is willing to use effective contraception: pre-menopausal women or women whose last 
menstrual period was within the preceding year, who have not been sterilised must agree 
to use a barrier method or an intrauterine device unless their partner has had a 
vasectomy; men who have not had a vasectomy must agree to use condoms. In Stage 2 
pre-menopausal women or women whose last menstrual period was within the preceding 
year, who have not been sterilised must agree to use two methods of contraception, for 
example a hormonal method and a barrier method 
7. Resides in the area and expected to remain for the duration of the study. 
 
In addition to the criteria above, for Stage 2 only, a patient will be eligible for randomisation to the 
study provided he/she: 
 
8. Has had a chest X-ray that is compatible with a diagnosis of pulmonary TB (if such a chest 
X-ray taken within 4 weeks of randomisation is available, a repeat X-ray is not required) 
9. Has normal K+, Mg2+ and corrected Ca2+ at screening. 
 
 
 
 
 


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5.2 Patient exclusion criteria 
A patient will not be eligible for randomisation into the study (Stage 1 or Stage 2) if he/she: 
1. Is infected with a strain of M. tuberculosis resistant to second-line injectables by line probe 
assay (Hain Genotype22) from a test performed at screening or from a test performed within 
the four weeks prior to screening 
2. Is infected with a strain of M. tuberculosis resistant to fluoroquinolones by line probe assay 
(Hain Genotype22) from a test performed at screening or from a test performed within the 
four weeks prior to screening 
3. Has tuberculous meningitis or bone and joint tuberculosis 
4. Is critically ill, and in the judgment of the investigator, unlikely to survive more than 4 months 
5. Is known to be pregnant or breast-feeding 
6. Is unable or unwilling to comply with the treatment, assessment, or follow-up schedule 
7. Is unable to take oral medication 
8. Has AST or ALT more than 5 times the upper limit of normal for Stage 1, and AST or ALT 
more than 3 times the upper limit of normal for Stage 2 
9. Has any condition (social or medical) which in the opinion of the investigator would make 
study participation unsafe 
10. In the investigator’s opinion the patient is likely to be eligible for treatment with bedaquiline 
according to local guidelines due to a pre-existing medical condition, such as hearing loss or 
renal impairment 
11. Is taking any medications contraindicated with the medicines in any trial regimen 
12. Has a known allergy to any fluoroquinolone antibiotic 
12.1 
Has previously experienced any serious adverse reaction when taking a quinolone or 
fluoroquinolone 
13. Is currently taking part in another trial of a medicinal product 
14. Has a QT or QTcF interval at screening or immediately prior to randomisation of more than 
or equal to 500 ms for Stage 1, and more than or equal to 450 ms for Stage 2 
 
In addition to the criteria above, for Stage 2 only, a patient will not be eligible for randomisation to 
the study if he/she: 
15. Has experienced one or more of the following risk factors for QT prolongation: 
 
A confirmed prolongation of the QT or QTcF more than or equal to 450 ms in the 
screening ECG (retesting to reassess eligibility will be allowed once using an 
unscheduled visit during the screening phase) 
 
Pathological Q-waves (defined as Q-wave more than 40 ms or depth more than 0.4-
0.5 mV) 
 
Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome) 
 
Electrocardiographic evidence of complete or clinically significant incomplete left 
bundle branch block or right bundle branch block 
 
Evidence of second- or third-degree heart block 
 
Intraventricular conduction delay with QRS duration more than 120 ms 
 
Bradycardia as defined by sinus rate less than 50 bpm 
 
Personal or family history of Long QT Syndrome 
 
Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with 
the exception of sinus arrhythmia 
 
Syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic 
causes) 


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 
Risk factors for Torsades de Pointes (e.g., heart failure, hypokalaemia, or 
hypomagnesemia) 
16. Has received treatment for MDR-TB in the 12 weeks prior to screening, other than the 
maximum permitted treatment specified in Section 5.2.1 
17. Has a history of cirrhosis and classified as Child’s B or C at screening or a bilirubin more than 
1.5 times upper limit of normal. 
18. Has an estimated creatinine clearance (CrCl) less than 30 mL/min based on the Cockcroft-
Gault equation 
19. Is HIV positive and has a CD4 count less than 50 cells/mm3   
20. Has pancreatic amylase elevation more than two times above the upper limit of normal 
21. Has a history of alcohol and/or drug abuse 
22. Has had previous treatment with bedaquiline 
23. Has taken rifampicin in the seven days prior to randomisation 
24. There has been a delay of more than four weeks between the screening consent and 
randomisation 
25. Is an employee or family member of the investigator or study site staff with direct involvement 
in the proposed study. 
 
5.2.1 MDR-TB treatment prior to screening 
Patients who are AFB smear positive who have received second-line treatment as part of an MDR-
TB treatment regimen in the 12 weeks prior to screening are permitted to have had up to a 
maximum of four weeks treatment.  However, if they have received more than seven days 
treatment they are only eligible for the trial if FDA vital staining of their sputum is positive.  
 
5.2.2 MDR-TB treatment between screening and randomisation 
MDR-TB treatment should not be initiated or continued between screening and randomisation 
unless clinically necessary or mandated by local policy, and if used may not exceed three weeks. 
5.3 Number and source of patients 
Stage 1 
A minimum of 400 participants from sites in four to five countries will be randomised to either 
Regimen A or Regimen B in the ratio 1:2 (i.e. 133 allocated to Regimen A, and 267 allocated to 
Regimen B) in Stage 1. 
 
Stage 2 
At the start of Stage 2 randomisation was to Regimen A, Regimen B, Regimen C and Regimen D in a 
ratio of 1:2:2:2 to a maximum of 1155 patients from sites in a number of countries.  From Version 
8.0 of the protocol onwards, the aim is to randomise at least 200 patients to each of Regimens B and 
C.  In addition, patients randomised to Regimen A or Regimen D prior to the implementation of 
Version 8.0 of the protocol will be part of the trial and therefore the overall sample size will be greater 
than 400 but is expected to be less than 800 patients.  
 
5.4 Screening procedures 
 
Written informed consent/assent must be obtained from the patient before any protocol-specific 
screening procedures are carried out. Each consenting/assenting patient will be assigned a study 
number which will be used to identify the patient throughout the study. 


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5.4.1 Screening visit 
At the first (screening) visit, the study, including potential risks and benefits of joining the trial, will 
be explained to prospective participants. This will include a general overview of the trial purpose and 
procedures as well as the samples to be collected at this visit. Each patient will be asked to sign (or 
provide a thumb print in the presence of a witness if illiterate) for the screening procedures and will 
be given a copy of the signed informed consent form and a patient information sheet to take home.  
 
After giving consent/assent for screening, patients will be assigned a unique study number by 
entering their name on to the next line of a screening register and evaluated for their eligibility 
according to the inclusion and exclusion criteria.  
 
Patients who at the time of screening have documented results of second line drug (SLD) resistance 
tests that provide evidence of resistance to fluoroquinolones or second-line injectables are not eligible 
for the trial.  
 
The following investigations will be undertaken: 
 
 
Sputum samples obtained for:  
 
AFB smear 
 
Culture 
 
Rifampicin resistance testing by LPA or GeneXpert (unless there is a phenotypic result from 
another reliable source indicating rifampicin resistance from a sputum sample taken no 
longer than four weeks from date of screening) 
 
Line probe assay (Hain Genotype22) for second-line injectable and fluoroquinolone, if 
rifampicin resistant, from a sputum sample taken no more than four weeks from date of 
screening) 
 
Blood samples obtained for:  
 HIV antibodies. In addition to the antibody test at the central lab, to minimise delays in 
randomisation local testing may be used (2 separate rapid tests plus a third test in the case 
of discordant results). Patients with a documented positive HIV result who are not receiving 
ART will need confirmation of this result by a single rapid test (plus a second rapid test in 
the case of discordance) prior to randomisation. Known HIV-positive patients who are 
receiving ART do not need further local rapid tests prior to randomisation. However, all 
patients, without exception, must have a sample for HIV antibodies sent to the central lab. 
 CD4 count and viral load (unless the patient is HIV negative) 
 Liver function tests (AST and ALT) 
 Pancreatic amylase 
 Serum potassium, calcium and magnesium 
 Creatinine clearance 
 TSH  
 Thyroxine or free thyroxine 
o Urine sample for HCG pregnancy test 
o 12 lead ECG  
o Audiometry 
 
 


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5.4.2 Repeat testing and re-screening 
 
Inconclusive LPA results at screening should be repeated on a second sample collected from the 
patient as soon as possible. Confirmation of rifampicin resistance is required before randomisation; 
patients with inconclusive LPA results for second-line drugs may be included if otherwise eligible (see 
Patient Management Guide for further details).   
 
In the event that a patient is found to be ineligible based on laboratory abnormalities at screening, 
abnormal tests may be repeated if there is clinical suspicion that the laboratory abnormality may 
resolve (with or without intervention). Re-tests must be conducted (and results received) within four 
weeks of screening consent and before randomisation. 
 
If the laboratory results remain abnormal on re-testing or if the re-tests cannot be done within four 
weeks of screening consent, the patients may still undergo a full re-screen in which the entire 
screening process must be repeated. 
 
Patients found not to be eligible for the STREAM trial due to a potentially modifiable reason or timing 
of previous treatment may also be rescreened once.  In addition, if a patient has not been randomised 
within four weeks of the start of screening, then they become ineligible for the trial but may be 
rescreened once.   
 
A patient who fails a second screening is permanently excluded from trial participation.  Patients who 
are rescreened should be reconsented/assented and given a new screening number for the second 
screening.  All patients who are not eligible for the STREAM trial will be managed according to local 
routine practice.   
 
If a patient is screened successfully and satisfies the criteria to participate in the STREAM trial, the 
patient should be randomised no more than 4 weeks after screening consent. 
 
5.5 Late identification of drug-resistance or drug-sensitivity 
 
5.5.1 Late identification of fluoroquinolone/injectable-resistance 
In sites that currently undertake phenotypic second-line drug susceptibility resistance testing (DST), 
results from pre-treatment samples that provide evidence of fluoroquinolone, or second-line 
injectable resistance may become available after randomisation.  In such cases, the patient’s clinical 
progress should be taken into account before making any changes on the basis of the results, in 
consultation with the central clinical team.  However, if patients are found to have XDR-TB (defined 
as resistance to fluoroquinolones and second-line injectables from phenotypic DST) these patients 
should be withdrawn from trial treatment and treated according to national guidelines. 
 
5.5.2 Late identification of rifampicin-sensitivity 
Any patients whose initial TB infection is found to be sensitive to rifampicin after they have been 
randomised, as confirmed by rpoB sequencing,23 should have their treatment amended 
appropriately and be followed up according to the trial schedule.  
 
 


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6 RANDOMISATION PROCEDURE 
6.1 Evaluations at the randomisation visit 
Patients will need to be re-assessed for eligibility when returning after their screening visit. The time 
between the screening consent/assent and randomisation visits should be kept as short as logistically 
possible, but should be no more than four weeks; those returning after four weeks will have to be 
re-screened prior to randomisation. Patients who have been on MDR-TB treatment since screening 
and have had more than three weeks of treatment between the screening consent and randomisation 
are not eligible for trial participation (see section 5.2.1) 
 
Patients attending the randomisation visit will be given further information about the trial and what 
would be expected of them in terms of follow-up visits and procedures. If they are still willing to take 
part, they will be asked to sign a participation informed consent form (or give a thumb print in the 
presence of a witness if illiterate) and will be given a signed copy to take home together with the 
Patient Information Sheet.  Patients below the age of consent according to local regulations require 
the consent of a parent or caregiver and will be asked to give their assent to participation. Patients 
who are ineligible or do not wish to take part will be referred to the NTP for further management.  
 
Once an eligible patient has given consent/assent to participate in the trial, the following will be done: 
o Interview to obtain and confirm demographic details, medical history (prior diagnoses and 
treatment, concomitant disease and medication, smoking history, and current symptoms) and 
key information on asset ownership to document socio-economic status will be requested at 
sites participating in the health economic component of the study 
o Record contact information  
o Record alcohol use 
o Clinical examination including height, weight and vital signs (temperature, systolic and 
diastolic blood pressure (BP) and pulse rate) 
o Visual acuity test 
o Collect at least two spot sputum samples with a third early morning sample if possible (for 
smear and culture) 
o Urinalysis (dipstick in Stage 1; via urine sample to central laboratory in Stage 2) 
o A urine pregnancy test (if pre-menopausal woman) 
o Serum creatinine, serum potassium, blood glucose, haemoglobin,  
o Posteroanterior (PA) chest X-ray, unless a good quality film is available that has been taken 
no longer than four weeks prior to randomisation; if possible this should be a digital x-ray 
o 12-lead ECG immediately before randomisation and at 4 hours after the first dose of allocated 
trial treatment. 
 
In addition to the above, in Stage 2 the following investigations will also be undertaken: 
o Other tests listed in the serum chemistry panel in section 8.2 
o Hepatitis A, B, and C  
 
If any of the ECGs performed pre-randomisation show a QT or QTcF greater than or equal to 450 ms 
then the patient will be ineligible for the trial. 
 
At sites participating in sample storage, all patients providing their consent/assent to participate in 
the study will also be asked to provide their consent/assent for the bio storage of additional specimens 


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for future investigation of potential predictors of disease outcome or effects of tuberculosis treatment. 
Those providing their consent/assent for bio storage of their specimens will be requested to give 
blood (at randomisation and at 16 weeks).  If human genetic testing is to be performed, specific 
consent will be sought. 
 
6.2 Allocation of treatment (following randomisation) 
In each stage of the trial, patients will be randomised using a web-based randomisation system. 
Access to the web-based system will be controlled through an authorised username and password. 
Before treatment allocation the patient's eligibility will need to be confirmed, their site and HIV 
status, and CD4 count entered into the database.  Local laboratory results can be used to 
determine a patient’s HIV status and CD4 count for randomisation, unless central laboratory results 
are available at the time of randomisation. 
 
Separate randomisation lists for each combination of strata will be prepared in advance, for each site 
according to whether they are participating in Stage 1 only, Stage 1 and 2, or Stage 2 only, by a 
statistician independent of the study, using varying block sizes. Should web access not be available 
at the time of randomisation, a manual alternative using sealed envelopes will be provided. 
 
Stage 1 (before Stage 2 begins, or for sites only participating in Stage 1) 
Patients will be randomised to Regimen A or Regimen B.  Randomisation will be in a 1:2 ratio in 
favour of Regimen B to allow more data on efficacy and safety to be collected on this regimen. 
Randomisation will be stratified by (1) site, (2) HIV status for sites with high TB-HIV co-infection 
rates.  
 
Stage 2  
Prior to the implementation of Version 8.0 of the protocol, in countries where the local NTP has no 
imminent plans to adopt a short regimen, in keeping with the WHO 2016 MDR-TB guidelines, 
patients will be randomised to one of four regimens, Regimen A, Regimen B or Regimen C, or 
Regimen D in a ratio of 1:2:2:2. In countries where the local NTP has adopted or has imminent 
plans to adopt a short regimen in keeping with the WHO 2016 guidelines and it has been agreed 
with the STREAM Trial Management Group that randomisation to Regimen A will not be offered, 
patients will be randomised to one of three regimens (Regimen B, Regimen C or Regimen D) in a 
ratio of 1:1:1 (see Section 2.1.4).  When Version 8.0 of the protocol has been implemented, 
randomisation to Regimen D will be discontinued as will Regimen A if it has not already been 
discontinued.  
 
Randomisation will be stratified by (1) site, (2) HIV status & CD4 count status (i.e. three categories: 
HIV-negative, HIV-positive with low CD4 count of 50 to less than 350 cells/mm3, or HIV-positive with 
high CD4 count of more than or equal to 350 cells/mm3), for all sites.  
 


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7 TREATMENT OF PATIENTS  
7.1 Introduction 
During Stage 1 of the STREAM trial, all patients will be randomised to receive either Regimen A or 
Regimen B.  In Stage 2 patients may be allocated one of four regimens  (Regimen A, Regimen B, 
Regimen C, or Regimen D).  However, with Version 8.0 of the protocol patients will no longer be 
randomised to Regimen A or Regimen D. 
 
Some sites may recruit only to Stage 1, other sites may only participate in Stage 2 and some will 
participate in both.    
7.2 Trial interventions 
7.2.1 Stage 1 
The control regimen for the Stage 1 comparison, Regimen A, is the locally-used WHO 2011 long MDR-
TB regimen. Country- or site-specific regimens are described in the STREAM Patient Management 
Guide. 
 
The investigative regimen for the Stage 1 comparison is Regimen Bmox, and consists of moxifloxacin, 
clofazimine, ethambutol and pyrazinamide given for 40 weeks, supplemented by kanamycin, isoniazid 
and prothionamide in the first 16 weeks.  
 
All drugs are given daily (seven days a week), except for kanamycin which is initially given daily and 
then thrice-weekly from Week 12 onwards in Regimen B. After the first 4 weeks of treatment has 
been completed, in sites where it is not possible to administer kanamycin seven days a week to 
outpatients, the dose may be changed to six days a week. These sites may then administer kanamycin 
six days a week for weeks 5-12 of treatment and reduce the frequency to three days a week from 
week 12 onwards. 
 
The intensive phase should be extended from 16 to 20 or 24 weeks for patients whose smear has 
not converted by 16 or 20 weeks, respectively, as described in section 7.3.2.  
Table 1: Regimen Bmox doses (for patients randomised under versions of the protocol prior to 
Version 8.0) 
Product 
Weight group 
Less than 33 kg 
33 kg to 50 kg 
More than 50 kg 
Moxifloxacin 
400 mg 
600 mg 
800 mg 
Clofazimine 
50 mg 
100 mg 
100 mg 
Ethambutol 
800 mg 
800 mg 
1200 mg 
Pyrazinamide 
1000 mg 
1500 mg 
2000 mg 
Isoniazid 
300 mg 
400 mg 
600 mg 
Prothionamide 
250 mg 
500 mg 
750 mg 
Kanamycin 
15 mg per kilogram body weight (maximum 1g) 


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7.2.2 Stage 2 
The control regimen for the primary comparison of Stage 2 is Regimen B. For all patients 
randomised according to versions of the protocol prior to Version 8.0, the details are given above in 
section 7.2.1. For patients randomised to Regimen B after Version 8.0 has been implemented, a 
modified version of the regimen will be used in which moxifloxacin is replaced by levofloxacin 
according to the doses in Table 2 below; all other details of the regimen and its administration are 
unaltered. This regimen is referred to as Regimen Blev. 
 
 Patients randomised to Regimen B after Version 10.0 has been implemented will be treated with 
amikacin instead of kanamycin in all sites in which the national TB program is using amikacin for 
patients requiring an injectable agent, and amikacin is available for the trial. Kanamycin will 
continue to be used until the transition to amikacin takes place within each country programme.   
 
Patients should be treated with the fluoroquinolone and injectable allocated at randomisation unless 
there is a clinical or operational reason to make a change.   
 
Table 2: Regimen Blev doses (for patients randomised under Version 8.0 of the protocol 
onwards) 
Product 
Weight group 
Less than 33 kg 
33 kg to 50 kg 
More than 50 kg 
Levofloxacin 
750 mg 
750 mg 
1000 mg 
Clofazimine 
50 mg 
100 mg 
100 mg 
Ethambutol 
800 mg 
800 mg 
1200 mg 
Pyrazinamide 
1000 mg 
1500 mg 
2000 mg 
Isoniazid 
300 mg 
400 mg 
600 mg 
Prothionamide 
250 mg 
500 mg 
750 mg 
Kanamycin/amikacin* 
15 mg per kilogram body weight (maximum 1g) 
 
*With Version 10.0 amikacin or kanamycin may be used 
 
The investigative regimens for the Stage 2 comparisons are Regimen C and Regimen D.   
 
Regimen C is an all-oral regimen that is a modification of Regimen B, and consists of bedaquiline, 
clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks, supplemented by 
isoniazid and prothionamide in the first 16 weeks (intensive phase).  All drugs are given daily (seven 
days a week), except for bedaquiline which is given daily for the first two weeks and then thrice-
weekly from Week 2 onwards.  The intensive phase should be extended from 16 to 20 or 24 weeks 
for patients whose smear has not converted by 16 or 20 weeks, respectively, as described in section 
7.3.2.  If the intensive phase is extended beyond 16 weeks, then the overall treatment time will be 
extended except for bedaquiline, which will not be given for longer than 40 weeks in total. 
 
 


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42 
Table 3: Regimen C doses, given daily unless otherwise stated 
 
Product 
Weight group 
Less than 33 kg 
33 kg to 50 kg 
More than 50 kg 
Bedaquiline  
400 mg once daily for first 14 days/200 mg thrice weekly 
thereafter 
Levofloxacin 
750 mg 
750mg 
1000 mg 
Clofazimine 
50 mg 
100 mg 
100 mg 
Ethambutol 
800 mg 
800 mg 
1200 mg 
Pyrazinamide 
1000 mg 
1500 mg 
2000 mg 
Isoniazid 
300 mg 
400 mg 
600 mg 
Prothionamide 
250 mg 
500 mg 
750 mg 
 
Regimen D is a six-month regimen that is a modification of Regimen B, and consists of bedaquiline, 
clofazimine, levofloxacin, and pyrazinamide given for 28 weeks, supplemented by kanamycin and 
isoniazid in the first eight weeks (intensive phase). All drugs are given daily (seven days a week) 
except for bedaquiline and isoniazid which are given daily for the first two weeks and then thrice-
weekly from Week 2 onwards. After the first 4 weeks of treatment has been completed, in sites where 
it is not possible to administer kanamycin seven days a week to outpatients the dose may be changed 
to six days a week from weeks 5-8.  The intensive phase should be extended from 8 to 12 weeks and 
12 to 16 weeks for patients with a smear positive of 2+ or more at 8 or 12 weeks, respectively, as 
described in section 7.3.2.  If the intensive phase is extended, kanamycin will be given then thrice-
weekly from Week 8 onwards. 
 
Table 4: Regimen D doses, given daily unless otherwise stated 
Product 
Weight group 
Less than 
33 kg 
33 kg to 
less than 
40 kg 
40 kg to 
50 kg 
More than 
50 kg to 
60 kg 
More than 
60 kg 
Bedaquiline  
400 mg once daily for first 14 days/200 mg thrice weekly thereafter  
Levofloxacin 
750 mg 
750 mg 
1000 mg 
Clofazimine 
50 mg 
100 mg 
100 mg 
Pyrazinamide 
1000 mg 
1500 mg 
2000 mg 
Isoniazid 
400 mg 
500 mg 
600 mg 
800 mg 
900 mg 
Daily for the first 14 days, thrice-weekly thereafter for the duration of the 
intensive phase 
Kanamycin 
15 mg per kilogram body weight (maximum 1g) 
*Note that in Regimen D isoniazid is administered daily for the first 14 days and then thrice weekly for the 
remainder of the intensive phase  
 


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Regimen D uses a higher dose of isoniazid than in the other treatment regimens in the trial.  The 
dose of isoniazid has been kept to a maximum dose of 15 mg/kg (given daily for the first 14 days 
only and then reduced to thrice-weekly dosing).  At this dose, isoniazid is unlikely to cause excessive 
adverse effects, the intention being to reach peak serum levels above the median resistance MIC of 
around 5 µg/ml, shown by the majority of strains with isoniazid resistance (i.e. the katG mutations) 
and not only the rarer strains with very low MICs due to inhA mutations  
 
During Stage 2, patients allocated to Regimen B, Regimen C or Regimen D will be prescribed 
pyridoxine to help minimize the risk of isoniazid-related peripheral neuropathy. 
 
All drugs should be given under directly observed treatment (DOT) by a treatment supervisor. 
Treatment supervisors may be clinic staff or family members or other members of the community, 
depending on local circumstances. At the end of the intensive phase of all the regimens, if the 
patient’s weight has increased drug doses should be adjusted to allow for changes in patient’s weight.  
7.2.3 Medicines supplies 
Supplies for Regimen A will be provided by the participating countries. The sponsor/funders will 
distribute the drug requirements for Regimen B, Regimen C, and Regimen D.  Bedaquiline will be 
supplied as 100mg oral tablets from commercial stock manufactured for Janssen Products, LP.  
Details of drug supplies, storage and distribution are provided in the STREAM Pharmacy Plan. 
7.2.4 Treatment cards 
Following randomisation, the patient and/or a treatment supervisor will be given the relevant 
Treatment Card and a prescription to take to the pharmacy. The treatment supervisors will be 
instructed about observing the patient swallowing their oral medication according to intake schedule 
(directly observed treatment) and recording treatment taken on the treatment card. Treatment Cards 
should be returned at each visit and a new card issued. 
 
7.3 Treatment procedures  
7.3.1 Dispensing and supervision of medicines 
Local policy will be followed as to whether the patient will be admitted to hospital during the intensive 
phase irrespective of the regimen allocated. 
 
All medicines in Regimen B, Regimen C and Regimen D should be given according to the intake 
schedule under strict conditions of direct observation of treatment (seen to be swallowed) by a trained 
treatment supervisor for the whole treatment period. For Regimen A, sites will be strongly encouraged 
to follow the same standard. Full details of the medicines, regimen, including dosages, for each 
patient and of the procedure to be followed are also given on each Treatment Card.  
 
The pharmacy staff will maintain drug accountability logs and provide, on a regular basis, a 
reconciliation report (between products delivered, in stock, dispensed and returned). 
 


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7.3.2 Transition from intensive to continuation phase in the regimens 
For patients allocated to Regimen B, Regimen C, or Regimen D the following algorithm will be used 
in Stage 1 and Stage 2 to determine when a patient can proceed from the intensive to the continuation 
phase.  
 
 


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Figure 9: Transition from intensive to continuation phase for patients on Regimen B and 
Regimen C 
 
 
Note: smear results based on regular AFB ZN or auramine staining and not FDA vital staining. 
 
Patients randomised to Regimen B or Regimen C will receive 40 weeks of treatment (16 weeks 
intensive phase plus 24 weeks continuation phase). In the event of positive (at least "scanty" on the 
IUATLD/WHO scale) AFB smear at week 16, the drugs in the intensive phase of these regimens 
should be extended by 4 weeks. This extension of treatment by 4 weeks should be repeated at week 
20 should the smear remain positive, allowing a maximum duration of the intensive phase of 24 
weeks treatment and a maximum total duration of 48 weeks treatment (except for bedaquiline, which 
will be given for a maximum duration of 40 weeks regardless of whether the regimen is extended).  


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Figure 10: Transition from intensive to continuation phase for patients on Regimen D 
 
 
Patients randomised to Regimen D will receive 28 weeks of treatment (eight weeks intensive phase 
plus 20 weeks continuation phase).  As Regimen D has shorter intensive phase duration than the 
other treatment regimens, it is expected that more patients would have a smear positive result at 


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the end of the intensive phase than in the other regimens due to the shorter time that patients will 
have been on treatment to that point.  Therefore, the less stringent criterion of a smear positive 
result of 2+ is sufficient for patients to require an extension of the intense period, i.e. patients can 
have a positive smear of 1+ and still advance on to the continuation phase, as opposed to Regimen 
B and Regimen C for which any positive smear result would result in an extension to the intensive 
phase. In the event of a 2+ or more positive smear at Week 8, the drugs in the intensive phase of 
the regimen should be extended by 4 weeks, and this extension should be repeated at Week 12 
should the smear result remain 2+, allowing a maximum total duration of 36 weeks treatment.   
 
The procedure for transition from the intensive to the continuation phase in Regimen A will be 
according to local policy. 
 
7.3.3 Procedure following missed treatment 
At the discretion of the investigator, any days missed in either the intensive or the continuation phase 
may be made up by extending this phase of the regimen by the number of days, with the exception 
of bedaquiline. Although small amounts of missed bedaquiline may be made up, any patient who has 
missed more than 30 days should not be given any further bedaquiline.  
 
For managing patients who have had a treatment interruption, refer to Section 8.5.1. 
 
7.3.4 Adherence assessment and counselling    
At each visit, patients will be counselled about the importance of taking their medication and the 
dangers of developing further resistance if they fail to do so 
 
7.3.5 Pregnancy & breastfeeding 
It is possible that some of the drugs in the regimens, if given to a pregnant woman, will harm the 
unborn child. As pregnant women in this study population have alternative treatment options, they 
should not enrol in this trial; neither should women who plan to become pregnant during the trial. 
Women who could become pregnant must use appropriate contraception (as defined in the inclusion 
criteria in section 5) while on treatment. Women who are pre-menopausal, or whose last menstrual 
period was less than one year ago, will be asked to have a pregnancy test before taking part to 
ensure that they are not pregnant. Any woman who finds that she has become pregnant while taking 
part in the trial should immediately tell her study doctor who will contact a member of the STREAM 
clinical team to discuss management of the patient.  
All pregnancies occurring in a patient or partner of a patient, in the trial, at any point during treatment 
or follow-up will be followed for outcome even if the pregnancy continues beyond 132 weeks from 
randomisation. 
 
Women taking part in Stage 2 of the trial, and are recruited to Regimen C or Regimen D, should not 
breastfeed when taking bedaquiline, as the effects to their new-born child are unknown. Women 
who have a new-born child should consult their physician about the best way to feed their child. 
 
 


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7.4 HIV 
 
Patients who are known to be HIV infected or who are found to be HIV infected at trial screening will 
be recruited into the study and follow the routine study procedures, provided they fulfil all other study 
eligibility criteria.  
 
Newly-diagnosed HIV positive patients will be given appropriate counselling about the medical 
consequences of their diagnosis and about the need to take responsible precautions to reduce the 
risk of infecting others. They will be referred to appropriate medical and social HIV treatment services, 
and will be given the option of not proceeding to the randomisation stage of the STREAM trial if they 
wish to re-consider their options.  
 
HIV co-infected patients in the STREAM trial will be managed or co-managed by clinicians with 
appropriate expertise in HIV medicine. It will be important therefore for the Principal Investigator at 
each participating site to establish links with the national AIDS programme and/or organisations that 
provide treatment in their country. Wherever possible, patients in the STREAM trial who are co-
infected with HIV will be managed in a joint treatment clinic to ensure close co-ordination of 
management of the two conditions, and to ensure that appropriate decisions can be made concerning 
the management of drug interactions and side-effects.  
  
Guidance on opportunistic infection prophylaxis, management of interactions between TB and HIV 
drugs, management of toxicity, and the timing of initiation of HIV and MDR-TB treatment are 
provided in the STREAM Patient Management Guide. 
 
7.4.1 Permissible ART 
 
All HIV co-infected patients who are taking ART during screening must be switched to one of the 
following permissible ART regimens during screening and at least one week prior to randomisation:  
 Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any two 
nucleoside reverse transcriptase inhibitors (NRTI)s 
 Nevirapine (NVP) based regimen consisting of NVP in combination with any two NRTIs 
 Integrase inhibitor based regimen consisting of an integrase inhibitor (either dolutegravir or 
raltegravir) in combination with any two NRTIs 
 Triple NRTI based regimen, e.g. a regimen made up of zidovudine, lamivudine, and abacavir, 
or in accordance with local standard of care 
The choice of regimen is dependent on local availability and preference of the treating clinician. 
 
Patients randomised to Regimen C or Regimen D who start ART while on randomised treatment must 
take one of the permissible ART regimens listed above; they may start alternative ART on completion 
of their study regimen. Regimen A and B patients may start alternative ART at any time after 
randomisation at the discretion of the treating clinician. 
  
The investigator must assess the risks and benefits of these antiretroviral regimens in the context 
of co-infection with MDR-TB, acknowledging the following caveats: 
a) Triple NRTI is generally not considered optimal long-term ART; 


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b) Nevirapine based regimens are associated with higher ART failure in subjects having or known to 
have previously had a viral load more than or equal to 100,000 copies/mL 
 
7.5 Other non-trial treatment 
 
The following medications and foods are not allowed during administration of bedaquiline: 
 The systemic use of moderate and strong CYP3A4 inhibitors (e.g., azole antifungals: 
ketoconazole, fluconazole, voriconazole, itraconazole; ketolides such as telithromycin; 
clarithromycin; integrase inhibitors containing cobicistat; or grapefruit juice) for more than 2 
weeks 
 The systemic use of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, 
St. John’s wort [Hypericum perforatum], rifamycins, and systemic, multiple dosing of 
dexamethasone).   
 
The investigator should consult the label information, and if necessary contact the appropriate 
sponsor representative. A full list of CYP3A4 inhibitors and inducers may also be accessed via the 
following link:      
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL
abeling/ucm093664.htm  
 
Unless part of the allocated regimen, drugs that are known to prolong the QT interval should not be 
used while the patient is on trial treatment. For patients whose allocated regimen includes bedaquiline 
(arms C and D), no drugs known to prolong the QT interval should be introduced until at least 4 
weeks after the last dose of bedaquiline. The following list includes some examples of drugs known 
to prolong QT, but is not comprehensive:  
 
 Antiarrhythmics Class IA, e.g. quinidine, hydroquinidine, disopyramide 
 Antiarrhythmics Class III, e.g. amiodarone, sotalol, dofetilide, ibutilide 
 Certain antifungals, e.g. fluconazole, ketoconazole 
 Certain neuroleptics, e.g. phenothiazines, pimozide, sertinodole, haloperidol, sultopride 
 Tricyclic antidepressive agents 
 Certain antimicrobials, e.g. moxifloxacin, gatifloxacin, sparfloxacin, erythromycin IV, 
pentamidine 
 Delamanid  
 Certain antimalarials, e.g. halofantrine 
 Certain antihistamines, e.g. terfenadine, astemizole, mizolastine 
 Others: cisapride, vincamine IV, bepedril, diphemanil. 
 
A more comprehensive list of QT-prolonging drugs may be accessed at www.crediblemeds.org 
 
 
 


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8. ASSESSMENTS AND FOLLOW-UP 
8.1.1 Assessment schedule 
See Table 5 in Section 8.1.1 for details of the assessments required for each visit for Stage 1, and 
Table 6 in Section 8.1.2 for details of the assessments required for each visit for Stage 2.  
 
The intensive phase of treatment may be extended for late smear conversion or missed treatment 
(see sections 7.3.2 and 7.3.3).  The continuation phase may also be extended for missed treatment.  
 
For selected sites, at randomisation and every 12 weeks thereafter, patients will be interviewed to 
document the costs e.g. transport and hospitalisation costs, incurred by them in adhering to the 
regimen. System costs will also be estimated. 
 
 
Stage 1 
In Stage 1, patients will be assessed at screening, randomisation (Week 0), Week 1, Week 2, Week 
3, Week 4, and at 4-weekly intervals throughout the study, until the end of follow-up, irrespective of 
whether on treatment or in the post-treatment follow-up phase. 
 
Sputum for smear and culture will be collected at every visit, except at Week 1, Week 2, and Week 
3, when no samples will be collected.  At most visits this will be a single specimen during Stage 1, 
unless otherwise indicated in section 8.1.1.  When two samples are required, if a patient does not 
bring an early morning sample, two spot samples will be collected at the visit.   
 
Stage 2 
In Stage 2, patients will be assessed at screening, randomisation (Week 0), Week 1, Week 2, Week 
3, Week 4, after which they will be seen 4-weekly until Week 52, then 8-weekly until Week 84, and 
12-weekly thereafter until end of trial follow-up.  
 
A minimum of two sputum specimens should be collected at the screening and randomisation visit 
(with a third being an early morning sample if possible).   
 
Two sputum specimens will be collected at every subsequent visit for smear and culture, except at 
Week 1, Week 2, and Week 3, when no samples will be collected. Because early morning samples 
are preferred, at the conclusion of each visit patients should be given a sputum container for sample 
collection to be presented at their next visit.  The second sample will be taken as a spot sample at 
the time of clinic attendance.  If a patient does not bring an early morning sample, two spot samples 
will be collected at the visit.   
 
Routine sputum collection will end when the last patient is projected to have reached Week 96 
(approximately end of November 2021).  Thereafter sputum will be collected only if clinically 
indicated. 
 
 
 


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Table 5: Assessment schedule – for all patients recruited in Stage 1 
Observation/ 
Investigation 
Screening 
Randomisation  
Treatment Phase 
Post-Treatment Phase 
Intensive Phase 
Continuation 
Phase 
Follow-up 
 
Weeks 1 – 3 
Weeks 4 onwards 
 
Written informed consent 
X 
X 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
Clinical Examination 
X 
X 
X 
X 
X 
X 
Clinical assessment (including AEs and 
concomitant medication during treatment) 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
Simple hearing test 
 
X 
If clinically indicated 
 
HIV antibody test 
X 
 
 
 
 
 
CD4 (in HIV positive patients) 
 
X 
According to national guidelines 
Haemoglobin 
 
X 
 
 
 
 
AST and ALT 
X 
 
X 
X 
 
 
Serum creatinine 
 
X 
X 
X 
 
 
Serum potassium 
 
X 
X 
X 
If clinically indicated 
Blood glucose 
 
X 
 
 
 
 
Urinalysis (dipstick) 
 
X 
X 
X 
 
 
Urine: hCG Pregnancy test 
X 
X 
If clinically indicated 
Chest X-ray 
 
X 
 
 
 
 
ECG  (12-Lead) 
X 
X4 
X 
Weeks 4 & 12 
Weeks 24 & 36 
 
Sputum smear and culture3 
X1 
X2 
 
X1 
X1 
X1 
Sputum for drug resistance testing 
X6 
 
 
 
 
 
Patient’s costs (in selected sites) 
 
X 
 
X 
X 
X 
Blood sample for storage (if patient 
consents) 
 
X 
 
 
X5 
 
X indicates assessments required at particular visits. 
1 At least one sample will be collected per visit, except at the final visit of each phase of treatment and at the Week 132 follow-up visit, when two samples will be 
collected.   
2 At least two samples will be collected at this visit.   
3 All positive strains post-randomisation onwards will be shipped to the reference laboratory for full drug susceptibility testing. 
4 One ECG will be done prior to randomisation and others at 4 hours after administering the first dose of treatment. 


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5 One sample will be collected for storage at 16 weeks, for patients consenting to sample storage. 
6  Sputum will be collected for LPA sensitivity testing for resistance to rifampicin, fluoroquinolones and  second-line injectables.  If results for  fluoroquinolones and  
second-line injectables sensitivity are inconclusive, then these tests need to be repeated on a new sputum sample before randomisation. 


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Table 6: Assessment schedule – for all patients recruited in Stage 2 
The following assessment schedule applies to all treatment arms in the STREAM trial as soon as Stage 2 begins (for sites participating in Stage 2).  
Observation/Investigation 
Screening Randomisation 
Treatment Phase 
Post-Treatment Phase 
Intensive Phase 
Continuation Phase 
Follow-up 
 
 
 
Weeks 1 – 3 
Weeks 4 onwards 
 
 
Written informed consent 
X 
X 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
Alcohol Use Questionnaire 
 
X 
 
Week 16 
Week 32 
Week 52 
Clinical Examination 
X 
X 
X 
X 
X 
X 
Clinical assessment (including AEs and 
concomitant medication during treatment) 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
Visual acuity and colour tests 
 
X 
 
Week 12 
(and if symptoms)  
Week 28 and 40 
(and if symptoms) 
 
Hearing test 
X 
 
Week 1 
(If clinically indicated) 
Week 4, 8 and 16 
At the start of the 
continuation 
phase11, Week 28 
and 40 
Weeks 52, 76 and 132 
Haemoglobin 
 
X 
 
 
 
 
 HIV antibody test 
X 
 
 
 
 
Week 7615 
CD4 (in HIV positive patients) 
X 
 
According to national guidelines, at end of BDQ dosing and at week 132 
Viral load (in HIV positive patients) 
X 
 
 
X13 
X13 
X13, 15 
Hepatitis A, B and C testing 
 
X 
 
 
 
 
Urinalysis (sample sent to) central lab 
 
X 
X 
X 
X 
X17 
Urine: HCG Pregnancy test 
X 
X 
If clinically indicated and at end of study 
Chest X-ray14 
X 
 
 
 
 
 
ECG (12-Lead)3 
X 
X 
X 
X 
X 
X 
Additional Post-Dose ECG (12 Lead) for 
sites in PK study4 
 
 
Week 2 
Week 12  
Weeks 24 & 40 
 
Sputum smear and culture2 
X1 
X1 
 
X1 
X1 
X1 
Sputum for drug resistance testing 
X6 
 
 
 
 
 
Patient’s costs (in selected sites) 
 
X 
 
X12 
X12 
X12 
Blood sample for storage (if consents)5 
 
X5 
 
 
X5 
 
PK samples7,8,9,18 
 
X 
Week 2 
Weeks 4 & 12 
Weeks 24 & 40 
Weeks  76, 120 & 132 


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Laboratory safety tests10 
X 
X 
 
X 
X 
X16 
TSH & thyroxine of free thyroxine 
X 
 
 
 
 
Weeks 40 & 76  
X indicates assessments required at particular visits 
1 At screening and randomisation two samples will be collected, with an additional third early morning sample if possible.  Two samples will be collected at each subsequent 
visit, ideally one early morning and one spot sample, or two spot samples if the patient does not provide an early morning sample.  Refer to the STREAM Microbiology Manual 
for details of the tests to be undertaken. 
2 Screening, randomisation, and all positive isolates of MTB post-randomisation from week 8 onwards will be shipped to the reference laboratory for full drug susceptibility 
testing. 
3 An ECG will be conducted prior to randomisation,  a further ECG will then be conducted 4 hours after administering treatment at the randomisation visit. A 12-lead ECG will 
then be collected at each visit until Week 76. In participants who at Week 76 have a QTcF increase from baseline, a 12-lead ECG will be collected at each visit until the QTcF 
returns to either less than a 10ms increase above the baseline value or less than 450 ms. Single ECGs will be collected; however for QTcF prolongatons of more than or equal 
to 500 ms, two further ECGs must be collected. 
4  For patients on arms C and D, enrolled at sites that have been pre-selected for the PK sub-study, an additional 12-lead ECG will also be conducted 4 hours after administering 
treatment at the week 2,  12,  24 and 40 visits    
5 A blood sample will be collected for storage at randomisation and week 16 , for patients consenting/assenting to sample storage. 
6  Sputum will be collected for drug sensitivity testing for resistance to rifampicin, fluoroquinolones and second-line injectables.  If LPA results for fluoroquinolones and second-
line injectables sensitivity are inconclusive, then these tests need to be repeated on a new sputum sample before randomisation. 
7 The PK samples will be collected pre-dose and post-dose (sample from Week 2 visit).  Details of PK sampling are specified in section 8.2.1. 
8 Samples for analysis of the plasma concentration of nevirapine (NVP) and lopinavir (LPV)/ritonavir(RTV) must be taken before intake of ARV and study drug. An additional 
pre-dose sample will be collected if the antiretroviral treatment regimen of a patient is changed, followed by sampling at time points indicated in the Assessment Schedule.  
9 Sample for analysis of the plasma concentration of nevirapine (NVP) and lopinavir (LPV)/ritonavir (RTV) and 4 β OH-cholesterol.  
10 See Section 8.2 for blood test details. 
11 Hearing test will be conducted at the first visit of the continuation phase. 
12 Patient costs collected every 12 weeks from after randomisation in selected sites. 
13 Viral load collected at Week 12, Week 24, Week 40, and Week 76. 
14 A chest X-ray is required at  randomisation that is compatible with a diagnosis of pulmonary TB, however if a good quality X-ray is available that was taken in the 4 weeks 
prior to randomisation it does not need to be repeated 
15 HIV test at week 76 (for patients who were found to be HIV negative at screening). For patients found to be HIV positive at this visit a week 76 viral load measurement 
should also be taken. 
16 Laboratory safety tests should be undertaken at each visit to Week 76.  After Week 76 only if clinically indicated. 
17  Urinalysis to central lab should be undertaken at each visit to Week 76.  After Week 76 only if clinically indicated. 
18 Samples will not be taken after the projected Week 96 visit of the last patient randomised i.e. approximately end of  November 2021. 
 
 


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8.2 Blood tests for Stage 2  
For patients recruited in Stage 2, a blood sample for hepatitis A (IgM), hepatitis B surface antigen 
(HBsAg), hepatitis B core antibody (HBcAb) and hepatitis C virus (HCV) antibody testing will be 
collected at the randomisation visit. 
 
Blood samples for complete blood count (CBC) and serum chemistry will be measured at every 
scheduled evaluation (this excludes visits at weeks 1, 2, and 3) until  the week 76 visit (as referred 
to as ‘laboratory safety tests’ in Table 6. After Week 76, blood tests will be undertaken if clinically 
indicated. All trial-specific samples taken at any time point will be processed and analysed centrally 
or at appropriately qualified local laboratories. 
 
The CBC panel includes: RBC, WBC, platelets, Hb level, haematocrit, MCV and MHC. 
The serum chemistry panel includes: sodium, serum bicarbonate, calcium (uncorrected), calcium 
(corrected for albumin), serum potassium, magnesium, chloride, blood glucose, blood urea nitrogen, 
serum creatinine, alkaline phosphatase, pancreatic amylase, human serum albumin, total protein, 
AST, ALT, total cholesterol, creatine phosphokinase, gamma-glutamyltransferase, creatine 
phosphokinase of muscle brain, total direct-indirect bilirubin, triglycerides, lipase, lactate 
dehydrogenase, uric acid. 
 
8.2.1 Pharmacokinetic (PK) Evaluations 
In Stage 2, the pharmacokinetics of bedaquiline will be assessed in all subjects from Regimen C and 
Regimen D enrolled at sites that have been pre-selected for the PK sub-study.  It is important that 
patients on these regimens be informed to take their bedaquiline around the same time each day 
(as bedaquiline intake should ideally not vary by more than 2hours each day) and to take their 
study regimen with food. 
 
To inform on drug-drug interactions of anti-tuberculosis drugs with ARTs, additional PK analysis will 
be performed in HIV positive patients who are enrolled into the PK sub-study; at least 20 patients 
who are receiving lopinavir/ritonavir and at least 20 patients who are receiving nevirapine as part of 
their ART will be included in the PK analysis. The history of ART intake up to one month prior to 
randomisation will be recorded in the CRF. 
 
8.2.2 PK Blood Sampling 
Venous blood samples for PK evaluation will be collected from all subjects at sites pre-selected for 
the PK sub-study at pre-specified time points outlined below.  Samples will be collected, processed 
and shipped to the central laboratory as instructed in a laboratory manual provided separately.  
 
All blood samples, with the exception of those taken at baseline, will be quantified for the 
determination of plasma concentrations of bedaquiline and M2. 4β-hydroxycholesterol and 
cholesterol will be quantified from PK samples collected at Baseline, and pre-dose samples of Week 
4, 12, 24, and 40 for an assessment of the 4β-hydroxycholesterol/cholesterol ratio. Pre-dose blood 
samples from HIV positive patients will also be quantified for lopinavir/ritonavir and nevirapine.  
 


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8.2.3. Timing of PK blood samples and ECGs 
A pre-bedaquiline dose blood sample must be taken within 1 hour of the next scheduled 
bedaquiline dose. A pre-ART blood sample should also be taken at this time in HIV co-infected 
patients on lopinavir/ritonavir and nevirapine. 
 
A 12-lead ECG, which is in addition to the 12-lead ECG performed at each study visit as per the 
Stage 2 assessment schedule (Table 6) above), must be done 4 hours after the bedaquiline dose. A 
post-bedaquiline dose blood sample must then be taken 4-5 hours after bedaquiline intake and 
within 20 minutes of the post-dose ECG. The schedule for collection of PK blood samples and post-
dose ECGs is outlined in Table 7 below. 
 
 
Table 7: PK Sample Collection Timings 
 
Visit 
Pre-
bedaquiline 
dose 
PK blood 
sample 
Pre-ART dose 
blood sample 
Post-
bedaquiline 
dose PK blood 
sample 
Additional 
post-
bedaquiline 
dose 12-lead 
ECG 
Randomisation 
√ 
√ 
 
2 
√ 
√ 
√ 
√ 
4 
√ 
 
 
 
12 
√ 
√ 
√ 
√ 
24 
√ 
√ 
√ 
40 
√ 
 
√ (Arm C only) 
√ (Arm C only) 
76 
√ 
 
 
1201 
√ 
 
 
1321 
√ 
 
 
1 PK samples will not be taken after the projected Week 96 visit of the last patient randomised i.e. 
approximately end of November 2021. 
 
8.2.4 Additional PK investigations for toxicity or change of ART 
An additional blood sample should be collected at any visit when BDQ is withheld for suspected 
toxicity. If the antiretroviral treatment regimen of a patient is changed during the 40-week 
treatment period for Regimen C or the 28-week treatment period for Regimen D, a pre-dose sample 
should be collected, followed by collections as described above. 
 
The exact date and time of each PK blood sample and the respective previous 2 doses of 
bedaquiline will be recorded in the CRF. For participants receiving lopinavir/ritonavir or nevirapine, 
the last three doses and dates of the ART prior to each PK sample time-point will be recorded in the 
CRF.  
 


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8.2.5 Bioanalysis 
The bioanalysis will be performed by a contract research organization (CRO), under the supervision 
of the Sponsor and/or Janssen. Samples will be analysed using a validated and sensitive liquid 
chromatography-mass spectrometry/mass spectrometry method 
8.3 Procedures for assessing safety 
Throughout this study, patients will be closely monitored for signs and symptoms of drug toxicity. All 
toxicities leading to the study therapy being temporarily or permanently discontinued and all Grade 
3 or greater toxicity effects will require thorough investigation with relevant clinical and laboratory 
tests, as clinically indicated.  
 
These should be repeated as needed until final resolution or stabilisation of the toxicity; if this is after 
the end of the trial, follow-up will be the responsibility of the treating clinician. All symptoms and 
laboratory findings will be graded according to severity using DAIDS criteria. Laboratory events will 
be reported as adverse events only if clinically significant. If the patient has a medical diagnosis at 
randomisation whose signs or symptoms worsen during the study to a Grade 3 or greater, this is a 
notable event (NE) that must be reported. Other notable events and SAEs will be reported as they 
occur to the MRC CTU, as well as to other bodies required to be notified in each country. For details 
of safety reporting see Section 13.   
 
8.3.1 ECG Monitoring 
Several of the drugs used in the STREAM regimens have the potential to prolong QT, therefore ECG 
monitoring is used in both Stage 1 and Stage 2 to identify and manage patients who are at risk.  
 
In Stage 1, all patients will have a 12-lead ECG immediately prior to randomisation and will be 
ineligible if the QT or QTcF interval is more than or equal to 500ms. An ECG will be recorded 4 hours 
after the first dose of trial treatment.  Further ECGs will be performed weekly for the first four weeks, 
and then every four weeks until 52 weeks after randomisation. If a patient has a QT or QTcF of 
450ms or more, then a second ECG should be conducted at least 10 minutes after the first ECG.  
 
In Stage 2, if there is a QT or QTcF measurement of 450 ms or more the patient will not be eligible 
for randomisation. ECG monitoring for Stage 2 involves 12-lead ECGs undertaken at baseline (pre 
and 4 hours post-dose at the randomisation visit), weekly for the first four weeks and at every visit 
until week 76. All patients whose QTcF at week 76 is higher than their baseline recordings will 
continue to have 12-lead ECG monitoring at every visit until the confirmed QTcF is either less than 
10 ms above the baseline value or below 450 ms. 
 
In addition, patients in arms C and D enrolled at sites that have been pre-selected for the PK sub-
study, should also have an ECG 4 hours after administering treatment at the week 2, 12, 24and 40 
visits (see Section 8.2.3).    
 
Any QT or QTcF prolongation to more than or equal to 500 ms while on treatment is considered a 
notable event and should be reported immediately to MRC CTU (See Section 13).  
 
Patients found to have a QT or QTcF more than or equal to 500 ms on a 12-lead ECG at any point 
during treatment will be further investigated. The ECG should be repeated and if confirmed, the 
investigator should attempt to identify the cause, including checking and correcting abnormal K+, 


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Ca+2, and Mg+2. If the patient is taking any drugs suspected of causing QT prolongation they should 
be withheld and the tests repeated to try to identify the cause.  Further details are provided in the 
STREAM Patient Management Guide. 
8.4 Post-treatment schedule  
After completion of treatment the patient will be reminded of the need for follow-up visits by the 
Principal Investigator, or recruiting clinician, and be informed of the date of their next visit.  
 
During the follow-up visits, the following procedures will be undertaken: 
 
 Clinical investigations (as outlined above) will be carried out  
 Patients will be asked about any adverse events that may have occurred after their last visit 
and any concomitant medications they may have received.  
 
There may be times when the PI requests additional tests for a patient depending on their disease 
progression at a particular visit.  
 
8.5 Changes to treatment or follow-up 
8.5.1 Interruptions to treatment 
The treatment regimens or selected drugs may be interrupted at the discretion of the local PI or 
treating clinician: 
 
For a serious adverse event 
 
For a QT or QTcF measurement of more than or equal to 500ms 
 
If  ALT/AST rise to more than or equal to 5 times ULN, or if AST/ALT rise to more than or 
equal to 3 times ULN in the presence of a total bilirubin rise to more than or equal to 2 times 
ULN 
 
If the investigator decides to withhold treatment in the interest of the safety and well-being 
of the participant. 
 
If treatment is interrupted for a suspected serious drug reaction, attempts should be made to identify 
the drug concerned. Further guidance on expected toxicities is provided in the STREAM Patient 
Management Guide. After resolution of the suspected adverse reaction, treatment may be gradually 
re-introduced until the allocated regimen has been re-instituted.   
If treatment with one of the core drugs other than bedaquiline (i.e. kanamycin or amikacin, isoniazid, 
moxifloxacin or levofloxacin, and clofazimine) is missed in either the intensive or continuation phase 
of one of the study regimens this can be made up by extending this phase of the regimen by the 
number of treatment days missed at the discretion of the treating physician and in the absence of 
ongoing toxicity. 
 
Bedaquiline treatment interruptions will be handled separately to those involving the other core drugs, 
and are managed based on the phase of bedaquiline dosing: 
 Treatment interruptions during the 14-day loading period: 
o All treatment interruptions during the loading phase of bedaquiline must be reported 
to the clinical team at the MRC CTU within one working day of the site becoming 
aware, and advice will be given on a case by case basis 


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o For interruptions of less than or equal to 14 days, bedaquiline loading should resume 
at the point of the last dose to complete the total doses required in the loading 
period with the doses previously received taken into account 
o For interruptions of >14 days, treatment should be re-started at the beginning of 
the loading period. The full 14 days of loading should be completed with no 
accounting for doses taken already 
o Only one treatment interruption is allowed during the loading phase and restarting 
treatment is not permitted after interruptions of >30 days  
 Treatment interruptions during the thrice-weekly maintenance dosing period: 
o Bedaquiline can be resumed at maintenance dosing for interruptions of up to 30 
days  
o More than one interruption of up to 14 days is allowed but only one interruption of 
between 15 and 30 days is permitted   
o Restarting bedaquiline after treatment interruptions of >30 days is not permitted 
 A maximum of 40 weeks’ of bedaquiline (measured by number of doses, not by time since 
first dose) can be administered to any patient 
 
There is no requirement to change the dates of scheduled PK sampling visits in response to treatment 
extensions. Treatment adherence must be accurately recorded, and this data can be used to adjust 
calculated pharmacokinetics. 
 
In the event that the local PI considers that treatment needs to be modified or changed, he or she 
should inform MRC CTU by submission of an SAE/NE form and discuss treatment plans with a member 
of the central clinical team. 
 
8.5.2 Missed visits 
For each patient, clinic staff will obtain or confirm contact information. In the event that a patient 
misses a scheduled appointment, a Home Visitor will try within the week following the missed 
appointment to establish communication with the patient and/or treatment supervisor through all 
possible means which they have approved and while protecting their confidentiality (e.g. by telephone 
if this is possible, writing to the patient and contacts, and/or visiting the patient’s home or workplace). 
All attempts to locate a patient following each missed appointment should be documented in their 
records. The need to attend all scheduled follow-up visits will be emphasised to all study patients at 
every visit.  
 
8.5.3 Visit after a missed appointment  
Patients who miss their scheduled appointment will be contacted and arrangements made for a new 
appointment. If patients are not successfully reached by phone/text messaging, a home visit should 
be made and the outcome recorded on a home visit form.  
 
Patients returning after missed appointments should undergo the scheduled assessments for the visit 
that is closest to the time from randomisation (e.g. if a patient returns to the clinic at or near to Week 
16 after missing their visits for weeks 8 and 12, the visit for that day should be recorded as Week 16 
and the Week 16 assessments undertaken). Subsequent visits will continue as scheduled. However, 
treatment to be prescribed should be determined by the actual number of days on which a patient 
has taken their medication and not by the length of time they have been in the study.  


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8.5.4 Loss to follow-up 
If a patient does not return to the clinic before the study is closed, a Final Form will be completed 
at the time of study closeout, after reasonable effort to contact the patient has been made.  The 
form should indicate that the patient was lost to follow-up.  The “loss to follow-up” designation 
cannot be made for any patient until after the patient’s scheduled Week 132 visit. 
 
8.5.5 Follow-up of patients discontinued from treatment 
Every effort should be made to follow up all patients for the full duration of the study, including those 
whose treatment is discontinued or whose treatment is changed. A reduced frequency of follow up 
may be appropriate, and if necessary, should be agreed with the MRC CTU. In this event, a final 
status form should be completed. For patients who have discontinued follow-up visits, but have not 
withdrawn consent, the vital status should be obtained at least every six months until Week 132, if 
necessary by telephone follow up.  
 
If a patient can be contacted and declines further study participation, an investigation into their 
reasons will be conducted, and the reasons documented. An attempt will be made to have him/her 
come to the clinic for a final visit, or at least obtain a sputum sample for the assessment of the 
primary efficacy outcome. 
 
8.6 Trial closure 
The trial will be considered closed when the last patient has completed their final visit and all follow-
up and laboratory reports have been received.  
 
The trial may be terminated early by the Trial Steering Committee (TSC), on the advice of the 
Independent Data Monitoring Committee (IDMC) (see sections 19.2 and 19.3). In addition, MRC CTU 
and the Sponsor have the right to close this trial and/or a site, at any time, although this should occur 
only after consultation between involved parties and with the agreement of the TSC.  
 
At trial closure, the local and central Research Ethics Committees/Institutional Review Boards and the 
regulatory authorities that approved the trial should be informed. It is the responsibility of the sponsor 
to inform the main REC within 90 days of the ‘end of the trial’ that the trial has closed. 
 
Following trial closure remaining samples will be transferred to a biobank following approval from the 
TSC.  
 
Should a site be closed prematurely, trial materials will be disposed of according to the site agreement 
with the Sponsor or MRC CTU. The Principal Investigator will retain all specified documents, for at 
least 15 (fifteen) years, until notification is given by MRC CTU for destruction. Patients currently on 
treatment will be transferred to another STREAM site where available, or referred to the National 
Tuberculosis Programme for completion of treatment and further management.  
 


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8.7 Bacteriology 
The following bacteriological tests will be performed at the site microbiology laboratory: smear, 
culture, diagnostic line probe assays or GeneXpert. At each visit, except for Week 1, Week 2, and 
Week 3, sputum samples will be collected.  At most visits during Stage 1 this will be a single specimen 
unless otherwise indicated in sections 8.1.1, and will be two specimens during Stage 2.  All specimens 
will be tested for AFB smear and culture.  Because early morning samples are preferred, at the 
conclusion of each visit patients should be given a sputum container for sample collection to be 
presented at their next visit.  The second sample will be taken as a spot sample at the time of clinic 
attendance.  When two samples are required, if the patient does not bring an early morning sample, 
two spot samples will be collected at the visit.  If a patient is unable to produce sputum this should 
be documented on the CRF.  
 
The selected methods and techniques for use by the sites may not be the most sensitive ones, but 
they are simple and applicable at any site with high reproducibility, thus allowing a high degree of 
standardisation. Long-term follow-up will compensate for imperfect sensitivity. These methods are: 
 
hot Ziehl-Neelsen (ZN) or auramine fluorescence technique for all study smears 
 
FDA vital staining for selected smears in some sites (see 5.2.1) 
 
decontamination without neutralisation centrifugation and direct inoculation on acidified 
Ogawa (Kudoh medium) for isolation of mycobacteria and subsequent identification of all 
positive study cultures using any locally available method (e.g. GeneXpert, Hain Genotype 
MTBDRplus, SD Bioline). 
 
Hain Genotype MTBDRPlus line probe assay (LPA) from smear-positive sputum or 
GeneXpert System (Cepheid automated diagnostic test to identify rifampicin resistant 
Mycobacterium tuberculosis) for screening of suspects. If one of these tests or other DST 
shows at least resistance to rifampicin, the Hain Genotype MTBDRsl LPA will be performed 
to exclude fluoroquinolone and second-line injectable resistance. 
 
To increase the probability of having at least one good baseline isolate, the sites should also inoculate 
the remaining part of the randomization and screening samples using their preferred culture method 
and medium (e.g. MGIT after neutralization and centrifugation). 
 
All positive isolates, except those of week 4, will be sent to the designated study reference 
laboratory, to confirm species identification and susceptibility status. This includes diagnostic strains 
and recurrence strains, in case of failure or relapse besides isolated positive cultures in-between 
successive negatives. Strains from recurrences will be tested for DST as well as fingerprinting, to 
confirm their identity and to compare their resistance pattern with the originally isolated strain. The 
reference laboratory will store all study strains at -80°C and local laboratories will store at -20°C. 
 
The techniques to be used at the reference laboratory are: 
 
Slow phenotypic DST using the proportion method on Löwenstein-Jensen medium for first 
line drugs and agar-based Middlebrook 7H11 medium for second line drugs; for difficult 
strains, the minimum inhibitory concentration (MIC) and DNA sequencing can be used to 
arrive at the most correct result 
 
Fingerprinting; MIRU-VNTR analysis (mycobacterial interspersed repetitive units–variable 
number of tandem repeats). 
 
A detailed description of the various laboratory tests is found in the STREAM Microbiology Manual. 


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Results of resistance tests undertaken by the reference laboratory are primarily for analysis purposes 
and will not be routinely provided to the sites. Treatment changes will not be suggested on the basis 
of these results unless a patient is not doing well and it is decided that a change of treatment is 
required.  
 
However, if any patients are found to have XDR-TB (confirmed resistance to fluoroquinolones and 
second-line injectables from phenotypic DST) from samples collected at baseline, these results will 
be provided to sites, and the patients should be withdrawn from trial treatment and treated according 
to national guidelines.  
 
8.8 Health economic assessment  
In sites participating in the health economic component of STREAM, data relevant to the health 
economic assessments will be collected as explained below: 
 
8.8.1 Health system costs  
Health system costs will be obtained through: 
 An analysis of health worker time involved in prescribing, monitoring, and supervising the 
regimens in each country, health worker salary and benefits data from the Ministry of Health 
and health facility records based on grade of staff rather than named individuals 
 A full assessment of the health system costs of delivering the MDR-TB regimens, including tests 
performed, consumables used, in-patient stay costs, drugs administered and overheads 
 Standard costs of supplies from hospitals’ accounting records where possible. Other 
appropriate sources such as private healthcare facilities costs will be used if data not available 
in hospitals’ records 
 An analysis of the costs associated with the diagnosis and management of serious adverse 
events (SAEs) caused by MDR-TB or its treatment. This will include all tests performed, 
examinations, investigations, in-patient stays and medication received, as well as staff costs.  
 Summing the costs of each resource used in delivering the MDR-TB regimens 
 
Costs will be assessed as one-off costs required for establishing the regimens and as costs for 
recurrent costs for sustaining it. 
 
8.8.2 Patient and household costs 
Data on patient and household costs will be collected through patient interviews based on the STOP-
TB questionnaire. Interviews will take place at intervals of 12 weeks after initiation of treatment.  The 
interviews will include questions out-of-pocket costs on fees paid to the health system, such as drugs 
and laboratory test costs, transport, food and accommodation costs incurred as a result of the 
treatment process.  In addition, there will be questions regarding quality of life as well as time lost 
from economic activities.  
 


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8.8.3 Socio-economic status 
The socioeconomic status of patients will be assessed through asking patients about asset ownership. 
The assets will be determined based on existing poverty analyses or similar sources (demographic 
and Health Surveys, population income surveys or census data) for the country or region within the 
country. These questions about asset ownership will be included in the demographic assessment at 
randomisation and again every 12 weeks after the initiation of treatment.   
 
 
 
 
 
 
 
 
 
 
 
 


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9 DISCONTINUATION FROM TREATMENT 
 
In consenting to trial participation, patients are consenting to study treatment, follow-up and data 
collection.  If a patient wishes to discontinue their allocated study treatment they should not be 
withdrawn from follow-up unless they expressly request it. Patients should be told about the 
importance of remaining on follow-up, or failing this, of allowing routine follow-up data to be used 
for study purposes.   
 
The treating clinician will be discouraged from changing or restarting treatment without evidence of 
treatment failure or recurrence of MDR-TB. As soon as the treating clinician has any indication of a 
treatment failure, recurrence, or serious toxicity, they should contact the STREAM central clinical 
team to discuss whether treatment should be modified. Guidelines for retreatment, in the STREAM 
Patient Management Guide, will be used to inform the decision, which will be made on a case-by-
case basis using all the available bacteriological and clinical data. If the decision is made not to 
retreat, then the case should be reassessed as further data accumulates with further discussions with 
the STREAM central clinical team as necessary. 
 
9.1 Discontinuation of allocated regimen 
The Investigator must make every reasonable effort to keep each patient on their allocated regimen 
and in follow-up for the whole duration of the study. However, if it is necessary to discontinue or 
change a patient’s allocated regimen, every reasonable effort will be made to ensure the patient 
continues to be followed-up. 
 
The following are justifiable reasons for the Investigator to discontinue or modify a patient’s allocated 
treatment: 
1. Unacceptable toxicity 
2. Patient refuses to take study drugs 
3. Serious violation of the study protocol (including persistent patient attendance failure, non-
adherence to treatment and persistent non-compliance) 
4. The Investigator decides to discontinue a patient’s treatment for clinical reasons not related 
to the regimens 
5. Evidence of treatment failure based on consistently positive bacteriology usually accompanied 
by signs and symptoms of disease 
6. Pregnancy; women who become pregnant will stop their allocated trial treatment, and be 
treated according to local practice 
7. A confirmed QT or QTcF more than or equal to 500 ms on 12-lead ECG in patients for whom 
no other cause can be identified 
8. Confirmed resistance to fluoroquinolones and second-line injectables from phenotypic DST. 
 
If it is local practice to do so, results from local drug susceptibility tests showing a patient’s isolate is 
resistant to trial medications may be used to justify a change of treatment for patients, although this 
is discouraged if the patient is doing well clinically. Drug susceptibility test results alone should not 
be used to justify a change or discontinuation of treatment for patients in the regimens, although 
patients found to have resistance to both fluoroquinolones and second-line injectables from 
phenotypic DST (confirmed XDR-TB) should be withdrawn from trial treatment and treated according 


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to national guidelines (see section 5.5.1).  If these results are obtained from a local laboratory, a 
patient can remain on trial medication at the discretion of the treating clinician if the patient appears 
to be doing well on treatment.  However, if results from the central laboratory confirm XDR-TB, then 
the patient should be removed from the trial and treated according to national guidelines. 
 
Should drug unavailability occur, local supply of drug(s) through the National Tuberculosis 
Programme or local market will be considered (after ensuring acceptable quality) for all study drugs 
except bedaquiline while regular study supplies are replenished. In instances where drug(s) remain 
unavailable for any period of time the central clinical team will be consulted to advise on appropriate 
management. 
 
Any change or discontinuation of treatment should be discussed with the STREAM central clinical 
team before a decision is made, unless in response to a medical emergency.  
 
9.2 Salvage regimens 
Salvage regimens will be provided for trial patients who require retreatment provided adequate 
follow up can be maintained. All patients who are treated with a salvage regimen should be 
appropriately monitored for any toxicity during their treatment, this monitoring may include ECG 
and laboratory monitoring, and the data recorded. The STREAM central clinical team should be 
contacted for guidance on the appropriate monitoring in such cases.  Trial patients who initiate a 
salvage regimen close to the end of their trial follow-up period may require treatment and follow up 
beyond this time point. In addition, where appropriate the Sponsor may initiate salvage regimens 
for patients who have completed their 132 week Study period. 
 
The composition of the salvage regimen will be based on treatment history and DST results and be 
selected by the site clinicians in consultation with the central clinical team. Salvage regimens will 
also take into account local guidelines and availability of medicines. Patients who are unwilling or 
unable to be followed during their salvage regimen treatment, including those whose planned 
intensive phase will not be completed prior to site closure, will be referred to the National 
Tuberculosis Programme for management. Upon site closure, patients still undergoing salvage 
regimen treatment will be referred to the National Tuberculosis Programme to ensure treatment 
follow up and completion. 
 
Procurement and provision of the salvage regimen for trial patients will be supported by the 
Sponsor as needed and site-specific approaches to ensuring availability of medicines will be 
developed and documented. Bedaquiline provided as IMP for the trial will be limited to 24 weeks in 
a salvage regimen and only utilized where trial patients initiate their salvage regimen within their 
132 week Study period. Outside of the Patient’s 132 week Study period, and where available, the 
Sponsor may, at their discretion, use bedaquiline in a salvage regimen from an alternative source. 
The safety and appropriateness of the salvage regimen is the responsibility of the investigator, as 
well as the reporting of Adverse Events. 
 
9.3 Patient transfers 
For patients moving out of the area, every effort should be made to continue to follow them if at all 
possible; this could include follow-up at another participating site.   
 


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9.4 Early stopping of follow-up 
If patients explicitly state that they do not wish to contribute further data to the study, MRC CTU 
should be informed in writing of the patient’s decision and a final form should be completed. Such 
patients who discontinue the study may not be re-randomised and will not be replaced.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10 DATA MANAGEMENT  
 
Data will be recorded on paper case report forms (CRFs) and entered into a database either at each 
local site or at a central location. At each visit, details of clinical findings, procedures, tests and results 
will be recorded in the patient’s case notes and on the appropriate CRF. The CRF top copy will be 
sent for data entry, and the duplicate retained in the patient’s Trial Folder. Entries made in the CRF 
must be either verifiable against source documents or have been directly entered into the CRF, in 
which case the entry in the CRF will be considered as the source data.  Instances where data may be 
entered directly in a CRF will be agreed by the Sponsor and documented.  The Investigator Site File 
and all source data should be retained until notification is given by the sponsor for destruction.  
 
Instructions on data capture, cleaning and subsequent storage can be found in the STREAM Data 
Management Plan. 
 
10.1 Blinding of data 
The co-chief investigators will be kept masked to allocation where possible, except in instances where 
the knowledge is needed for the review of adverse events. However, one of the co-chief investigators, 
Professor Andrew Nunn, will be kept entirely blinded to treatment allocation throughout the trial.  The 
trial statisticians and data manager in the central team will not be blinded to the allocation. However, 
before database lock the only data summarised by treatment allocation will be within reports to the 
IDMC, which will not be distributed outside of the IDMC.  The Trial Statisticians will be responsible 
for preparing the IDMC reports, and will be the only persons outside the IDMC who will have access 
to these reports.  Should any modifications to the trial design be required, the unblinded statisticians 
will be excluded from the discussion.    
 
 
 
 
 


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11 STATISTICAL CONSIDERATIONS 
11.1 Analysis population definitions 
 
Only patients randomised in Stage 1 of the STREAM trial will be included in the Stage 1 analysis 
population.  
 
The analysis populations for Stage 2 only include patients that are randomised after the start of Stage 
2. Recruitment to Stage 2 may not begin simultaneously at all sites. Therefore, all patients 
randomised on or after the site-specific start date at that site will be included in the Stage 2 analysis.  
Intention-to-treat (ITT) 
All randomised patients will be included in the ITT analysis population. 
Safety population 
All randomised patients who have taken at least one dose of trial treatment will be included in the 
safety analysis population. 
Modified intention-to-treat (mITT) 
 
The mITT population is defined as all randomised patients that have a positive culture for M. 
tuberculosis at screening or randomisation, with the exception of patients with isolates taken before 
randomisation that are subsequently found to be susceptible to rifampicin, and patients with 
isolates taken before randomisation that are subsequently found to be resistant to both 
fluoroquinolones and second-line injectables (i.e. XDR-TB) on phenotypic DST.  Results from the 
central reference laboratory will take priority over any results from local laboratories where 
available.  Rifampicin susceptible phenotypic DST results will be confirmed by rpoB sequencing.  
 
Per protocol (PP) 
The PP population will be the same as the mITT population with the exclusion of patients not 
completing a protocol-adherent course of treatment (see Section 11.2.3), other than for treatment 
failure, change of treatment for an adverse event or death.  Treatment failure is defined as failure to 
attain and maintain culture negativity until the end of allocated treatment.   
11.2 Outcome measures 
Culture results obtained using acidified Ogawa (Kudoh medium) will be used in the primary 
analysis, although results from other culture media will be used if the Ogawa result is missing.  Any 
culture result that is missing because the patient is no longer able to produce sputum will be 
treated as a negative result, providing their last 2 available culture results (from sputum samples 
taken at separate visits) are negative. 
11.2.1 Primary efficacy outcome 
The primary outcome for the Stage 1 comparison between Regimen B and Regimen A is efficacy 
status at 132 weeks after randomisation.  
 
The primary outcome for the Stage 2 comparison is efficacy status at 76 weeks after randomisation.  
 
The status for all efficacy study comparisons is determined as follows:  
  


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Favourable  
A patient’s outcome will be classified as favourable if their last two sputum culture results are 
negative, unless they have previously been classified as unfavourable.  These two sputum samples 
must be taken on separate visits, the latest of which being no more than six weeks earlier than Week 
132 (for the Stage 1 comparison) or Week 76 (for the Stage 2 comparison), the time-points of interest 
for primary outcomes in the Stage 1 comparison and Stage 2 comparisons, respectively.  
 
For the purpose of the analysis of primary outcome measures in Stage 1 and Stage 2, the visit 
windows for the Week 132 (for Stage 1) and Week 76 (for Stage 2) are defined as no more than six 
weeks prior to, or six weeks after 132 or 76 weeks, respectively, from randomisation.   
 
The end dates in the above windows will be extended for any Stage 2 patients whose Week 76 
appointment is scheduled to occur during the COVID-19 pandemic and did not occur due to 
restrictions on movement, unacceptable risk of exposure to COVID-19 in connection with the 
scheduled visit, or any other reason related to the pandemic. For those patients, the Week 76 sputum 
samples must be taken in a window beginning six weeks prior to the scheduled visit date and ending 
within the Week 84 visit window.  
 
Unfavourable  
A patient’s outcome will be classified as unfavourable if: 
 
1. They are discontinued from their allocated study treatment and subsequently restarted on a 
different MDR-TB regimen.  
2. Treatment is extended beyond the scheduled end of treatment for any reason other than 
making up days when no treatment was given (missed treatment) for a maximum of eight 
weeks. A maximum of 14 days of extra treatment (irrespective of reason) is acceptable before 
it is classified as treatment extension. In addition, if the intensive phase of treatment has 
been extended for delayed sputum conversion (maximum 8-week extension permitted) the 
scheduled end of treatment will also be extended by the same amount, in accordance with 
Section 7.3.2. 
3. They are restarted on any MDR-TB treatment after the scheduled end of treatment, but before 
132 weeks after randomisation for Stage 1 and before 76 weeks after randomisation for Stage 
2. 
4. They change their allocated study treatment for any reason other than (1) the replacement 
of a single drug* or (2) for patients allocated to Regimen A when the change is as a result of 
changes in local guidelines and not related to any change in the patient’s circumstances or 
condition. 
5. Bedaquiline is started where the allocated regimen did not originally contain that drug 
(Regimen A or B) 
6. A second line injectable agent is started in Regimen C. 
7. A drug from the class of nitroimidazoles or linezolid is started. 
8. They die at any point during treatment or follow-up. 
9. At least one of their last two culture results, from specimens taken on separate occasions, is 
positive. 
10. They do not have a culture result at Week 76 or thereafter for the Stage 1 comparison, or 
within the Week 76 window for the Stage 2 comparison.  


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11. The failure or recurrence specimen at or before the Week 76 window was a different strain 
to their randomisation specimen, i.e. re-infection (the Stage 2 comparison only). 
* Excluding changes from kanamycin to amikacin  
 
Starting a single drug is not considered to be a substantial change to the regimen and therefore does 
not result in an unfavourable outcome, with the exception of adding bedaquiline (in Regimen A or 
B), a second-line injectable in Regimen C or a drug from the class of nitroimidazoles or linezolid (in 
any regimen).   
 
Following publication of the revised WHO guidelines in 2018 it became more likely that a salvage 
regimen following bedaquiline use would contain linezolid rather than an injectable agent. To reflect 
the resulting imbalance in the likelihood of point 5 and 6 occurring based on drug choice, starting 
linezolid alone was added as an unfavourable outcome (point 7 above) in version 11.0. 
 
For analysis of the Stage 1 comparison, re-infections with a different strain are classified as not 
assessable. 
 
Only data before or within the Week 76 window will be used for the determination of the primary 
efficacy outcome for Stage 2, even though patient follow-up continues to end of trial.  Participants 
with no sputum sample available at Week 76 due to Covid-19 who are not otherwise classified as 
unfavourable will be considered unfavourable in line with the above definition. Sensitivity analyses 
will reclassify these participants as i) non-assessable and excluded  from the primary efficacy 
analysis, and ii) unfavourable/favourable if their culture result at their Week 68 visit is 
positive/negative respectively. 
 
An extension of the intensive phase of treatment in any study arm does not constitute an 
unfavourable outcome, as long as the extension is in accordance with either the algorithms described 
in Figures 9 and 10 (section 7.3.2) for patients on Regimen B, Regimen C, or Regimen D, or the 
locally-used WHO 2011 long MDR-TB regimen for patients on Regimen A. Similarly, the 
discontinuation of drugs that are not replaced does not constitute an unfavourable outcome. 
 
During Stage 1, a patient who has a culture result within the Week 76, but not within the Week 132 
window having not otherwise been classified as unfavourable (based on the definitions above) will 
be regarded as not assessable and will be excluded from the primary analysis provided their last 
two cultures, from specimens taken on separate occasions, are negative; one of these cultures should 
be from a sample taken at week 76. Any patient who does not have a culture result within the Week 
132 window and does not fulfil these criteria will be classified as unfavourable.  These definitions 
apply to both Regimen A and Regimen B in Stage 1 of the trial.   
 
11.2.2  Secondary efficacy outcome at Week 132 in Stage 2 
 
Secondary efficacy analyses will be based on data from all visits occurring on or before the projected 
Week 96 visit of the last patient randomised i.e. approximately end of November 2021.  A participant’s 
scheduled last efficacy visit will be their latest scheduled trial visit on or before this date. 
 
For purposes of analysis of the secondary efficacy outcome measures at Week 132 in Stage 2, a 
patient’s outcome will be classified as favourable if their last two sputum culture results are 


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negative, unless they have previously been classified as unfavourable.  These two sputum results 
must be from samples taken at separate visits; the latest must be no more than six weeks before 
their scheduled last efficacy visit. 
 
The visit window for the scheduled last efficacy visit is defined as no more than six weeks prior to 
and up to six weeks after (or on 30 Nov 2021 if this is earlier) the scheduled last efficacy visit. The 
end dates of the window will be extended for any Stage 2 patients whose scheduled last efficacy visit 
was due during the COVID-19 pandemic and did not occur due to restrictions on movement, 
unacceptable risk of exposure to COVID-19 in connection with the scheduled visit, or any other reason 
related to the pandemic. For such patients, sputum samples must be taken in a window between six 
weeks prior to and twelve weeks after the last scheduled visit date (or on 30 Nov 2021 if this is 
earlier).   
 
A patient’s outcome at their scheduled last efficacy visit will be classified as unfavourable if: 
 
They are unfavourable at Week 76 
 
They start any MDR-TB treatment between their Week 76 and scheduled last efficacy visits  
 
They die between their Week 76 and scheduled last efficacy visits 
 
At least one of their last two culture results, from specimens taken on separate occasions, is 
positive. 
 
A patient who does not have a culture result within the window for their scheduled last efficacy visit, 
having not otherwise been classified as unfavourable, will be regarded as not assessable and 
excluded from the analysis provided their last two cultures, from specimens taken on separate 
occasions, are negative.   
11.2.3 Definition of a protocol-adherent course of treatment 
Patients will be excluded from the per-protocol analysis if they do not complete a protocol-adherent 
course of treatment, other than for treatment failure, change of treatment for an adverse event or 
death. 
 
A patient will have completed a protocol-adherent course of treatment when they have taken 80% 
of doses within 120% of the minimum duration in both the intensive phase and in the whole treatment 
period.  For this purpose, a dose is defined as all the study medications at the correct dose for that 
particular day.   
 
Stage 1 
For Regimen B, with or without an extension of the intensive phase, a patient will have completed 
a protocol-adherent course of treatment if they have taken: 
 
90 doses (80% of 16 weeks) within 134 days (120% of 16 weeks) in the intensive phase, and 
 
224 doses (80% of 40 weeks) within 336 days (120% of 40 weeks) over the whole treatment 
period (i.e. the combined intensive and continuation phases) regardless of treatment 
extensions.   
 
The same algorithm will apply for Regimen A, the control regimen for Stage 1, and the exact number 
of doses and days depends on the duration of the intensive and continuation phases of Regimen A. 
 


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Stage 2 
For Regimen B and Regimen C, with or without an extension of the intensive phase, a patient will 
have completed a protocol-adherent course of treatment if they have taken: 
 
90 doses (80% of 16 weeks) within 134 days (120% of 16 weeks) in the intensive phase, and 
 
224 doses (80% of 40 weeks) within 336 days (120% of 40 weeks) over the whole treatment 
period (i.e. the combined intensive and continuation phases) regardless of treatment 
extensions. 
 
For Regimen D, with or without an extension of the intensive phase, a patient will have completed a 
protocol-adherent course of treatment if they have taken: 
 
45 doses (80% of 8 weeks) within 67 days (120% of 8 weeks) in the intensive phase, and 
 
157 doses (80% of 28 weeks) within 235 days (120% of 28 weeks) over the whole treatment 
period (i.e. the combined intensive and continuation phases) regardless of treatment 
extensions. 
 
11.3 Sample size: Stage 1 
A meta-analysis of treatment outcome in patients with MDR-TB found an overall favourable outcome 
of 64% (95% CI 59-68) in patients given individualised treatment and 54% (95% CI 43-68) in 
patients given standardised treatment8. A reasonable estimate of the efficacy of Regimen A in the 
STREAM trial would therefore be 70%.  
 
Based on the experience with Regimen B, a reasonable estimate of its efficacy in the STREAM trial 
would be between 75% and 85%. The lower estimate is used for the sample size calculations below. 
11.3.1 Power to demonstrate non-inferiority in the primary efficacy outcome 
Based on a 2:1 allocation ratio in favour of Regimen B to Regimen A, Table 8 gives the total number 
of patients required to demonstrate non-inferiority under the specified scenarios using a margin of 
non-inferiority of 10%, assuming that Regimen B is actually 5% better. These totals allow for 20% 
of patients being classified as not assessable in a per protocol analysis and are based on a one-sided 
level of significance of 2.5%.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 8: Power to demonstrate non-inferiority in the primary efficacy outcome 
Power 
Percentage favourable 
outcomes in Regimen 
A 
Difference in percentage favourable 
outcomes in Regimen B compared to  
Regimen A 
0% 
5% 
10% 
80% 
60% 
1060 
464 
255 
65% 
1005 
435 
238 
70% 
928 
398 
214 
90% 
60% 
1419 
620 
340 
65% 
1345 
583 
318 
70% 
1242 
533 
287 
 
Therefore, 398 patients would be required (rounding to 400 gives: 267 on Regimen B and 133 on  
Regimen A) to demonstrate non-inferiority with 80% power assuming 70% favourable outcomes in 
Regimen A and 75% in Regimen B and 20% not assessable. A larger difference in response rates of 
10% would require fewer patients and could also be demonstrated with greater than 90% power 
with a total recruitment of approximately 400 patients. 
 
A 10% margin of non-inferiority is considered an acceptable reduction in efficacy given the 
considerably reduced pill burden and duration and the expected increase in adherence in reducing a 
treatment regimen from 104 weeks (as with Regimen A), to 40 weeks (as with Regimen B). 
 
If the difference in response rates in favour of Regimen B is more than 10% it may be possible to 
demonstrate superiority of that regimen over the control for the Stage 1 comparison, Regimen A.  
 
A minimum of 400 patients will need to be recruited across all countries to give sufficient power to 
demonstrate non-inferiority. Patients will be randomised to Regimen B and Regimen A in the ratio 
2:1.  
11.3.2 Power to demonstrate non-inferiority in the primary safety outcome 
Assuming a sample size of 400 on a 2:1 allocation ratio in favour of Regimen B  to Regimen A, Table 
9 gives the power available to demonstrate non-inferiority in the primary safety outcome under 
different proportions of grade 3 or 4 events on Regimen A and Regimen B.  These calculations assume 
a margin of non-inferiority of 10% and a one-sided level of significance of 2.5%. All randomised 
patients who have received at least one dose of study medication will be included in the safety 
analysis. 
 
 
 
 
 
 
 
 
 
 
 


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Table 9: Power to demonstrate non-inferiority in the primary safety outcome 
 
Proportion 
grade 3 or 4 on 
Regimen A 
Assuming same 
proportion in 
Regimen A and 
Regimen B  
Assuming an absolute 
5% lower proportion on 
Regimen B than 
Regimen A 
10% 
88% 
99% 
15% 
75% 
99% 
20% 
65% 
96% 
25% 
58% 
93% 
30% 
53% 
89% 
35% 
50% 
86% 
40% 
48% 
83% 
 
 
11.4 Sample size: Stage 2 
11.4.1 Power to demonstrate non-inferiority in the primary efficacy outcome (primary 
objective relating to Regimens B and C) 
Stage 2 will aim to randomise at least 200 patients to each of Regimen B (Bmox or Blev)  and 
Regimen C. This revised sample size was determined based on the assumption that the proportion 
of patients with a favourable efficacy outcome at Week 76 is 80% for Regimen B (estimated based 
on preliminary Stage 1 results) and 82% for Regimen C (based on an anticipated minimum benefit 
in efficacy of using 40 weeks treatment with bedaquiline compared to 16 weeks treatment with 
kanamycin). Using a non-inferiority margin of 10% and a one-sided significance level of 2.5%, 172 
evaluable patients will be required in each of the two regimens to demonstrate non-inferiority of 
Regimen C to Regimen B with 80% power. To account for 14% of patients excluded from the 
primary per protocol efficacy analysis population, a total of 400 patients will need to be enrolled 
across the 2 regimens. A sample size of 400 patients enrolled to the comparison of Regimens  B 
and C is necessary to rule out an 8% increased mortality in Regimen C compared to the 8% 
observed on Regimen B in the preliminary analysis of STREAM Stage 1. This will provide 80% 
power with a one-sided 0.025 type I error. 
 
An interim analysis will be performed for the purpose of determining the final sample size needed to 
achieve adequate power for testing the Stage 2 primary hypothesis of non-inferiority. The interim 
analysis will be performed when at least 40% of the 400 patients on Regimen B and C complete 
24 weeks of treatment and at least 10% of the 400 patients complete Week 76. Based on data from 
the interim sample, the number of additional patients needed to achieve 80% conditional power will 
be determined and, if necessary, the sample size will be increased. The maximum sample size will be 
capped at 330 patients per regimen (ie, the initial sample size). The sample size re-estimation will be 
performed by an independent Statistical Support Group (SSG). Details on methodology, type I error 
control, decision rules of the sample size re-estimation will be provided in the statistical analysis plan 
to be completed prior to the interim analysis. 
 
 


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Table 10: Power to demonstrate non-inferiority in the primary efficacy outcome 
(Regimens B and C only) 
  
Proportion favourable 
outcomes 
 
80% power 
 
90% power 
Regimen B 
 
 
Regimen C 
 
Total 
evaluable 
patients 
Total 
sample size 
accounting 
for 14% 
exclusions. 
 
Total 
evaluable 
patients 
Total 
sample size 
accounting 
for 14% 
exclusions 
75% 
76% 
484 
562 
646 
750 
75% 
77% 
402 
466 
536 
624 
78% 
79% 
444 
516 
592 
688 
78% 
80% 
368 
428 
490 
570 
80% 
81% 
414 
482 
554 
644 
80% 
82% 
344 
398 
458 
532 
 
 
Assuming a favourable efficacy outcome at week 76 in Regimen B (Bmox and Blev combined) of 80% 
(consistent with the status of Regimen B at 76 weeks in Stage 1) and an increased favourable 
response of 82% in Regimen C, using a non-inferiority margin of 10% and a one-sided significance 
level of 2.5%, a total of 344 patients will be required to demonstrate non-inferiority of Regimen C 
with 80% power. To account for the 14% of patients being excluded from the per protocol 
population a total of 400 patients will be required across the two arms: Regimen B (Bmox or Blev) and 
Regimen C.   
 
 
The number of patients excluded from the mITT analysis population will be less than the per 
protocol population and, therefore, this sample size will be adequate for this analysis.  
 
As only the comparison between Regimen C and Regimen B (Bmox and Blev combined) is primary, no 
adjustment is made for multiplicity. 
 
11.4.3 Secondary efficacy analyses involving Regimen A in Stage 2 
Secondary objectives of Stage 2 include to estimate the difference in the proportion of patients with 
a favourable response at 132 weeks between Regimens B, C, D and A. With version 8.0 of the 
protocol it is now anticipated that approximately 100 patients will be randomised to Regimen D and 
no more than 50 patients to Regimen A.  
11.4.4 Sample size 
 
Stage 1 
A minimum of 400 participants from sites in four or five countries will be randomised to either 
Regimen A or Regimen B in the ratio 1:2 (i.e. 133 allocated to Regimen A, and 267 allocated to 
Regimen B). 
 


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Stage 2 
At the start of Stage 2, randomisation was to Regimen A, Regimen B, Regimen C and Regimen D in 
a ratio of 1:2:2:2 to a maximum of 1155 patients from sites in a number of countries.  With Version 
8.0 of the protocol at least 200 patients will be randomised to each of Regimens B and C.  In addition, 
patients randomised to Regimen A and Regimen D prior to the implementation of Version 8.0 of the 
protocol will be part of the trial and therefore the overall sample size will be greater than 400 but is 
expected to be less than 800 patients.  
  
11.5 Interim monitoring and analyses 
There will be no formal interim analyses of the data (with the exception of that mentioned in Section 
11.7), but the Independent Data Monitoring Committee (IDMC) will review efficacy and safety data 
every six months after commencement of recruitment or as required, including an early assessment 
of QT data after three months from the start of Stage 1, and an early assessment of safety data after 
three months from the start of Stage 2 (unless recruitment is low at three months, in which case this 
initial assessment would be delayed).  The IDMC will give particular attention to the QT and QTcF 
data at these times and at other times as necessary, with technical assistance provided by a 
cardiologist to enable them to interpret the results and their implication on the study. The IDMC will 
also consider failure rates, and give attention to mortality data; reviewing numbers and cause of 
failure/death by treatment arm. 
 
Following the interim analysis to be performed by the SSG for the purpose of determining the final 
sample size needed to achieve adequate power for testing the Stage 2 primary hypothesis of non-
inferiority of Regimen C to Regimen B, the results will be given to the IDMC who will make 
recommendation to the Trial Steering Committee on the numbers of patients required (see section 
11.4.1).     
 
It is not the intention to stop the trial in Stage 2 based on differences in efficacy between any of 
the treatment arms unless this is regarded as a safety issue.  Recommendations to stop the trial 
prematurely will be based only on safety considerations; therefore no type I error correction will be 
done for the primary analysis.   
 
Further details of the role and function of the IDMC is given in Section 19 and in the STREAM IDMC 
charter.   
 
Interim plasma concentration data (including an evaluation of patients receiving bedaquiline and 
LPV/rtv) will be reviewed during the first 3 IDMC meetings of Stage 2 (where PK data are available) 
and on an ad-hoc basis thereafter if deemed necessary by the IDMC/Sponsor. 
 
11.6 Preliminary analysis plan  
Sites participating only in Stage 1 will only contribute data to the analysis of that stage.   
 
All patients included in the analysis will be analysed in the treatment group to which they were 
originally assigned.  
 


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Detailed analysis plans for the primary and/or final analyses of Stage 1 and Stage 2 will be developed 
and approved prior to database lock for the relevant analysis of the respective stages. These will 
include details of a number of sensitivity analyses. 
 
Results concerning time to sputum conversion will be shared with the TREAT-TB transmission 
modelling team in order that the longer-term impacts of reducing treatment times may be assessed. 
 
In Stage 2, data from patients on Regimen A will be included in the efficacy and safety analyses at 
132 weeks, but not the primary Week 76 efficacy analyses. The Week 132 analyses comparing 
Regimens C and D with Regimen B will mirror the Stage 1 analyses described above and will be 
described fully in the statistical analysis plan.  
 
Stage 1 
In general, the primary efficacy analysis will be based on both per protocol and modified intention-
to-treat (mITT) populations.  
 
For the primary analysis, the difference in proportion of favourable outcomes between Regimen A 
and Regimen B with 95% confidence intervals will be estimated. The analysis will be stratified by the 
randomisation stratification factors. For the non-inferiority comparisons, the analyses will be repeated 
on a per protocol sub-population.  Non-inferiority will be shown if the upper bound of the 95% 
confidence interval of the difference in proportion of favourable outcomes between Regimen A and 
B is less than the 10% margin of non-inferiority; this must be shown in both the mITT and the PP 
populations. 
 
The proportion of unfavourable outcomes with 95% confidence intervals will be estimated for each 
country. The primary safety outcome is the occurrence of a Grade 3 or greater adverse events. This 
analysis will be repeated in subgroups according to HIV infection status and drug resistance patterns. 
 
 
Stage 2 
For the primary analysis of Stage 2, the difference in favourable outcome rate between Regimen B 
(Bmox and Blev combined) and Regimen C with corresponding two-sided 95% confidence interval and 
p-value will be estimated using a stratified analysis of the risk difference from each stratum using 
Cochran-Mantel-Haenszel weights.24  For Regimen C, non-inferiority will be shown if the upper bound 
of the 95% confidence interval of the difference in proportion of favourable outcomes is less than 
the 10% margin of non-inferiority; this must be shown in both the mITT and PP populations. The 
analysis will be stratified by HIV status with three strata: HIV negative, HIV positive with CD4 count 
between 50 cells/mm3 and less than 350 cells/mm3, and HIV positive with CD4 count more than or 
equal to 350 cells/mm3.   
 
The secondary non-inferiority outcome at Week 132 for Regimen B compared to Regimen C will be 
analysed using time to unfavourable outcome, thereby using information on all participants.  Data 
from participants whose scheduled last efficacy visit is before Week 132 will be censored at the time 
of their last visit, unless they have already become unfavourable. Non-inferiority must be shown in 
both the mITT and the PP populations. A sensitivity analysis will estimate the proportion unfavourable 
at Week 132 on the subset of participants randomised at least 132 weeks on or before 30 November 


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2021. For the superiority comparisons e.g. of Regimen C compared to Regimen B, at Week 76 and 
Week 132 only the mITT analysis will be considered.   
 
    
 
Mortality rates will be calculated for the individual treatment arms and treatment group differences 
in mortality rates will be calculated together with a 95% confidence interval. In addition, the 
number of deaths, per-patient years of exposure will be calculated by treatment arm.  
 
Differences in proportions with Grade 3 or greater adverse events will be compared and 95% 
confidence intervals calculated for overall comparisons, and repeated in subgroups according to HIV 
infection status and drug resistance patterns.   
ECG data for safety analyses for Stage 2 will be from the central cardiology reading facility for the 
study.  
 
Analyses will only include concurrently randomised patients. For example, analyses involving 
comparisons with Regimen A will only include data from patients who were part of the four-arm 
randomisation. Data from sites that only recruited to three regimens will be excluded from these 
comparisons, as will data from patients randomised after the change from four to three regimens in 
sites where this change was made. Details are provided in the Statistical Analysis Plan. 
 
11.7 IDMC review of Stage 1 results 
An additional IDMC meeting will be scheduled to occur immediately after the results of Stage 1 are 
available. The IDMC will be asked to review the entirety of the results from Stage 1 including all 
efficacy and safety endpoints as well as available data from Regimen A and Regimen B from Stage 
2 and data from other relevant studies and external sources. The IDMC will be asked to consider 
recommending to the TSC termination of recruitment to Regimen A if there is sufficient evidence to 
show that Regimen B is safe and non-inferior to Regimen A. 
 
If Regimen B is shown to have inferior efficacy to Regimen A or has an inferior safety profile that is 
considered clinically significant, the IDMC will be asked to consider making an appropriate 
recommendation for Stage 2 based on all available data and external evidence as appropriate. 
11.8 IDMC review of recruitment to Regimen A in Stage 2 
The IDMC will also be asked to review at their regular meetings recruitment to Regimen A, and 
subsequent withdrawals.  If there are predicted to be insufficient numbers of patients to provide 
useful data on the regimen they may recommend to the TSC that all recruitment to Regimen A should 
be discontinued. 
11.9 Pharmacokinetic Analysis 
Individual plasma concentrations will be listed and descriptive statistics will be generated for all 
quantified drugs, metabolites, cholesterol and 4β-hydroxycholesterol at each respective sampling 
time. Pharmacokinetic parameters will be derived based on the individual plasma concentration-
time data, including AUC24h (week 2) and AUC168h (week 12 and week 24). A population PK 
model will be used to provide individual estimates of PK parameters. . 
 


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The drug-drug interaction between bedaquiline and ARTs will be assessed by descriptive statistics 
and graphical analysis of plasma concentration-time data and pharmacokinetic parameters. 
 
Pharmacokinetic/pharmacodynamic relationships between bedaquiline concentrations and efficacy 
and safety parameters will be investigated.  
 


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12 TRIAL MONITORING 
Before the trial can be initiated, the prerequisites for conducting the trial must be clarified and the 
organisational preparations made with the sites. MRC CTU must be informed immediately of any 
change in the personnel involved in the conduct of the study. 
 
The purposes of trial monitoring are to verify that:  
 
The rights and well-being of human participants are protected 
 
The reported trial data are accurate, complete, and verifiable from source documents 
 
The conduct of the trial is in compliance with the currently approved protocol/amendment(s), 
with the principles of GCP, and with the applicable regulatory requirement 
12.1 Risk assessment 
A risk assessment was carried out during the feasibility assessment for this trial and is updated and 
reviewed approximately annually as the trial progresses and ahead of Stage 2 of the trial. The 
outcome of this assessment and its components are detailed in a separate document; the STREAM 
Monitoring Plan, which reflects issues identified in the study risk assessment and periodic reviews. 
 
12.2 Monitoring plan 
A detailed monitoring plan has been developed to reflect specific needs of the trial as determined by 
the risk assessment. This plan specifies the responsibilities and qualifications of monitors, central 
monitoring procedures, and the site monitoring visit procedures. Site visits by MRC CTU (or delegated 
collaborators) will be made in accordance with MRC CTU SOPs to assure the quality and accuracy of 
data collected and entered in the database, to determine that the applicable regulatory requirements 
are met and that rights and well-being of trial participants are protected. 
 
On-site monitoring visits will be made at a frequency determined by the risk assessment and pre-
defined triggers, including ‘for-cause’ monitoring as detailed in the monitoring plan. These visits will 
be made by the Trial Manager, Data Manager and/or other members of MRC CTU Trial Team, and/or 
delegated collaborators.   
 
12.3 Clinical site monitoring 
12.3.1 Direct access to data 
Participating investigators must agree to allow trial-related monitoring and audits, ethics committee 
review and regulatory inspections by providing direct access to source data/documents, including 
electronic records, as required. Patients’ consent/assent for this is obtained as part of the trial consent 
process. 
 
During the trial the MRC CTU TM is responsible for monitoring data quality in accordance with MRC 
CTU SOPs. Before the study start, the Local Trial Coordinator will be advised of the anticipated 
frequency of the monitoring visits and will receive reasonable notification before each monitoring 
visit. Responsibilities of the monitors are outlined in the Monitoring plan. 
 
During the course of this trial, the TM will maintain contact with the study sites on a regular basis. 
This will include a training/initiation visit prior to participant randomisation; a monitoring visit soon 


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after screening/randomisation begins and further visits as detailed in the monitoring plan. The 
monitor will meet with the investigators on a regular basis during the study to provide feedback on 
study conduct.  Closeout visits will be conducted after trial participation is completed. The sites will 
be contacted in advance to schedule each visit.  All participant records, CRFs, and other source 
documents for the patients recruited in this study will, where possible, be made available for review 
by the monitor(s).  A site-visit log will be maintained at each study site to record all STREAM-related 
site visits made by authorised individuals.   
 
12.3.2 Quality assurance (QA) procedures 
QA procedures at MRC CTU include a systematic review of the trial protocol by the Protocol Review 
Committee (PRC), the preparation of a Risk Assessment and Quality Management documents. A 
review of these documents is undertaken by the MRC CTU Research Governance Committee (RGC) 
and Quality Management Advisory Group (QMAG) which form the QA function of MRC CTU. Internal 
audits of the Trial Master File will be conducted as directed by the RGC. Audits of sites may be 
conducted by or on behalf of the sponsor.  These audits will require access to all study records, 
including source documents, for inspection and comparison with the CRFs. Participant privacy, must 
however, be respected. The Investigator and staff are responsible for being present and available 
for consultation during routinely scheduled site audit visits.  Similar procedures may also be 
conducted by agents of any regulatory body, either as part of a national GCP compliance 
programme or to review the results of this study in support of a regulatory submission. The 
investigator should immediately notify the sponsor if they have been contacted by a regulatory 
agency concerning an upcoming inspection. 
 
Good Clinical Practice (GCP) training, and where appropriate Good Laboratory Practice (GLP)25   
training will be provided for all staff involved in the trial. This will form part of the capacity 
strengthening component of the trial. 
 
12.3.3 Microbiology laboratory quality control 
Details of the arrangements for laboratory quality control (QC) are found in the STREAM Laboratory 
Manual. 
 
ITM Antwerp will assess and prepare all laboratories before start of the trial, and assure quality of 
the sites’ microscopy and cultures throughout the trial and GeneXpert MTB/RIF and/or LPA during 
the screening.  Test performance will be periodically monitored and reported. 
 
The following QC procedures will be used:   
 
Microscopy: internal control of newly prepared lots of staining solutions at the sites, 
together with random checking of smears performed at the presumed end of the intensive 
phase.  
 
Cultures: monitoring of false negative and contamination rates. 
 
LPA DST: a water blank in each run, to check for cross-contamination; strip-inbuilt controls 
for QC of amplification and colour reaction. EQA will be performed by sending panels 
composed of bacilli suspensions with known resistance patterns (Proficiency Testing).   
 
GeneXpert MTB/RIF: monitoring of errors plus proficiency testing panels will be used for 
the sites. There will be QC of phenotypic DST, DNA sequencing of resistance-conferring 
mutations performed at the central laboratory in Antwerp. 


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Details of QC will be provided in the laboratory manual. 
12.4 Central monitoring 
Central monitoring of data at MRC CTU will be conducted by CRF review, with appropriate and range 
and consistency checks programmed into the database. MRC CTU will raise any concerns they may 
have about the data captured by use of query forms sent to the site, as detailed in the Data 
Management Plan. 
 
The Trial Master File will be stored at MRC CTU and at Vital Strategies and will be maintained by the 
TM throughout the trial. All trial specific documents will be centrally tracked and copies obtained from 
the sites for all communication with regulatory bodies. Details about maintaining trial files and any 
other monitoring that will be carried out centrally are in the Monitoring Plan, other study 
documentation and plans as appropriate. 


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13 SAFETY REPORTING 
GCP requires that both investigators and sponsor follow specific procedures when notifying and 
reporting adverse events/reactions in clinical trials.  These procedures are described in this section 
of the protocol.  Section 13.1 lists definitions, section 13.2 gives details of the institution/investigator 
responsibilities and section 13.3 provides information on MRC CTU responsibilities. 
 
AEs are collected from the time the informed consent form is signed at screening until follow-up is 
completed or the participant withdraws from the trial.  If a patient is found to be ineligible for the 
trial at screening, or chooses not to be randomised, no further AE data should be collected from that 
point.   
13.1 Definitions 
The definitions of the EU Directive 2001/20/EC Article 2 based on GCP apply in this protocol.  These 
definitions are given in Table 11.   
 
Table 11: Safety reporting definitions 
Term 
Definition 
Adverse Event (AE)*  
Any untoward medical occurrence in a patient or clinical trial 
participant to whom a medicinal product has been administered 
including occurrences which are not necessarily caused by or related 
to that product. 
Adverse Reaction (AR)
 
 
Any untoward and unintended response to an investigational 
medicinal product related to any dose administered. 
Unexpected Adverse 
Reaction (UAR) 
An adverse reaction, the nature or severity of which is not consistent 
with the information about the medicinal product in question set out 
in the summary of product characteristics (or Investigator brochure) 
for that product. 
Serious Adverse Event 
(SAE) or Serious Adverse 
Reaction (SAR) or 
Suspected Unexpected 
Serious Adverse Reaction 
(SUSAR) (see 13.2.1 (d) 
for causality definition) 
 
Respectively any adverse event, adverse reaction or unexpected 
adverse reaction that:  
 
Results in death 
 
Is life-threatening** 
 
Requires hospitalisation or prolongation of existing 
hospitalisation*** 
 
Results in persistent or significant disability or incapacity 
 
Consists of a congenital anomaly or birth defect  
 
Other medically important condition, including suspected 
transmission of any infectious agent via administration of a 
medicinal product; 
 
Is a combination of the above (to be specified). 
 
13.1.1 Clarifications and exceptions 
*In addition, events from the point that the participant gives informed consent/assent to screening 
until randomisation are also defined as AEs for patients in stage 2. 
 
**The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient 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. 


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***Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalisation is a precautionary measure for continued observation.  Hospitalisations for a pre-
existing condition that has not worsened (including elective procedures) do not constitute an SAE; 
nor do hospital admissions for social and not medical reasons. Due to the seriousness of the disease 
in this study, some patients may be admitted to hospital for the initial phase of their trial treatment.  
This would not qualify as an SAE, although if that hospitalisation had to be prolonged beyond the 
normal length of admission, then it would be an SAE.  
 
Medical judgement should be exercised in deciding whether an AE/AR is serious in other situations. 
Important AE/ARs that are not immediately life-threatening or do not result in death or hospitalisation 
but may jeopardise the participant or may require intervention to prevent one of the other outcomes 
listed in the definition above, should also be considered serious. 
 
13.1.2 Trial specific exceptions to expedited SAE notification and reporting 
Data on disease relapse or progression are collected as part of the primary outcome of the trial and 
are not considered to be SAEs, unless fatal or in stage 2, requires hospitalisation. QT prolongation 
does not require grading since the actual QT and QTcF values are collected as part of routine 
monitoring, but QT or QTcF prolongation to more than or equal to 500 ms should be recorded as a 
notable event as specified in 13.1.3. Planned hospitalisations for the initial phase of trial treatment 
are also not considered as SAEs as noted in section 13.1.1 above.  
 
In Stage 2, adverse events which are not serious should be reported on the Stage 2 AE log. 
However, abnormal laboratory results that are not deemed by the PI to be clinically significant or 
do not result in change in therapy are exempt from event reporting i.e. they do not need to be 
added to the AE log. A clinically significant lab value is one that indicates a new disease process, an 
exacerbation or worsening of an existing condition, or requires further action(s) to be taken. 
 
13.1.3 Additional notable events 
The following notable events should also be identified and reported to the MRC CTU within the 
same time frame as an SAE (unless they also meet the criteria for an SAE, in which case they 
should be reported as such): 
 
Pregnancy in a patient or partner of a patient during protocol treatment or follow-up 
 
QT or QTcF measurement more than or equal to 500 ms while on treatment  
 
ALT/AST more than or equal to ten times ULN, or ALT/AST more than or equal to three 
times ULN in the presence of total bilirubin more than or equal to 2 times ULN  
 
Creatinine kinase more than or equal to 10 times ULN 
 
Pancreatic amylase more than or equal to 2 times ULN 
 
The occurrence of any grade 3 or higher adverse event  
 
Any toxicity that leads to withholding or stopping of allocated treatment for more than 24 
hours 
 
A clinically significant dysrhythmia, such as an episode of ventricular tachycardia, with three 
or more irregular beats in a row. 
 
An overdose of trial medication.    


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13.2 Institution/investigator responsibilities 
The severity (i.e. intensity) of all AEs/ARs (serious and non-serious) in this trial should be graded 
using the DAIDS criteria except for hearing loss, which will be graded using Brock’s Criteria.  
13.2.1 Investigator assessment  
(a) Seriousness 
When an AE/AR occurs the investigator responsible for the care of the patient must first assess 
whether the event is serious using the definition given in Table 11. If the event is serious and not 
exempt from expedited reporting, then an SAE/NE form must be completed and the MRC CTU 
notified.  
 
(b) Causality 
The Investigator must assess the causality of all serious events/reactions in relation to each trial drug 
that the patient has received using the definitions in Table 12.  There are 5 categories: unrelated, 
unlikely, possibly, probably and definitely related to trial treatment.  If the causality assessment is 
“unrelated” or “unlikely to be related” to trial treatment the event is classified as an unrelated SAE.  
If the causality is assessed as possible, probable or definitely related then the event is classified as a 
Serious Adverse Reaction (SAR). 
 
(c) Expectedness 
If the event is a SAR the Investigator must assess the expectedness of the event, with the exception 
of events thought to be caused by bedaquiline, which will be assessed for expectedness at MRC CTU.  
The definition of an unexpected adverse reaction (UAR) is given in Table 11. A list of expected 
toxicities associated with the drugs being used in this trial is provided in the STREAM Patient 
Management Guide.  If a SAR is assessed as being unexpected it is a Suspected Unexpected Serious 
Adverse Reaction, or SUSAR.   
 
(d) Notification  
Investigators should notify the MRC CTU of all SAEs and other notable events as defined above, 
within one working day of them becoming aware of the event.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 12: Definitions of causality 
Relationship 
Description 
Event Type 
Unrelated 
There is no evidence of any causal relationship 
Unrelated SAE 
Unlikely 
There is little evidence to suggest there is a causal relationship 
(e.g. the event did not occur within a reasonable time after 
administration of the trial medication).  There is another 
reasonable explanation for the event (e.g. the patient’s clinical 
condition, other concomitant treatment). 
Unrelated SAE 
Possible 
There is some evidence to suggest a causal relationship (e.g. 
because the event occurs within a reasonable time after 
administration of the trial medication).  However, the influence 
of other factors may have contributed to the event (e.g. the 
patient’s clinical condition, other concomitant treatments). 
SAR 
Probable 
There is evidence to suggest a causal relationship and the 
influence of other factors is unlikely. 
SAR 
Definitely 
There is clear evidence to suggest a causal relationship and 
other possible contributing factors can be ruled out. 
SAR 
 
 
Notification procedure: 
1. 
The SAE/NE form must be completed by the Investigator (consultant named on the signature 
list and delegation of responsibilities log who is responsible for the patient’s care), with due 
care being paid to the grading, causality and expectedness of the event as outlined above.  
In the absence of the responsible investigator the form should be completed and signed by a 
member of the site trial team delegated to do so.  The responsible investigator should 
subsequently check the form, make changes as appropriate, sign and then re-send to the 
MRC CTU as soon as possible.  The initial report shall be followed by detailed, written reports 
as appropriate 
2. 
Send the SAE/NE form by email to the MRC CTU within one working day. 
Email: mrcctu.streamdata@ucl.ac.uk.  
3. 
Follow-up: Patients must be followed-up until clinical recovery is complete and laboratory 
results have returned to normal or baseline, or until the event has stabilised. Follow-up should 
continue after completion of protocol treatment if necessary.  Follow-up information should 
be noted on a further SAE/NE form by ticking the box marked ‘follow-up’ and emailing it to 
the MRC CTU as information becomes available.  Extra, annotated information and/or copies 
of test results may be provided separately. The patient must be identified by study number, 
date of birth and initials only.  The patient’s name should not be used on any correspondence 
4. 
Staff at the investigator site must notify the research ethics committee and local Regulatory 
Authority of the event (as per the institutions standard local procedure).  
 
 
 
 
 
 
 
 
 
 


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Figure 11: Safety reporting flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.3 MRC CTU responsibilities 
 
Medically qualified staff at the MRC CTU or the Co-CI’s medically qualified delegate will review all SAE 
reports received.  This may involve discussions with the STREAM central clinical team as outlined in 
the Patient Management Guide. The causality assessment given by the local clinical investigator 
cannot be overruled and in the case of disagreement, both opinions will be provided in any 
subsequent reports. The investigator’s assessment of expectedness may be modified by the medical 
reviewer.  
 
The MRC CTU is undertaking the duties of trial management and is responsible for providing the 
Sponsor’s research ethics committee and the regulatory authorities that have approved the trial with 
the safety reports that they require. 
 
Was the event serious? 
• 
Resulted in death 
• 
Life-threatening 
• 
Required inpatient hospitalisation or prolongation of 
existing hospitalisation 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect 
• 
Other medically important condition, including suspected 
transmission of any infectious agent via administration of 
a medicinal product 
 
Was the event notable? 
 
Pregnancy in a patient or partner of a patient while on 
protocol treatment or during follow-up 
 
QT or QTcF measurement more than or equal to 500 ms 
while on treatment  
 
ALT/AST more than or equal to 10 times ULN, or ALT/AST 
more than or equal to 3 times ULN in the presence of total 
bilirubin more than or equal to 2 times ULN  
 
Creatinine kinase more than or equal to 10 times ULN 
 
Pancreatic amylase more than or equal to 2 times ULN 
 
The occurrence of any grade 3 or higher adverse event  
 
Any toxicity that leads to a withholding or stopping of 
allocated treatment for more than 24 hours 
 
A clinically significant dysrthymia, such as an episode of 
ventricular tachycardia, with three irregular beats in a row 
Adverse Event/Adverse Reaction 
SAE or NE 
Record on an SAE or NE form and notify the central clinical 
team within one working day of becoming aware of the event 
Yes 
Yes 
AE/AR 
Record on the ‘Patient 
Assessment Form’ 
No 


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The MRC CTU will provide the Independent Data Monitoring Committee (see section 19) with 
aggregated reports of SAEs for their review and will keep all investigators informed of any safety 
issues that arise during the course of the trial. After receipt and review of these reports, MRC CTU 
will also notify the trial sponsor. 
 
 
 
 
 
 
SAE/NE NOTIFICATION 
 
 
Within one working day of becoming aware of an  SAE/NE, 
please email a completed SAE/NE form to the MRC CTU on: 
 
 
Email: mrcctu.streamdata@ucl.ac.uk 
 
 
 
 
 
13.4 Product quality complaint handling 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labelling, or packaging, i.e. any dissatisfaction relative to the identity, quality, 
durability, and reliability of a product, including its labelling or package integrity. PQCs may have an 
impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from clinical studies are crucial for the protection of participants, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide.  
13.4.1 Procedures 
All initial PQCs must be reported to the MRC CTU and the Sponsor by the site staff as soon as possible 
after being made aware of the event. 
 
If the defect is combined with an SAE, the site staff must report the PQC to the MRC CTU according 
to the SAE reporting timelines (see Section 13.2). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor. 
 
 
 


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14 ETHICAL CONSIDERATIONS AND APPROVAL 
14.1 Ethical considerations 
The study will abide by the principles of the Declaration of Helsinki. 
14.1.1  Research Ethics Committee (REC) review and approval 
Before initiating the study at any given site, the study must be approved in writing by the local REC 
and/or Institutional Review Board (IRB), where appropriate, as well as the Ethics Advisory Group of 
The Union. The study will be conducted in accordance with all conditions of approval by the REC. The 
local Principal Investigator will forward the approval letter to MRC CTU.  
 
Before starting the trial, the protocol, patient information sheet, informed consent and assent forms, 
study specific patient cards and any local advertising materials must be reviewed by the MRC CTU 
Protocol Review Committee; and be approved by the Trial Steering Committee (TSC) and the 
appropriate Ethics Committee in all participating countries. 
 
It is the local Principal Investigator’s responsibility to update patients (or their authorised 
representatives, if applicable) whenever new information becomes available that might affect the 
patient’s willingness to continue in the trial.  The Principal Investigator must ensure this is 
documented in the patient’s medical notes and the patient is re-consented/assented, where 
appropriate. 
 
The sponsor and Investigators must ensure that the study is carried out in accordance with the 
principles of Good Clinical Practice (GCP) as laid down by the ICH topic E6 (Note for Guidance on 
GCP),  the Declaration of Helsinki and applicable regulations in each country. 
 
14.1.2 Informed consent/assent 
No patient may be screened for or randomised into this study until the investigator has obtained 
his/her informed consent/assent. Informed consent/assent encompasses all oral or written 
information given to the participant about the study and the study materials.  All such information 
will be in a language which is understandable to him/her. The information will not include any 
language in which the participant is made to waive any of their rights or which releases (or appears 
to release) the investigator, the investigator’s institution or the MRC CTU, from liability for negligence. 
 
Consent/assent for study participation will be based on a template Patient Information Sheet (PIS), 
which will be provided to all participating sites. The information contained in the PIS will be translated 
into the relevant local languages and verified to ensure consistency of content. Literate patients will 
be asked to read the form and illiterate patients will have the contents explained to them by a 
counsellor, in the presence of a witness who will be present during the whole consent/assent process. 
Patients will have the opportunity to discuss the PIS with the medical officer/treatment supervisor. 
They will be assured that their decision to participate in the trial or not will not affect the quality of 
care they will receive. Once this person is satisfied that the patient has understood the PIS and the 
informed consent/assent form, the patient will be asked to give consent/assent. 
 
The patient will sign (or thumbprint) and the investigator or designee will also sign the informed 
consent/assent form.  If the patient is illiterate, their witness will also sign the form. One copy of the 


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signed informed consent/assent form will be offered to the participant, a second copy will be filed in 
the patient’s medical notes (where available) and the original signed informed consent form will be 
kept in his/her study file. The investigator is also responsible for developing tools that may help in 
explaining the study to patients, these materials will also be submitted to MRC CTU at least one week 
before submission to the local REC. 
14.1.3 Randomisation 
Prior to the start of any trial procedures, the randomisation process will be explained as part of the 
patient information sheet at the patient’s randomisation visit. Patients will be given a chance to ask 
any questions they may have before they consent to taking part in the trial.  
 
14.1.4 Patient confidentiality 
The confidentiality of all patients participating in this study will be protected to the fullest extent 
possible.  All patient information will be kept secure and will be available only to the treatment staff 
and representatives of the sponsors, regulators, and ethics committees.  
 
Study patients should not be identified by name on any case report form, email or on any other 
documentation sent to MRC CTU and will not be reported by name in any report, presentation or 
publication resulting from data collected in this study. Patients’ data/specimens will be identified by 
study number or hospital number only.  
 
The trial will comply with the principles of the UK Data Protection Act and the equivalent 
regulation/legislation of the country of the participating site. 
 
14.1.5 Additional trial requirements 
Patients may be required to provide additional samples or may be required to come to the clinic for 
more visits if clinically indicated.  
 
14.1.6 Record retention 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate 
records to enable both the conduct of a clinical trial and the quality of the data produced to be 
evaluated and verified.   
 
All essential documents (according to GCP and MRC CTU SOPs) required to be held by the Investigator 
must be stored in such a way that ensures that they are readily available, upon request, to the local 
Regulatory Agency, the sponsor, or for US FDA or EMA inspection, for the minimum period required 
by national legislation or for longer if needed by MRC CTU. Records must not be destroyed without 
prior written approval from MRC CTU. 
 
The medical files of trial participants shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
 
At the end of the trial, photocopies of pertinent study documentation (such as REC correspondence, 
etc.) will be kept by MRC CTU. CRFs will remain in the patient’s study file at the participating sites. 
The signed original informed consent/assent documents for each participant and originals of other 


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study documentation (e.g. drug inventory forms, participant clinic records, original laboratory reports, 
etc.) will be retained by the local PI for a minimum of 15 years (as specified in MRC CTU working 
instructions on archiving).  If those years have passed with no request for the data, the sites may 
request permission in writing from MRC CTU to destroy the records.  No records may be destroyed 
without written permission from MRC CTU. 
 
14.1.7 Audit 
The investigator may be subject to a field audit by Vital Strategies, MRC CTU, or a health authority 
inspection to validate the participation of study patients, to verify the data reported on the Case 
Report Forms and to confirm the compliance of the conduct of the trial with applicable regulations 
and requirements and the protocol.  This audit could occur while the study is in progress, several 
years after the study is completed, or when the data are under review. All of the patients’ records 
and other study documentation must be filed and accessible on short notice (3-5 days) during the 
study and subsequent retention period. 
 
14.2 Protocol deviations 
No waivers will be given by MRC CTU on behalf of the sponsor for patients who do not fulfil the 
eligibility criteria for this trial. No deviations from, or changes to, the protocol should be initiated 
without prior written REC/IRB, regulatory authority approval/favourable opinion and approval from 
MRC CTU on behalf of the sponsor.  
 
The reporting procedures and how to handle deviations are detailed in the MRC CTU SOPs and trial-
specific Working Practice Documents for protocol deviations. 
 
14.3 Ethical approval 
The Union’s Ethics Advisory Group has given a favourable opinion for the trial and protocol and has 
indicated in broad terms that the trial concept is consistent with ethical requirements. Each 
participating site will submit the protocol to their relevant Ethical Review Committees and/or 
Institutional Review Boards. All substantial amendments to this protocol will have to be submitted for 
approval. 
 
A copy of local REC/IRB approval of the protocol and of the participant information sheet (PIS) and 
informed consent/assent form (ICF) on local headed paper and any other written information given 
to the participant should be forwarded to MRC CTU before patients are randomised into the trial. 
Each patient’s consent/assent to participate in the trial should be obtained after a full explanation 
has been given of the treatment options, including the conventional and generally accepted methods 
of treatment.   
 
The right of the patient to refuse to participate in the trial without giving reasons must be respected. 
After the patient has entered the trial, the clinician must remain free to give alternative treatment to 
that specified in the protocol, at any Stage, after discussions with the STREAM central clinical team, 
if he/she feels it to be in the best interest of the patient. However, the reason for doing so should be 
recorded and the patient will remain within the trial for the purpose of follow-up and data analysis 
according to the treatment option to which they have been allocated. Similarly, the patient must 


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remain free to withdraw at any time from the protocol treatment and trial follow-up without giving 
reasons and without prejudicing his/her further treatment. 
 
 
  


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15 REGULATORY ISSUES 
All Investigators will be expected to obtain, in writing, approval to participate from their local 
Regulatory Authority. Copies of the approval (or non-approval) must be submitted to MRC CTU no 
later than 5 working days from receipt of the same. 
 
A special authorisation of importation for the medicines to be used in the study should be obtained, 
by the responsible person at each site, from the National Drug Regulatory Authorities (NDRA) and 
provided to Vital Strategies.  
 
 
16 INDEMNITY 
The sponsor of the trial is Vital Strategies.  Global insurance coverage for the trial was obtained by 
Vital Strategies. Country-specific insurance policies for the trial were also obtained by the Sponsor 
where required.  
 
The local Principal Investigator/Investigator’s institution is liable for negligent harm, for each of the 
participating sites unless alternative provisions have been made by the Sponsor. All personnel 
involved in the trial will be expected to be indemnified by their employing authority; in exceptional 
circumstances, the country-specific policies may also cover local investigator/practitioner liability.  
 
 
17 ANCILLARY STUDIES 
Ancillary studies may be conducted at selected sites participating in STREAM provided they have 
been approved by the Trial Steering Committee to ensure no negative impact on the main STREAM 
trial. Each ancillary study will have its own protocol and informed consent/assent forms and be 
approved by the relevant ethical and regulatory committees. 
 
 
 
18 FINANCE 
The trial is sponsored by Vital Strategies.  The primary funder of the trial is the United States 
Agency for International Development (USAID), with additional funding from the UK Medical 
Research Council (MRC) and the UK Department for International Development (DFID) under the 
MRC/DFID Concordat agreement and Janssen Research & Development, LLC. This trial will be 
managed and coordinated by the Medical Research Council Clinical Trials Unit at UCL (MRC CTU). 
 
Each participating site will be supported according to the submissions of their budgetary 
requirements. 
 
Reimbursements will be made according to sub-agreements signed between the the Sponsor and the 
participating sites.  
 


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19 TRIAL COMMITTEES 
19.1 Trial Management Group (TMG) 
The Trial Management Group (TMG) will consist of representatives from different disciplines involved 
in the day to day running and management of the trial. It will include the Co-Chief Investigators, a 
member with clinical expertise in MDR-TB, members of the MRC CTU involved in the running of 
STREAM, namely the Trial Manager, the Data Manager, Project Manager and Trial Statistician. The 
group will also include representatives from Vital Strategies, including the Trial Pharmacist and others 
involved in the trial operations. Trial staff from ITM in Antwerp the Impact Assessment team from 
the Liverpool School of Tropical Medicine and the MRC CTU Data Management Systems will attend 
TMG meetings periodically upon request. The TMG will have access to clinical expertise in cardiac 
arrhythmias and hepatology for review of safety. Input to the TMG from relevant operational staff of 
Janssen Pharmaceuticals may be requested intermittently, on an as needed basis.  The TMG will 
convene approximately monthly and it will report to the TSC on progress and issues.  
 
19.2 Trial Steering Committee (TSC) 
A TSC with an independent chair and a majority of independent voting members will be responsible 
for the oversight of the trial and provide advice to the investigators. No important decision should be 
made in the absence of a Co-Chief Investigator. Additional observers, including other investigators, 
a sponsor representative, and funder representatives, may be in attendance at the TSC meetings; 
they may provide additional input as requested. A STREAM TSC charter describes the membership 
and responsibilities of the TSC which include:  
 
 
providing expert oversight of the trial 
 
making decisions as to the future continuation (or otherwise) of the trial 
 
monitoring recruitment rates and encourage the TMG to develop strategies to deal with any 
recruitment problems 
 
reviewing regular reports of the trial from the trials unit (sent on behalf of the Trial 
Management Group (TMG)) 
 
assessing the impact and relevance of any accumulating external evidence 
 
approving any amendments to the protocol, where appropriate 
 
approving any proposals by the TMG concerning any change to the design of the trial, 
including additional sub-studies 
 
overseeing the timely reporting of trial results 
 
approving the statistical analysis plan 
 
approving the publication policy 
 
approving the main trial manuscript 
 
approving any abstracts and presentations of any results during the running of the trial 
 
Approving external or early internal requests for release of data or subsets of data or samples 
including clinical data and stored biological samples. 
 
19.3 Independent Data Monitoring Committee (IDMC) 
The IDMC will review safety and efficacy data regularly. The list of members and their 
responsibilities is included in the STREAM IDMC charter. The IDMC could, in exceptional 
circumstances, recommend termination of the study or termination of one of the treatment 


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regimens due to unacceptable levels of drug toxicity, or mortality; the trial should not be modified 
on account of differences in efficacy between treatment arms unless there is a concern for patient 
safety (except the possibility of the IDMC recommendation of termination of recruitment to 
Regimen A, see section 11.7). The IDMC will be asked to give advice to the TSC on whether the 
accumulated data from the trial, together with results from other relevant trials, justifies continuing 
recruitment of further patients. They may recommend modification or closure of the study in a 
country or sub-group of patients, such as those who are HIV-infected.    
 
The IDMC will convene approximately 6-monthly but may meet more frequently if it becomes 
necessary to do so. A charter describes in full the responsibilities of the IDMC and the format of their 
meetings and members will be required to sign this before the first meeting.  
 
 
 
 


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20 PUBLICATION 
20.1 Publication 
The definition of publication for this purpose is any public representation of the data emerging from 
this trial. Results of this study will be submitted for publication in a peer reviewed journal. This will 
be the analysis of the primary objectives of the study and this manuscript, together with subsequent 
manuscripts, including any single site data, will require the review and agreement of the TSC prior to 
submission.  
 
Details for producing manuscripts, abstracts, press releases and any other publications including 
guidelines for authorship are outlined in the STREAM Publication Policy.  
 
20.2 Dissemination of results to trial participants 
Study results will be shared with participants through mechanisms and materials reviewed and 
approved by The Union’s Ethics Advisory Group and other relevant stakeholders. 
 
 


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21 APPENDICES 
Appendix 1: High-dose moxifloxacin safety summary 
 
1. Rationale  
 
Gatifloxacin (400mg daily for patients less than 33kg, 600mg for those 33-50kg, and 800mg if more 
than 50kg) was considered to be a critical component of the success of the regimen developed by 
van Deun et al; the ofloxacin-containing regimens tested were associated with inferior outcomes2 . 
Because an internationally acceptable, quality-assured supply of gatifloxacin is not available, it was 
necessary to substitute a different fluoroquinolone, and moxifloxacin was judged to be the best 
alternative. Gatifloxacin and moxifloxacin have similar bactericidal activity at the same dose1 and 
based on pharmacokinetic modelling there is reason to believe that the higher than standard doses 
are needed to prevent secondary fluoroquinolone resistance26.  
The standard dose of moxifloxacin is 400mg daily without any weight adjustment. In the STREAM 
study, as in the regimen developed by van Deun et al, 400mg will be used for patients less than 
33kg, 600mg for those 33-50kg, and 800mg if more than 50kg. The main concern about the 
substitution of moxifloxacin for gatifloxacin is the potential for cardiac toxicity.  
 
 
2. Cardiac safety of moxifloxacin at the standard dose  
Moxifloxacin is an 8-methoxy quinolone, a member of the widely used fluoroquinolone family of anti-
bacterial agents, which are some of the most frequently prescribed antibiotics in the world. 
Fluoroquinolones, in particular moxifloxacin, are known to prolong the QT interval, which occurs when 
drugs prevent the outward flow of potassium through cardiac voltage-gated potassium channels27. 
This causes a delay in cardiac repolarisation and may increase the risk of Torsades de pointes (TdP), 
a life threatening ventricular tachycardia. However, despite this propensity and its extensive use, 
there are very few reported cases of TdP induced by moxifloxacin28.  
 
QT prolongation is defined as a QT interval above the upper limit of normal: 450 ms for men and 470 
ms for women29,30. However, the best indicator that a drug has the potential to induce arrhythmias 
is if it causes QTc (QT interval corrected for heart rate) prolongation to greater than 500ms30.  
 
The QTc increase following moxifloxacin has been well documented. Florian et al. reported an average 
increase of 10-14 ms following a single 400 mg dose across several investigations31. Tsikouris et al. 
acquired similar results after conducting an open label cross-over study in 13 healthy participants, 
including moxifloxacin at 400 mg, revealing an average QTc increase of 11 ms at 2-hours post dose32.  
Based on all the clinical trial data for moxifloxacin at the standard dose, ventricular tachyarrythmias 
are estimated to occur in less than 1/1,000 and Torsades de pointes and cardiac arrest in less than 
1/10,00033. The case reports of TdP potentially related to moxifloxacin have occurred in elderly 
patients with pre-existing heart conditions34,35,36.  
 
Rubinstein’s 2002 review reported that there were no cases of cardiovascular morbidity attributable 
to QTc prolongation recorded in 6000 patients involved in moxifloxacin phase II-IV clinical trials, 


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though there were four cases of arrhythmias (three non-specified) and one case of TdP in one elderly 
female patient with pre-existing risk factors including hypokalaemia, coronary artery disease, digoxin 
treatment and a pacemaker. They concluded that the fluoroquinolones in question (including 
moxifloxacin) were safe but should be closely monitored in patients with pre-existing conditions or 
those taking concomitant medication36.  
 
The trial data includes a randomised trial comparing the cardiac safety of moxifloxacin 400mg and 
levofloxacin 500mg in 387 elderly patients with community acquired pneumonia over 70% of whom 
had pre-existing cardiac disease; no difference in cardiac safety was detected37.  
 
 
3. Higher doses of moxifloxacin  
 
Investigations using higher doses of moxifloxacin have been conducted although there is considerably 
less experience than with the standard dose. Démolis et al. conducted a placebo-controlled crossover 
study in 18 healthy volunteers in which both 400mg and 800mg prolonged the QT interval compared 
to placebo, but there was little difference between the two doses: the 400mg and 800mg doses 
increased QTc by 4.0% ± 5.1% and 4.5% ± 3.8%, respectively38. At two hours post dose, mean QTc 
intervals were recorded as 394 ±33 ms (400mg) and 396 ±28 ms (800mg) compared with the 
placebo mean of 379 ± 24ms. 800mg doses of moxifloxacin were also used in a 4-sequence cross-
over study in 48 healthy patients across a spectrum of ages was conducted by Noel et al.39. Mean 
corrected QTc (Bazett) was recorded at 425-430 ms post-dose, with the peak between 2-4 hours; 
6/47 patients (12.8%) had QTc intervals above the normal limits. All adverse events (six following 
moxifloxacin treatment) were described as mild, brief and spontaneously resolving.  
 
In a trial of moxifloxacin-based treatments for H. pylori a total of 94 patients with a mean age of 50 
received 800 mg moxifloxacin daily in conjunction with amoxicillin and esomeprazole for 10 days, 102 
for 7 days and 98 for 5 days (294 in total) without any cardiac adverse events40; no ECG monitoring 
was undertaken.  
 
Stass et al. conducted a study of moxifloxacin at doses ranging from 50mg – 600 mg in 7 healthy 
participants41. The study drug was well tolerated at all doses, with no clinically relevant changes in 
electrocardiogram data and only mild adverse events with no deaths or drop-outs.  
 
In addition, there is one case report of a patient with miliary TB whose treatment included 800 mg 
moxifloxacin42. Results confirmed that the peak plasma concentration was between 2-4 hours with a 
mean QTc of 442.  
 
 
 
4. Safety monitoring in STREAM  
 
The available literature suggests that the difference in the effects of moxifloxacin on the QT interval 
at doses between 400 and 800mg are unlikely to be substantial, while the benefits in relation to 
prevention of acquired resistance are likely to be integral to the regimen.  
The safety measures to be undertaken in STREAM are robust and designed to monitor the possible 
effects of moxifloxacin at peak concentration and to detect any possible cumulative effects. In Stage 


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STREAM Protocol V111 15 Dec 2020 
 
99 
1 any patient with a QT or QTc above 500 ms prior to treatment will be excluded from the trial. In 
Stage 2 any patient with a QT or QTc above 450 ms prior to treatment will be excluded from the trial.  
 
In Stage 1, all patients will be monitored with a 12-lead ECG at 4 hours post the initial dose to capture 
the peak QTc increase, with further ECGs at weeks 1-4, and then every 4 weeks until Week 52. In 
Stage 2, the 4-weekly 12-lead ECGs will continue until Week 76; 
 
As described in Section 8.31, patients found to have a QT or QTc more than or equal to 500 ms on 
a 12-lead ECG at any point during treatment will be further investigated to confirm the finding and 
identify the cause. If moxifloxacin is found to be the cause, and no other cause can be identified and 
eliminated, moxifloxacin at the standard dose (400 mg) should be tried.  If standard dose moxifloxacin 
also causes persistent QT or QTc more than 500 ms moxifloxacin will be discontinued and levofloxacin 
tried instead. Concomitant medications will be closely monitored throughout the trial, in particular 
anti-retroviral therapy; however, the recent findings from the SMART trial would suggest that their 
effects are likely to be small43.  
 
Although ECG monitoring of this intensity would not be feasible in routine practice, it is being 
implemented here both to protect the patients in the trial and to determine the safety of the regimen. 
The current data suggests that TdP with moxifloxacin is a rare event. The STREAM protocol is 
designed to closely monitor patients and those at greatest risk of cardiac toxicity will be excluded. 
The potential risks of the regimens, Regimen B, Regimen C and Regimen D, should be balanced 
against both the risks of MDR-TB for which outcomes are poor and mortality is high (11% of patients 
in a systematic review of 33 studies of MDR-TB treatment died during treatment)8, as well as the 
widely documented and serious adverse effects related to alternative MDR-TB treatment regimens.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STREAM Protocol V111 15 Dec 2020 
 
100 
Appendix 2: Levofloxacin Safety Summary 
 
Stage 1 of STREAM (The evaluation of a standardized treatment regimen of anti-tuberculosis drugs 
for patients with MDR-TB is an ongoing trial to evaluate the “Bangladesh regimen” compared to the 
WHO standard of care. In Stage 1 patients receive moxifloxacin (MFX) adjusted for weight instead of 
gatifloxacin which was used in the observational trial in Bangladesh.2  This change was necessitated 
by the withdrawal of gatifloxacin by the marketing authorization holder. The weight adjusted MFX 
dosing in Stage 1 of STREAM was used to provide maximal fluoroquinolone activity which was felt by 
many experts to be critical to the reported success of the “Bangladesh regimen”. In Stage 2 of 
STREAM, levofloxacin will be used in the bedaquiline containing arms (C and D) instead of MFX to 
minimize the QT prolongation associated with bedaquiline. Levofloxacin (LFX) will be dosed at 
750mg/day in subjects weighing < 50 kg and 1,000 mg in subjects weighing > 50kg. In Arm B MFX 
will be dosed at 400mg/day in subjects weighing < 33 kg, 600 mg/day in subjects weighing > 33 kg 
to < 50 kg, and 800 mg in subjects weighing > 50kg. This document summarizes information about 
the relative in vitro potencies against Mycobacteria tuberculosis of each fluoroquinolone. In addition, 
pertinent articles from the limited clinical literature that directly compares the use of both agents for 
the treatment of MDR TB is discussed. 
Error! Reference source not found. shows the MIC values obtained by Dr. Ji’s group for ofloxacin 
(OFX), LFX, clinafloxacin (CFX) and MFX against banked clinical isolates of MTB. The MIC50 and MIC90 
were 0.50 and 1.0 ug/ml, respectively, for both LFX and MFX. Other investigators have reported that 
MFX was more potent in vitro than LFX.44 However, lower MICs for MFX in comparison to LFX were 
not predictive of superior efficacy based upon pharmacokinetics/pharmacodynamics principles.  
 
Table 13: MIC values for fluoroquinolones 
Compound 
MIC range 
MIC50 
MIC90 
Reference 
OFX 
0.50-2.0 
1.0 
1.0 
Ji et al. 199545 
LFX 
0.25-1.0 
0.50 
1.0 
Ji et al. 199545 
MFX 
0.12-0.50 
0.50 
1.0 
Ji et al. 199846 
CFX 
0.12-1.0 
0.50 
1.0  
Ji et al, 199846 
 
 
A recent evaluation of MDR-TB like treatment regimens given for 6 or 7 months in the mouse model 
of infection (see Error! Reference source not found.4) reported similar relapses at 5 months, but 
fewer relapses with MFX compared to LFX at months 6 and 7.  
 
 
 
 
 
 
 
 
 
 


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STREAM Protocol V111 15 Dec 2020 
 
101 
Table 14: Relapse* after Treatment Completion 45 
 
% (Proportion) of Mice Relapsing after Treatment for: 
Regimen 
5 mo 
6 mo 
7 mo 
2 mo RHZ + RH 
23 (7/30) 
0 (0/30) 
not done 
2 mo MEtZA + MEtZ 
97 (28/29) 
59 (17/29) 
20 (6/30) 
2 mo LEtZA + LEtZ 
100 (26/26) 
79 (23/29) 
38 (11/29) 
Definition of abbreviations: A = amikacin; Et = ethionamide; H = isoniazid; L = levofloxacin; M 
= moxiflocacin; R = rifampin; Z = pyrazinamide. 
 
* Relapse was defined by a positive culture upon plating the entire lung homogenate harvested 
3 mo after completing the indicated duration of treatment. 
 
 
• 
Using an extended Early Bactericidal Activity study design (eEBA)16 described the early and 
extended bactericidal activity (eEBA) of LFX, gatifloxacin and MFX in patients with drug 
sensitive pulmonary tuberculosis. In this randomised, open-label trial, 40 adults with newly 
diagnosed smear-positive DS TB (10 subjects/arm) were assigned to receive: isoniazid (INH) 
300 mg, LFX 1000 mg, gatifloxacin 400 mg, or MFX 400 mg daily for 7 days. Sputum for 
quantitative culture was collected for 2 days before and daily during 7 days of monotherapy. 
Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days 
(EBA 0–2) and last 5 days of monotherapy (extended EBA, EBA 2–7). The EBA 0–2 days of 
INH (0.67 log10 cfu/ml/day) was significantly greater than that of MFX and gatifloxacin (0.33 
and 0.35 log10 cfu/ml/day, respectively), but was not significantly greater than LFX 1000 mg 
daily (0.45 log10 cfu/ml/day) (P=0.14). Bactericidal activity between days 2 and 7 was similar 
for all three fluoroquinolones. The authors concluded that MFX, gatifloxacin, and high-dose 
LFX have excellent EBA, only slightly less than for INH, and greater extended EBA and that 
these drugs warrant further study in the treatment of drug-susceptible TB. 
• 
In a recent retrospective analysis from China, the efficacy of MFX and LFX was explored in 
the treatment of multidrug-resistant tuberculosis (MDR-TB).47 158 patients with MDR-TB 
receiving either MFX- or levofloxacin-containing regimens were described. Clinical data from 
patients were subjected to univariate analysis, stratification and multiple logistic regression to 
compare the roles of moxifloxacin and levofloxacin in multidrug regimens. In total, 72 patients 
received 400 mg of moxifloxacin once daily and 86 patients received 509.9 ± 79.4 mg (mean 
± standard deviation) of levofloxacin once daily together with similar active agents for similar 
durations. The time to sputum culture conversion were similar. Adverse reactions occurred at 
comparable rates. The success rates for the MFX group were 65.3% (overall), 77.1% 
(ofloxacin-susceptible cases) and 54.1% (ofloxacin-resistant cases) in comparison with 
55.8%, 60.4% and 50.0%, respectively, for the LFX group. No demographic, clinical, 
bacteriological or treatment characteristics were independent predictors of favourable 
outcome. Fourteen patients from the MFX group and twelve patients from the levofloxacin 
group had bacteriological relapse after treatment cessation. The authors concluded that 
compared with levofloxacin, MFX did not show superior efficacy when incorporated into 
multidrug regimens used for the treatment of MDR-TB. 
• 
Koh et al.48 described the effectiveness of LFX and MFX compared in terms of culture 
conversion after 3 months of treatment for MDR-TB. In this prospective multicentre 
randomised open label trial, 182 patients with MDR-TB (sensitive to LFX and MXF) received 


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STREAM Protocol V111 15 Dec 2020 
 
102 
either LFX (750 mg/day; 90 patients) or MXF (400 mg/day; 92 patients) with a background 
drug regimen. The primary outcome was the proportion of patients who achieved sputum 
culture conversion at 3 months of treatment. Secondary outcomes were the proportions of 
adverse drug reactions. At 3 months of treatment, 68 (88.3%) of the 77 patients in the LFX 
group and 67 (90.5%) of the 74 in the MXF group showed conversion to negative sputum 
cultures (odds ratio for LFX compared with MXF, 0.78; 95% confidence interval, 0.27-2.20). 
Adverse drug reactions were reported in six patients (7.7%) in the LFX group and four (5.2%) 
in the MXF group (P = 0.75). The authors concluded that the choice of LFX or MXF for 
treatment of patients with MDR-TB did not affect sputum culture conversion at 3 months of 
treatment. 
Another group of investigators from Korea reported results from a retrospective review of the use of 
LFX and MFX in the treatment of MDR TB.49  The outcomes of 171 patients are described. Detailed 
information on dosing and duration are not provided. One hundred and twenty-three of the 171 
received LFX and 97 (78.9%) were classified as treatment successes compared to 40 treatment 
successes (83.3%) in the 48 who received MFX. 
In conclusion, many authorities believe that MFX is more potent than LFX in vitro but that superior 
potency does translate into a better efficacy either in animal models or the treatment of MDR-TB in 
patients. In the mouse, there is a trend for fewer relapses when MFX is used as part of an MDR TB 
like regimen compared to LFX. However, an EBA study and several recent small clinical reports 
describe acceptable and generally similar clinical outcomes when either LFX or MFX was used as part 
of an MDR TB regimen. This data supports the use of levofloxacin adjusted for weight in Arms C and 
D of the STREAM trial. 
 
Based the necessity of using LFX with bedaquiline and the design of the ongoing STREAM trial which 
utilizes weight based dosing for MFX we assert that the weight based dosing of LFX proposed in Stage 
2 of STREAM is justified. This is supported by the limited clinical data and expert opinion.50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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103 
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Florian J et al. Population Pharmacokinetic and Concentration-QTc Models for Moxifloxacin: 
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Tsikouris J et al. Effects of Three Fluoroquinolones on QT Analysis After Standard Treatment 
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34. 
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Dale K M et al. Moxifloxacin and Torsade de Pointes (Case Report). The Annals of 
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Rubenstein E and Camm J. Cardiotoxicity of fluoroquinolones. Journal of Antimicrobial 
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37. 
Morganroth J et al. A Randomized Trial Comparing the Cardiac Rhythm Safety of Moxifloxacin 
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38. 
Demolis J-L et al. Effect of a single oral dose of moxifloxacin (400mg and 800mg) on 
ventricular repolarization in healthy subjects. Clincal Pharmacology & Therapeutics 2000; 8: 658-66. 
39. 
Noel G J et al. Effects of three fluoroquinolones on QT interval in healthy adults after single 
doses. Clinical Pharmacology & Therapeutics 2003; 73: 292-303. 
40. 
Sacco F et al. Efficacy of four different moxifloxacin-based triple therapies for first-line H. 
pylori treatment. Digestive and Liver Disese 2010; 42: 110-4. 
41. 
Stass H et al. Pharmacokinetics, Safety and Tolerability of Ascending Single Doses of 
Moxifloxacin a New 8-Methoxy Quinolone, Administered to Healthy Subjects. Antimicrobal Agents and 
Chemotherapy 1998; 42(8): 2060–5. 
42. 
Alffenaar J et al. Plasma and Cerebrospinal Fluid Pharmacokinetcis of Moxifloxacin in a Patient 
with Tuberculosis Meningitis (Letter). Antimicrobal Agents and Chemotherapy 2008; 52: 2293-5. 
43. 
Soliman E Z et al. Boosted protease inhibitors and the electrocardiographic measures of QT 
and PR durations. AIDS 2011; 25(3): 367-77. 
44. 
Angeby KA, Jureen P, Giske CG, et al. Wild-type MIC distributions of four fluoroquinolones 
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45. 
Ji B, Lounis N, Truffot-Pernot C, Grosset J. In vitro and in vivo activities of levofloxacin against 
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46. 
Ji B, Lounis N, Maslo C, Truffot-Pernot C, Bonnafous P, Grosset J. In vitro and in vivo activities 
of moxifloxacin and clinafloxacin against Mycobacterium tuberculosis. Antimicrob Agents Chemother 
1998; 42(8): 2066-9. 
47. 
Jiang RH, Xu HB, Li L. Comparative roles of moxifloxacin and levofloxacin in the treatment of 
pulmonary multidrug-resistant tuberculosis: a retrospective study. Int J Antimicrob Agents 2013; 
42(1): 36-41. 
48. 
Koh WJ, Lee SH, Kang YA, et al. Comparison of levofloxacin versus moxifloxacin for multidrug-
resistant tuberculosis. Am J Respir Crit Care Med 2013; 188(7): 858-64. 
49. 
Lee J, Lee CH, Kim DK, et al. Retrospective comparison of levofloxacin and moxifloxacin on 
multidrug-resistant tuberculosis treatment outcomes. Korean J Intern Med 2011; 26(2): 153-9. 
50. 
Yew W-W, Nuermberger E. High-dose fluoroquinolones in short-course regimens for 
treatment of MDR-TB: the way forward?[Editorial]. Int J Tuberc Lung Dis 2013; 17(7): 853-4. 
 
 
 
  

SAP_001.pdf: 
 
 
 
 
 
 
 
 
1 
 
STREAM 
The evaluation of a standard streatment regimen of 
anti-tuberculosis drugs for patients with MDR-TB 
 
 
ISRCTN 18148631 (Stage 2) 
 
CORE STAGE 2 STATISTICAL 
ANALYSIS PLAN 
Version 6.0  |  9th September 2022 
 
Authorised by: 
 
Name:     
Prof. Andrew Nunn 
Role: 
Co-Chief Investigator 
Signature: 
Date: 
 
 
Name:     
Dr. Sarah Meredith 
Role: 
Co-Chief Investigator 
Signature: 
Date: 
 
 
Name:     
Dr. Ruth Goodall 
Role: 
Trial Statistician 
Signature: 
Date: 
 
 
Name:     
Dr. Katleen Callewaert 
Role: 
Janssen Statistician 
Signature: 
Date: 
 
 


STREAM 
 
2 
Version history: 
 
 
Version Date 
Who 
Comments 
0.1 
30th Sep 2014 
Patrick Phillips 
 
Based on protocol version 5.30 
0.2 
15th Oct 2014 
Patrick Phillips 
Tom Godec 
Expanded first draft 
0.3 
28th Nov 2014 
Ben Van 
Baelen 
Els De Paepe 
Comments from Janssen 
0.4 
28th Nov 2014 
Patrick Phillips 
Incorporation of comments from Janssen 
0.5 
4th Dec 2014 
Ben Van 
Baelen 
Els De Paepe 
Comments from Janssen 
1.0 
12th Dec 2014 
Patrick Phillips 
Up-versioned as final 
1.1 
20th Nov 2020 
Ruth Goodall 
Update on basis of protocol version 11.0 
- 
Update trial description, objectives, sample size, 
definition of favourable, in line with protocol 
- 
Add randomisation protocol as a stratification factor 
- 
Extension of wk76/132 analysis windows for COVID 
- 
Use of Ogawa (or LJ if missing) culture results in 
analysis; unable to produce sputum=negative culture 
result 
- 
Primary outcome: add subgroups in line with stage 1, 
sensitivity analyses, Bayesian analysis, estimands 
notation 
- 
Add/update analyses: time to failure or relapse, 
favourable outcome at wk132, PK analysis in line with 
IDMC report, time to cessation of clinical symptoms, 
WHO classification of outcome, TB outcome 
irrespective of treatment changes 
- 
Statement on multiple testing 
1.2 
17th Dec 2020 
Ruth Goodall 
Combined comments from Co-PIs and 
statistician 
1.3 
18th Dec 2020 
Ruth Goodall 
Responses and changes based on comments 
from Co-PIs and statistician after joint meeting 
- 
Clarified window extension for COVID 
- 
Add sensitivity analysis for missing COVID results at 
wk76 
- 
Clarified identification done at ITM 
- 
Independent review of FoR classification 
- 
Events with missing event date allocated to earliest 
study phase only 
- 
Independent review of cause of death 
1.4 
22nd Dec 2020 
Ruth Goodall 
Cleaned version circulated to Angela Crook 
and Janssen 
1.5 
5th Feb 2021 
Ruth Goodall 
Combined comments from Angela Crook and 
Janssen, with responses from Ruth Goodall 
- 
Clarification that stratification will prioritise 
randomisation protocol if small numbers 
- 
Update to estimands notation for primary endpoint 
- 
Culture with no identification and <14 days incubation 
will be excluded (was 7) 
- 
mPP population added for sensitivity analysis of primary 
endpoint 


STREAM 
 
 
3 
- 
mortality further sensitivity analyses and PK/PD analyses 
removed, will be in extensive SAP only 
1.6 
1st Apr 2021 
Ruth Goodall 
Final comments from Janssen, with responses 
from Ruth Goodall after joint meeting.  
- 
changes to definition of TEAEs to align with Extensive 
SAP. 
1.7 
13th May 2021 
Ruth Goodall 
Changes after discussion of both SAPs with 
Janssen.  
- 
Clarification of time point for FoR analysis 
- 
Not excluding non-assessables from time to 
unfavourable analysis at Wk132 
- 
New WHO definition of treatment outcomes 
- 
Clarification of analysis populations  
2.0 
14th May 2021 
Ruth Goodall 
Up-versioned as final 
2.1 
22nd Sept 2021 
Ruth Goodall 
Clarification on wording after programming of 
primary analyses 
- 
Word change : Failure or recurrence (not 
relapse) 
- 
Word change: race not ethnicity 
- 
Clarification that randomisation date = day 
1 when assigning analysis windows 
- 
Clarification that genotypic DST will be 
used for determination of the mITT 
population when phenotypic DST is 
unavailable. 
3.0 
24th Sept 2021 
Ruth Goodall 
Up-versioned as final (after review by Janssen) 
3.1 
19th Nov 2021 
Ruth Goodall 
Clarification of wording after double 
programming. 
4.0 
22nd Nov 2021 
Ruth Goodall 
Up-versioned as final (after review by Janssen) 
4.1 
8th April 2022 
Ruth Goodall 
Clarifications in response to feedback from 
FDA and PPD 
5.0 
21st April 2022 
Ruth Goodall 
Up-versioned as final (after review by Janssen 
and CIs) 
5.1 
19th August 2022 
Ruth Goodall 
Clarifications in response to Janssen double 
programming exercise plus addition of 
comparison of long-term efficacy and safety 
for regimen C vs regimen D. 
5.2 
6th September 
2022 
Ruth Goodall 
Incorporating comments from MRC CTU (co-
PIs and statisticians) for circulation to Janssen 
for review. 
6.0 
9th September 
2022 
Ruth Goodall 
Incorporating additional comments from 
Janssen. 
 
 


STREAM 
 
4 
GENERAL INFORMATION 
This document describes and substantiates the statistical principles and methods used for the 
analysis of data from Stage 2 of the STREAM trial.  This document is designed to support the 
STREAM protocol but this Statistical Analysis Plan (SAP) supersedes the SAP as written in the 
protocol.  Every care was taken in the drafting of this SAP, but corrections or amendments 
may be necessary.  A pre-final version (v1.0) of this SAP was signed off before first patient 
first visit. The final version of the SAP will be signed off before database lock for the primary 
Week 76 Stage 2 analysis. 
 
The STREAM trial consists of two stages.  Stage 1 involves the comparison of two treatment 
regimens: Regimen A and Regimen B.  Stage 2 involves two additional regimens, Regimen C 
and Regimen D, and makes the comparison between Regimen B and Regimen C for the 
analysis of the primary endpoint. All treatment regimens are described in detail in the 
STREAM protocol, Section 2.1.3.   Stage 1 and Stage 2 of the STREAM trial each have 
separate SAPs listed below.  Each SAP has differences, but the fundamental statistical 
principles will be consistent across all SAPs. 
 
Document 
Description 
Stage 1 SAP 
All analyses relating to stage 1 
Core Stage 2 SAP 
Core analyses for stage 2 
Extensive Stage 2 SAP 
Expanded analyses for stage 2 supporting CSR 
 
Compliance: 
The trial will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, in accordance with the principles of Good Clinical Practice (GCP) 
as laid down by the ICH topic E6 (Note for Guidance on GCP), and the applicable regulatory 
requirements in the participating countries. 
  
Sponsor: 
Vital Strategies, f/k/a The International Union Against Tuberculosis and Lung Disease, Inc.  
100 Broadway, Fourth Floor, New York, NY 10005 USA 
Tel (main): +1 212 500 5720   
Fax: +1 212 480 6040 
Email: STREAM@vitalstrategies.org 
 
Funders: 
The United States Agency for International Development (USAID) 
UK Medical Research Council (MRC) / Department for International Development (DFID) 
Janssen Research & Development, LLP (Stage 2 only) 
 
Main Contacts: 
Co-Chief Investigator 
 
Prof. Andrew Nunn 
MRC Clinical Trials Unit at UCL 
Institute of Clinical Trials and Methodology 
90 High Holborn, London, WC1V 6LJ 
Tel: +44 (0)20 7670 4703 
Fax: +44 (0)20 7670 4829 
Email: a.nunn@ucl.ac.uk 
Co-Chief Investigator 
 
Prof. Sarah Meredith 
MRC Clinical Trials Unit at UCL 
Institute of Clinical Trials and Methodology 
90 High Holborn, London, WC1V 6LJ 
Tel: +44 (0)20 7670 4703 
Fax: +44 (0)20 7670 4829 
Email: s.meredith@ucl.ac.uk 


STREAM 
 
 
5 
CONTENTS 
1 
Trial overview .......................................................................... 8 
1.1 
Study design ................................................................................................ 8 
1.2 
Trial objectives ............................................................................................. 8 
1.3 
Patient eligibility criteria ................................................................................ 9 
1.4 
Study interventions ....................................................................................... 9 
1.5 
Treatment phases ........................................................................................ 10 
1.6 
Randomisation procedure ............................................................................. 14 
2 
Sample size............................................................................ 14 
2.1 
Power to demonstrate non-inferiority in the primary efficacy outcome (primary 
objective relating to Regimens B and C) ........................................................................ 14 
3 
Primary outcome ................................................................... 15 
3.1 
Primary analysis Week 76 window ................................................................. 15 
3.2 
Primary efficacy outcome ............................................................................. 15 
3.3 
Primary outcome defined using estimands notation......................................... 16 
4 
Analysis populations.............................................................. 17 
4.1 
Intention-to-treat (ITT) ................................................................................ 17 
4.2 
Safety population ......................................................................................... 17 
4.3 
Modified intention-to-treat (mITT) ................................................................. 17 
4.4 
Per protocol (PP) ......................................................................................... 18 
4.5 
Modified per protocol (mPP) ......................................................................... 19 
5 
General analysis principles .................................................... 19 
5.1 
Analysis populations ..................................................................................... 19 
5.2 
Treatment and follow-up phase definitions ..................................................... 19 
5.3 
Visit window definitions ................................................................................ 19 
5.4 
Definition of a culture result .......................................................................... 21 
5.5 
Definition of culture negative status .............................................................. 22 
5.6 
Definition of a smear result ........................................................................... 22 
5.7 
Reference laboratory bacteriology ................................................................. 22 
5.8 
Adverse events ............................................................................................ 22 
6 
Analysis of primary outcomes ............................................... 23 
6.1 
Primary efficacy analyses .............................................................................. 23 
6.2 
Tabulation of primary endpoint classification .................................................. 23 
6.3 
Subgroup analyses ....................................................................................... 23 
6.4 
Sensitivity analyses ...................................................................................... 24 
6.5 
Bayesian analysis of non-inferiority ................................................................ 24 
7 
Analysis of secondary outcomes ........................................... 25 
7.1 
Efficacy outcomes ........................................................................................ 25 
7.2 
Safety outcomes .......................................................................................... 29 
7.3 
Health Economics ........................................................................................ 31 
7.4 
Testing multiple outcomes ............................................................................ 31 
8 
Additional exploratory analyses ............................................ 32 
8.1 
Time to cessation of clinical symptoms based on PI assessment ...................... 32 
8.2 
WHO classification of outcome ...................................................................... 33 
8.3 
TB outcome irrespective of treatment changes at Week 132 ............................ 33 
8.4 
Lung surgery ............................................................................................... 33 


STREAM 
 
6 
9 
Data summaries .................................................................... 34 
9.1 
Recruitment and baseline characteristics ........................................................ 34 
9.2 
Efficacy and adherence ................................................................................ 34 
9.3 
Safety ......................................................................................................... 35 
10 
References ............................................................................. 36 
 
 
LIST OF TABLES 
Table 1: Randomisation according to protocol version Randomisation protocol………………..13 
Table 2: Visit window definitions ................................................................................... 19 
 
 
LIST OF FIGURES 
Figure 1: Regimen treatment phases ...............................................................................9 
Figure 2: Transition from intensive to continuation phase for patients on Regimen B and 
Regimen C .................................................................................................... 11 
Figure 3: Transition from intensive to continuation phase for patients on Regimen D ......... 12 
 
 
 


STREAM 
 
 
7 
ABBREVIATIONS AND GLOSSARY 
 
AE 
AFB 
Adverse Event 
Acid Fast Bacilli 
AR 
Adverse Reaction 
AST 
Aspartate aminotransferase 
ALT 
BDQ 
Alanine aminotransferase 
Bedaquiline 
CI 
Chief Investigator 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DOT 
Directly Observed Treatment 
DST 
Drug Susceptibility Test 
ECG 
Electrocardiogram 
FDA 
Fluorescein diacetate staining 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
IDMC 
Independent Data Monitoring Committee 
ISRCTN 
International Standard Randomised Controlled Trial Number 
ITM 
Institute of Tropical Medicine 
ITT 
Intention To Treat 
LFX 
Levofloxacin 
LPA 
Line Probe Assay 
M2 
Metabolite 2 
MDR 
Multi-Drug Resistant 
MIC 
Minimal Inhibitory Concentration 
MRC CTU 
Medical Research Council Clinical Trials Unit 
NE 
Notable Event 
NTP 
National Tuberculosis Programme 
PK 
Pharmacokinetics  
PI 
Principal Investigator 
QT Interval 
 
QTc 
QTcF 
A measure of time between the start of the Q wave and the end of the T wave in 
the ECG complex 
QT interval corrected for heart rate 
QT interval corrected for heart rate using the Fridericia correction 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
STREAM 
The Evaluation of a Standardised Treatment Regimen of Anti-Tuberculosis Drugs 
for Patients with MDR-TB 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
ULN 
Upper limit of normal 
USAID 
United States Agency For International Development 
WHO 
World Health Organisation 
XDR 
Extensively Drug Resistant 
ZN 
Ziehl-Neelsen 
 
Note. In this statistical analysis plan, time (in weeks) refers to the time from randomisation, 
e.g. Week 76 refers to 76 weeks from randomisation. 


STREAM 
 
8 
1 TRIAL OVERVIEW 
1.1 Study design 
The STREAM study is an international, multi-centre, parallel-group, open-label, randomised, 
controlled trial studying participants with rifampicin-resistant tuberculosis (MDR-TB).  
1.2 Trial objectives 
The primary objective of Stage 2 of the STREAM trial is: 
 
To assess whether the proportion of participants with a favourable efficacy outcome on 
Regimen C, the fully oral regimen, is non-inferior to that on Regimen B at Week 76, using 
a 10% margin of non-inferiority 
 
The secondary objectives of the Stage 2 comparison of the STREAM trial are: 
 
1. To assess whether Regimen C is non-inferior to Regimen B with regards to the proportion 
of participants with a favourable efficacy outcome at Week 132 
2. To assess whether Regimen C is superior to Regimen B with regards to the proportion of 
participants with a favourable efficacy outcome at Week 76 and Week 132 (if non-
inferiority is demonstrated at either time-point) 
3. To compare the efficacy of 40 weeks of bedaquiline in combination with the other drugs 
of Regimen C with Regimen B during treatment and follow-up 
4. To compare the efficacy of 28 weeks of bedaquiline in combination with the other drugs 
of Regimen D with Regimen B during treatment and follow-up 
5. To estimate the difference between Regimen C and Regimen Bmox in the proportion of 
participants with a favourable efficacy outcome at Week 76 and Week 132 
6. To estimate the difference between Regimen C and Regimen Blev in the proportion of 
participants with a favourable efficacy outcome at Week 76 and Week 132  
7. To estimate the difference between Regimen D and Regimen B in the proportion of 
participants with a favourable efficacy outcome at Week 76 and Week 132 
8. To estimate the difference between Regimen B and Regimen A in the proportion of 
participants with a favourable efficacy outcome at Week 132 
9. To estimate the difference between Regimen C and Regimen A in the proportion of 
participants with a favourable efficacy outcome at Week 132 
10. To estimate the difference between Regimen D and Regimen A in the proportion of 
participants with a favourable efficacy outcome at Week 132 
11. To investigate the safety, including the effect on mortality and tolerability of 40 weeks of 
bedaquiline in combination with the other drugs of Regimen C compared to Regimen B 
during treatment and follow-up 
12. To investigate the safety, including the effect on mortality and tolerability of 28 weeks of 
bedaquiline in combination with the other drugs of Regimen D compared to Regimen B 
during treatment and follow-up 
13. To compare the proportion of patients who experience grade 3 or greater adverse events 
during treatment or follow-up in Regimen B as compared to Regimen A 
14. To compare the proportion of patients who experience grade 3 or greater adverse events 
during treatment or follow-up in Regimen C as compared to Regimen B 
15. To compare the proportion of patients who experience grade 3 or greater adverse events 
during treatment or follow-up in Regimen C as compared to Regimen Bmox 


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9 
16. To compare the proportion of patients who experience grade 3 or greater adverse events 
during treatment or follow-up in Regimen C as compared to Regimen Blev 
17. To compare the proportion of patients who experience grade 3 or greater adverse events 
during treatment or follow-up in Regimen D as compared to Regimen B 
18. To investigate the safety, including the effect on mortality and tolerability, of bedaquiline-
containing regimens compared to Regimen B during treatment and follow-up. 
19. To investigate the effect on mortality of bedaquiline-containing regimens compared to 
non-bedaquiline containing regimens 
20. To evaluate the pharmacokinetics of bedaquiline and M2 in all participants randomised 
to Regimen C or Regimen D at sites selected for the PK study and assess 
pharmacokinetic/pharmacodynamics relationships of bedaquiline for safety and efficacy 
21. To evaluate the pharmacokinetics of bedaquiline and M2 in a subset of HIV co-infected 
patients on Regimen C or Regimen D receiving antiretroviral treatment 
22. To evaluate the 4β-hydroxycholesterol/cholesterol ratio as a measure of cytochrome P450 
3A (CYP3A) activity in patients on Regimen C and Regimen D at sites selected for the PK 
study. 
23. To compare the economic costs incurred during treatment by patients (transport and food 
costs for attending DOTs and patient assessment visits, food supplements costs and 
income loss) and by the health system (inpatient stay, laboratory tests, medication, staff, 
consumables and serious adverse events costs) in Regimen B and C. To calculate 
economic costs associated with regimen D, and compare these with regimen B, for those 
sites where this is possible  
24. To compare the proportions of patients having undergone lung surgery (resection or 
pneumonectomy) by Week 76 and Week 132 in Regimen C and Regimen D as compared 
to Regimen B 
25. To compare the development of resistance to background drugs, especially resistance 
leading to the development of pre-XDR or XDR strains of TB in Regimen C and Regimen 
D as compared to Regimen B 
26. To investigate the development of increased MIC to bedaquiline in Regimen C and 
Regimen D 
 
1.3 Patient eligibility criteria 
Patient eligibility criteria are listed in Section 5 of the protocol. 
1.4 Study interventions 
In Stage 2 of the STREAM trial, the primary comparison being made is between Regimen C 
and Regimen B, with secondary comparisons between Regimen D and Regimen B.  In 
addition, a limited number of secondary analyses will make comparisons between Regimen 
A and the other regimens. 
 
Regimen A: The locally-used MDR-TB regimen in accordance with 2011 WHO MDR-TB 
treatment guidelines1. 
 
Regimen B: Regimen B forms the control regimen for the primary and secondary 
comparisons, and is based on the regimen described by Van Deun 20102 (updated results3) 
consisting at the start of STREAM of clofazimine, ethambutol, moxifloxacin, and pyrazinamide 
given for 40 weeks, supplemented by isoniazid, kanamycin, and prothionamide for the first 16 
weeks; this combination is referred to as Regimen Bmox. With Version 8.0 of the protocol 
Regimen B is modified by replacement of moxifloxacin with levofloxacin (referred to as 
Regimen Blev).  Regimen B without specification of which fluoroquinolone is in the regimen 


STREAM 
 
10 
refers to either (Bmox or Blev). With Version 10.0 of the protocol, Regimen B is further modified 
to replace kanamycin with amikacin in sites where:   
• the national TB program has replaced kanamycin with amikacin in line with revised WHO 
guidance4 and  
• amikacin is available for the trial.  
Kanamycin will continue to be used until the transition takes place within each country 
programme.  
 
Regimen C: Regimen C is an all-oral modified version of Regimen B, consisting of 
bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks, 
supplemented by isoniazid, and prothionamide for the first 16 weeks.  
 
Regimen D: Regimen D a shortened modified version of Regimen B, consisting of 
bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks, supplemented 
by isoniazid, and kanamycin for the first 8 weeks.  
 
All patients in Stage 2 of the study will be followed up to Week 132.  The primary analysis will 
be based on data accrued to Week 76; the data accrued to the date when the last patient is 
projected to have reached Week 96 will be used for the secondary long-term efficacy analysis; 
all data accrued to Week 132 will be used in the long-term safety analysis.  
1.5 Treatment phases 
Regimen B, Regimen C, and Regimen D each consist of 2 phases; an intense phase followed 
by a continuation phase, as shown in Figure 1. 
Figure 1: Regimen treatment phases  
 
 
 
For patients randomised to Regimen B or Regimen C the algorithm described in Figure 2 will 
be used to determine when a patient can proceed from the intensive to the continuation 
phase.  
 


STREAM 
 
 
11
Patients randomised to Regimen B or Regimen C will receive 40 weeks of treatment (16 weeks 
intensive phase plus 24 weeks continuation phase). In the event of positive (at least "scanty" 
on the IUATLD/WHO scale) AFB smear, the drugs in the intensive phase of these regimens 
may be extended by 4 weeks twice, allowing a maximum total duration of 48 weeks treatment 
(except for bedaquiline, which will be given for a maximum duration of 40 weeks regardless 
of whether the regimen is extended).  
 
Patients randomised to Regimen D will receive 28 weeks of treatment (eight weeks intensive 
phase plus 20 weeks continuation phase).  As Regimen D has shorter intensive phase duration 
than Regimen B and Regimen C, it is expected that more patients would have a smear positive 
result at the end of the intensive phase due to the shorter time that patients will have been 
on treatment to that point.  Therefore, the less stringent criterion of a smear positive result 
of 2+ is sufficient for patients to require an extension of the intense period, i.e. patients can 
have a positive smear of 1+ and still advance on to the continuation phase, as opposed to 
Regimen B and Regimen C for which any positive smear result would result in an extension to 
the intensive phase. In the event of a 2+ or more positive smear, the drugs in the intensive 
phase of the regimen may be extended by 4 weeks twice, allowing a maximum total duration 
of 36 weeks treatment (Figure 3). 
 
The procedure for transition from the intensive to the continuation phase in Regimen A will 
be according to local policy. 
 


STREAM 
 
12 
Figure 2: Transition from intensive to continuation phase for patients on Regimen B 
and Regimen C 
 
Note: smear results based on regular AFB ZN or auramine staining and not FDA vital staining. 
 
 


STREAM 
 
 
13
Figure 3: Transition from intensive to continuation phase for patients on Regimen D 
 
 
   
 


STREAM 
 
14 
1.6 Randomisation procedure 
Patients were initially randomised to Regimen A, Regimen B, Regimen C, or Regimen D, in a 
ratio 1:2:2:2, respectively. From protocol version 6.3 onwards randomisation to Regimen A 
and/or Regimen D were restricted or stopped (Table 1).  
 
Randomisation will be stratified by (1) site, (2) HIV status (split into three strata: HIV negative, 
HIV positive with CD4 count ≥ 350 cells/mm3, and HIV positive with CD4 count < 350 
cells/mm3).  
 
Table 1: Randomisation according to protocol version 
Protocol version 
Allocation ratio 
Regimens 
6.2  
1:2:2:2 
A:B:C:D 
6.3 or 7.0 
1:1:1 
B:C:D in countries where the local NTP adopted 
or has imminent plans to adopt the WHO 2016 
short regimen; as for v6.0 elsewhere 
8.0 onwards 
1:1 
B:C 
 
All analyses will be stratified by randomisation protocol to ensure comparisons are made to 
concurrent controls: 
 
comparisons of Regimen C to Regimen B will include all participants allocated to these 
regimens but be stratified by a 3 level variable : v6.2 vs v6.3/7.0 vs 8.0/10.0 
 
comparisons of Regimen D to Regimen B will be restricted to participants randomised 
under protocol v6.2/6.3/7.0 and be stratified by a 2 level variable : v6.2 vs v6.3/7.0 
 
comparisons to Regimen A will be restricted to participants randomised under v6.2 of the 
protocol 
Analyses of the primary endpoint will also be stratified by HIV status as defined above, 
unless there is insufficient data within strata. If this is the case initially the two HIV positive 
groups will be combined, but if there is still insufficient data within strata then stratification 
by randomisation protocol will be prioritised. 
 
 
2 SAMPLE SIZE 
2.1 Power to demonstrate non-inferiority in the primary efficacy 
outcome (primary objective relating to Regimens B and C) 
Stage 2 aimed to randomise at least 200 patients to each of Regimen B (Bmox or Blev)  and 
Regimen C. This revised sample size in protocol version 8.0 was determined based on the 
assumption that the proportion of patients with a favourable efficacy outcome at Week 76 is 
80% for Regimen B (estimated based on preliminary Stage 1 results) and 82% for Regimen 
C (based on an anticipated minimum benefit in efficacy of using 40 weeks treatment with 
bedaquiline compared to 16 weeks treatment with kanamycin). Using a non-inferiority 
margin of 10% and a one-sided significance level of 2.5%, 172 evaluable patients will be 
required in each of the two regimens to demonstrate non-inferiority of Regimen C to 
Regimen B with 80% power. To account for 14% of patients excluded from the primary per 
protocol efficacy analysis population, a total of 400 patients will need to be enrolled across 
the 2 regimens.  


STREAM 
 
 
15
 
A sample size of 400 patients enrolled to the comparison of Regimens B and C is necessary 
to rule out an 8% increased mortality in Regimen C compared to the 8% observed on 
Regimen B in the preliminary analysis of STREAM Stage 1. This will provide 80% power with 
a one-sided 0.025 type I error. 
 
 
3 PRIMARY OUTCOME  
3.1 Primary analysis Week 76 window 
The Week 76 window is defined as the time period from six weeks before 76 weeks since 
randomisation to six weeks after 76 weeks since randomisation, i.e. from Week 70 to Week  
82. 
 
3.1.1 Extension of visit window due to the COVID-19 pandemic 
The end dates of the Week 76 window will be extended for any Stage 2 patients whose 
Week 76 appointment is scheduled to occur during the COVID-19 pandemic and did not 
occur due to restrictions on movement, unacceptable risk of exposure to COVID-19 in 
connection with the scheduled visit, or any other reason related to the pandemic. For those 
patients, the Week 76 sputum samples must be taken in a window beginning six weeks prior 
to the scheduled visit date and ending within the Week 84 visit window i.e. within 14 weeks 
of the scheduled Week 76 visit date.  
3.2 Primary efficacy outcome 
The primary efficacy outcome measure is the proportion of patients with a favourable outcome 
(as defined below) at Week 76.   
 
Only data from events occurring before the end of the Week 76 window will be included in 
the primary analysis of the primary efficacy outcome.  
 
Culture results obtained using acidified Ogawa (Kudoh medium) will be used in the primary 
analysis, unless missing, when results from Löwenstein-Jensen (LJ) media will be used.  
 
A positive culture is defined as at least one colony and a negative culture is defined as 
absence of growth (no colonies). 
 
Favourable  
A patient’s outcome will be classified as favourable if their last two culture results are 
negative unless they have previously been classified as unfavourable.  These two cultures 
must be taken on separate visits (on different days); the latest of which being within the Week 
76 window. 
 
Patients that don’t have a culture result within the Week 76 window because they were 
unable to produce sputum or their sample was contaminated, will be classified as favourable 
if their last two cultures before the Week 76 window are negative and they have not 
previously been classified as unfavourable;  such patients will be identified separately in 
tables.  
 


STREAM 
 
16 
Participants with no sputum sample available at Week 76 due to Covid-19 restrictions who are 
not otherwise classified as unfavourable will be considered unfavourable. Sensitivity analyses 
will reclassify these participants as i) non-assessable and excluded from the primary efficacy 
analysis, and ii) favourable if they meet the definition of favourable above, with the latest of 
the 2 negative culture results being within the Week 68 window, and unfavourable otherwise. 
 
Unfavourable  
A patient’s outcome will be classified as unfavourable in Stage 2 if: 
1. They are discontinued from their allocated study treatment and subsequently restarted 
on a different MDR-TB regimen. 
2. Treatment is extended beyond the scheduled end of treatment for any reason other than 
making up days when no treatment was given (missed treatment) for a maximum of eight 
weeks. A maximum of 14 days of extra treatment (irrespective of reason) is acceptable 
before it is classified as treatment extension. 
3. They are restarted on any MDR-TB treatment after the scheduled end of treatment, but 
before 76 weeks after randomisation. 
4. They change their allocated study treatment for any reason other than the replacement 
of a single drug. 
5. Bedaquiline is started where the allocated regimen did not originally contain that drug 
(Regimen A or B). 
6. A second line injectable agent is started in Regimen C. 
7. A drug from the class of nitroimidazoles (delamanid or pretomanid) or linezolid is started. 
8. They die at any point during treatment or follow-up. 
9. At least one of their last two culture results, from specimens taken on separate occasions, 
is positive. 
10. They do not have a culture result within the Week 76 window. 
 
Starting a single drug other than bedaquiline (in Regimen A or B) or from the class of 
nitroimidazoles (delamanid or pretomanid) or linezolid (in any regimen) is not considered to 
be a substantial change to the regimen and therefore does not result in an unfavourable 
outcome, providing none of the other criteria above are met.  
 
An extension of the intensive phase of treatment in any study arm does not constitute an 
unfavourable outcome, as long as the extension is in accordance with the algorithms described 
in Figure 5 and Figure 6 in Section 1.5 for patients on Regimen B, Regimen C, and Regimen 
D. Similarly, the discontinuation of drugs that are not replaced does not constitute an 
unfavourable outcome. 
 
These definitions of favourable and unfavourable apply to all four treatment regimens and for 
analyses of both the mITT, PP and mPP analysis populations.   
3.3 Primary outcome defined using estimands notation 
We define 2 co-primary estimands that are the same in all components other than the 
handling of intercurrent events.  Information on the estimator and estimation procedure are 
given in Section 6. 
 
The estimands for the primary objective are defined as follows:  
(a) the comparison is between Regimen C and Regimen B as defined in Section 1.4;  
(b) the patient population of interest are patients with confirmed RR-TB that meet the 
inclusion/exclusion criteria as given in the trial protocol, Section 5  (see Section 4.4);  
(c) the endpoint is favourable outcome at Week 76 as defined in Section 3.2;  


STREAM 
 
 
17
(d) the population level summary is the difference in proportions of favourable outcome 
between treatment arms (See Section 6.1.1). Non-inferiority will be shown if the upper 
bound of the 2-sided 95% confidence interval of the difference in proportion of favourable 
outcomes at Week 76 between Regimens B and C is less than the 10% margin of non-
inferiority;  
(e) the intercurrent events will be handled as described below. 
  
Intercurrent Event 
Strategy for Addressing 
Intercurrent Event for 
Primary Estimand 1 
Strategy for Addressing 
Intercurrent Events for 
Primary Estimand  2 
Change of 1 non-major drug 
in the allocated treatment 
regimen 
Treatment policy strategy: use 
primary variable regardless of 
whether or not this intercurrent 
event had occurred 
Treatment policy strategy: use 
primary variable regardless of 
whether or not this intercurrent 
event had occurred 
Treatment extension to make 
up for days when no 
treatment was given (up to 8 
weeks) 
Treatment policy strategy: use 
primary variable regardless of 
whether or not this intercurrent 
event had occurred 
Treatment policy strategy: use 
primary variable regardless of 
whether or not this intercurrent 
event had occurred 
Other changes to allocated 
treatment regimen (drug 
substitutions, other treatment 
extensions, use of salvage 
regimens) 
 
Composite strategy: occurrence 
of this intercurrent event is 
captured in the primary 
composite variable definition, a 
participant with this intercurrent 
event is considered 
unfavourable  
Composite strategy: occurrence 
of this intercurrent event is 
captured in the primary 
composite variable definition, a 
participant with this intercurrent 
event is considered 
unfavourable  
Failure to complete a 
protocol adherent course of 
allocated treatment   
 
Treatment policy: same as 
above  
Principal Stratum: population is 
the subgroup of participants 
who would adhere to treatment, 
whichever treatment they are 
allocated 
Reinfection 
Composite strategy: same as 
above 
Composite strategy: same as 
above 
Death 
Composite strategy: same as 
above 
Composite strategy: same as 
above 
 
 
4 ANALYSIS POPULATIONS 
4.1 Intention-to-treat (ITT) 
All randomised patients will be included in the ITT analysis population. 
4.2 Safety population 
All randomised patients that have taken at least one dose of treatment will be included in 
the safety analysis population. 
4.3 Modified intention-to-treat (mITT) 
The mITT population is defined as all randomised patients that have a positive culture for M. 
tuberculosis at screening or randomisation, with the exception of patients with isolates taken 
before randomisation that are subsequently found to be susceptible to rifampicin, and 
patients with isolates taken before randomisation that are subsequently found to be 


STREAM 
 
18 
resistant to both fluoroquinolones and second-line injectables (i.e. XDR-TB) on phenotypic 
DST.  Results from the central reference laboratory will take priority over any results from 
local laboratories where available. Genotypic DST from the central reference laboratory will 
be used when phenotypic DST is unavailable. Rifampicin susceptible phenotypic DST results 
will be confirmed by rpoB sequencing. If a participant has rifampicin DST results at 
screening and randomisation which are discordant they will be considered resistant and 
included in the mITT population. Participants randomised in error i.e. late screening failures, 
will be excluded from the mITT population. 
4.4 Per protocol (PP) 
The PP population will be the same as the mITT population with the exclusion of patients 
not completing a protocol-adherent course of treatment, other than for treatment failure, 
change of treatment for an adverse event or death.  Treatment failure is defined as failure 
to attain and maintain culture negativity until the end of allocated treatment.  
 
4.4.1 Definition of a protocol-adherent course of treatment 
A patient will have completed a protocol-adherent course of treatment when they have taken 
80% of doses within 120% of the duration in both the intensive phase and in the whole 
treatment period.  For this purpose, a dose is defined as all the study medications at the 
correct dose for that particular day.   
 
For Regimen B and Regimen C, with or without an extension of the intensive phase, a 
patient will have completed a protocol-adherent course of treatment if they have taken 80% 
of doses within 120% weeks. For example, in participants with no treatment extensions: 
 
90 doses (80% of 16 weeks) within 134 days (120% of 16 weeks) in the intensive phase, 
and 
 
224 doses (80% of 40 weeks) within 336 days (120% of 40 weeks) over the whole 
treatment period (i.e. the combined intensive and continuation phases),  
or in participants with a four week extension:   
 
112 doses (80% of 20 weeks) within 168 days (120% of 20 weeks) in the intensive phase, 
and 
 
246 doses (80% of 44 weeks) within 370 days (120% of 44 weeks) over the whole 
treatment period (i.e. the combined intensive and continuation phases). 
 
For Regimen D, with or without an extension of the intensive phase, a patient will have 
completed a protocol-adherent course of treatment if they have taken 80% of doses within 
120% weeks. For example, in participants with no treatment extensions: 
 
45 doses (80% of 8 weeks) within 67 days (120% of 8 weeks) in the intensive phase, 
and 
 
157 doses (80% of 28 weeks) within 235 days (120% of 28 weeks) over the whole 
treatment period (i.e. the combined intensive and continuation phases) with no treatment 
extensions. 
or in participants with a four week extension:   
 
67 doses (80% of 12 weeks) within 101 days (120% of 12 weeks) in the intensive phase, 
and 
 
179 doses (80% of 32 weeks) within 269 days (120% of 32 weeks) over the whole 
treatment period (i.e. the combined intensive and continuation phases). 
 
The same algorithm will apply for Regimen A, the control regimen; the exact number of 
doses and days depends on the duration of the intensive and continuation phases of 
Regimen A as implemented locally. 


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19
4.5 Modified per protocol (mPP) 
Sensitivity analyses for analyses of favourable outcome at Week 76 and Week 132 will use 
the definition of PP population as specified in version 10.0 of the STREAM protocol, denoted 
the modified per-protocol population (mPP). Specifically, the mPP population will be the same 
as the mITT population with the exclusion of patients not completing a protocol-adherent 
course of treatment, other than for treatment failure or death.   
 
 
 
5 GENERAL ANALYSIS PRINCIPLES 
Analysis of the primary outcome is described in Section 6. Otherwise, descriptive statistics 
will be reported overall and by randomised group, and percentages will be of non-missing 
values, with the number (%) of non-missing values given if data are not complete. 
Statistical tests will be 2-sided and estimates will be presented with a 2-sided 95% CI. 
Appropriate transformations for all variables will be applied after inspection of the data. 
Percentages will be reported to 0 decimal places, unless <0.5% when they will be given to 
one decimal place. P-values will be given to 2 significant figures. 
5.1 Analysis populations 
The analyses of the primary outcome will be based on both the mITT and the PP populations 
for determining non-inferiority. All analyses will be based on the mITT population for 
determining superiority, with the PP population as a sensitivity analysis.  All patients included 
in the analysis will be analysed in the treatment group to which they were originally 
randomised.  
5.2 Treatment and follow-up phase definitions 
For the purpose of analysis, the treatment and follow-up phases for an individual patient will 
be defined as follows: 
 
Screening phase 
o Start: date of screening consent 
o End: day before randomisation 
 
Treatment phase 
o Start: date of randomisation. 
o End: date of last dose of any TB treatment defined as last dose of any TB treatment 
(including retreatment for relapse), plus 7 days.   
 
Follow-up phase  
o Start: the day after the end of the treatment phase. 
o End: date of the last patient contact (scheduled or unscheduled visit, or other contact 
e.g. phone call). 
 
The treatment phase includes any extension of treatment or retreatment, and so the 
Allocated Treatment phase is defined as follows: 
 
Allocated Treatment phase 
o Start: date of randomisation. 
o End: date of last dose of trial treatment defined as last dose of allocated regimen or last 
dose before the addition of a new drug, whichever happens sooner, plus 7 days.   
5.3 Visit window definitions 
In Stage 2, patients will be assessed at screening, randomisation (Week 0), Week 1, Week 2, 
Week 3, Week 4, after which they will be seen 4-weekly until Week 52, after which they will 


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20 
be seen 8-weekly until Week 84, after which they will be seen 12-weekly until Week 132 post 
randomisation.  
 
Baseline is defined as the date of randomisation (Study day 1). For all variables the baseline 
measurement will be the one taken at the randomisation visit. If this does not exist the 
measurement from the screening visit will be used if available. For ECG measurements, the 
mean of all available measurements from the randomisation visit will be used. 
For the purpose of analysis, each scheduled visit will have a window before and 
after the target date, calculated from date of randomisation.  When referring to a 
visit hereon, this implies within the defined visit window as specified below in 
Table 2. 
Table 1: Visit window definitions 
Visit 
Target study day 
Analysis window (study days) 
Screening / 
Baseline 
 
1 
Date of screening consent – 1 
Week 4 
29 
2-42 
Week 8 
57 
43-70 
Week 12 
85 
71-98 
Week 16 
113 
99-126 
Week 20 
141 
127 – 154 
Week 24 
169 
155 – 182 
Week 28 
197 
183 – 210 
Week 32 
225 
211 – 238 
Week 36 
253 
239 – 266 
Week 40 
281 
267 – 294 
Week 44 
309 
295 – 322 
Week 48 
337 
323 – 350 
Week 52 
365 
351 – 392 
Week 60 
421 
393 – 448 
Week 68 
477 
449 – 490 
Week 76 
533 
491 - 574* 
Week 84 
589 
575 – 630 
Week 96 
673 
631 – 714ꭞ 
Week 108 
757 
715 – 798ꭞ 
Week 120 
841 
799 – 882ꭞ 
Week 132 
925 
883 – no upper boundꭞ 
NB. Study day 1 = date of randomisation 
 * see section 3.1.1 
 ꭞ see section 5.3.1 
 
Any visit, scheduled or unscheduled, that falls into the analysis window will be assigned to 
that visit for the purpose of analysis. If two visits fall within the same interval, the one 
closest to the target date will be used for analyses by visit, so that there is only one unique 
visit for each patient and analysis time-point.  
 


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21
There are additional study visits at Weeks 1, 2 and 3 only for ECG monitoring. For the 
analysis of ECG data only, there will be additional visit windows: Week 1 (2-11), Week 2 
(12-18), Week 3 (19-25) and the Week 4 visit window will be modified to (26-42). 
 
5.3.1 Extension of visit window due to COVID 
The end dates of the Week 76 window will be extended for any Stage 2 patients whose 
Week 76 appointment is scheduled to occur during the COVID-19 pandemic and did not 
occur due to restrictions on movement, unacceptable risk of exposure to COVID-19 in 
connection with the scheduled visit, or any other reason related to the pandemic. For those 
patients, the Week 76 sputum samples must be taken in a window beginning six weeks prior 
to the scheduled visit date and ending within the Week 84 visit window.  
 
A participant’s scheduled last efficacy visit will be their latest scheduled trial visit on or 
before the projected Week 96 visit of the last patient randomised. The visit window for the 
scheduled last efficacy visit is defined as no more than six weeks prior to and up to six 
weeks after (or on 30 Nov 2021 if this is earlier) the scheduled last efficacy visit. The end 
dates of the window will be extended for any Stage 2 patients whose scheduled last efficacy 
visit was due during the COVID-19 pandemic and did not occur due to restrictions on 
movement, unacceptable risk of exposure to COVID-19 in connection with the scheduled 
visit, or any other reason related to the pandemic. For such patients, sputum samples must 
be taken in a window between six weeks prior to and twelve weeks after the last scheduled 
visit date .   
5.4 Definition of a culture result 
A culture result will be called positive for M. tuberculosis if the culture tests positive for the 
presence of microorganisms, at least one colony, and the microorganisms present are then 
identified as being M. tuberculosis.  Identification will be based on tests performed at the 
central laboratory (ITM).  If an identification test is not carried out for a particular culture, 
then for analysis purposes a culture will still be considered positive for M. tuberculosis if the 
culture tests positive for the presence of microorganisms and if that culture result is 
obtained fourteen days or more since the start date of sputum processing and incubation of 
the inoculated Ogawa or Löwenstein-Jensen (LJ) media.  If the culture result is obtained less 
than fourteen days since the start date of sputum processing and incubation, the culture 
result will not be considered as positive for M. tuberculosis (if the identification test is not 
carried out), and the culture result will be considered missing in the analysis. 
 
Culture results obtained using acidified Ogawa (Kudoh medium) will be used in analysis if 
available; results from LJ media will be used if the Ogawa result is missing.  The only 
exception to this is within the baseline window, when Ogawa, LJ or MGIT culture results will 
be considered to determine if a participant is positive at baseline. 
 
Any culture result that is missing because the patient is no longer able to produce sputum 
will be treated as a negative result, providing their last 2 available culture results (from 
sputum samples taken at separate visits) are negative. 
 
If more than one culture result is available from sputum collected on the same day, this will 
be regarded as a single culture result for the purposes of all analyses with the following 
overall result: 
i. 
Positive, if at least one of the culture results is positive  
ii. 
Negative, if at least one of the culture results is negative and none of the culture 
results are positive 


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22 
iii. 
Contaminated if at least one of the culture results is contaminated and none of the 
culture results are positive or negative.   
iv. 
Missing, if no culture result is available 
5.5 Definition of culture negative status 
Sputum culture negative status is defined as two consecutive negative cultures from sputa 
collected on different days without an intervening positive. The date of the first of these 
negative cultures is the date at which negative culture status is obtained. Culture negative 
status continues until there are two positive culture results at different visits without an 
intervening negative culture, or until there is a single positive culture not followed by two 
negative cultures. Culture negative status can be achieved at any point during treatment or 
follow-up but before any re-treatment. Culture negative status can be re-established. 
5.6 Definition of a smear result 
A smear result will be called positive if it is graded as ‘scanty’ or ‘rare AFB’ or at least 1+. If 
more than one smear result is available from sputum collected on the same day, this will be 
regarded as a single smear result for the purposes of all analyses with the following overall 
result: 
i. 
Positive, if at least one of the smear results is positive  
ii. 
Negative, if at least one of the smear results is negative and none of the smear 
results are positive 
iii. 
Missing, if no smear result is available. 
5.7 Reference laboratory bacteriology 
All positive isolates from Week 8 onwards will be sent from the STREAM sites to a reference 
laboratory at the Institute of Tropical Medicine (ITM) in Antwerp, Belgium. Drug sensitivity 
results from the reference laboratory will be used in all analyses in preference to those 
obtained from local site laboratories where available.  Identification of MTB will be done at 
ITM; local culture results will be excluded from analysis if identified as non-MTB. 
5.8 Adverse events 
For all analyses of adverse events (AE), only treatment-emergent AEs will be included. An 
AE will be considered treatment-emergent in a particular phase if it is worse in severity than 
the corresponding baseline observation. If the baseline observation is missing, the AE is 
always considered as treatment-emergent. For ECG, laboratory events, weight changes and 
hearing loss, only the maximum grade within phase will be reported. For laboratory and 
weight AEs, a shift from ‘abnormally low’ at baseline to ‘abnormally high’ post baseline (or 
vice versa) is also treatment-emergent. Laboratory AEs starting on day 1 will be considered 
treatment emergent since it is impossible to know whether the blood samples were taken 
before or after administration of the first dose of trial treatment and this is the most 
conservative approach. 
 
SAEs will be analysed as episodes, with all components of the same clinical SAE presented 
as one episode.  Analyses of grade 3 or 4 adverse events will consider each component as 
separate events.  Hearing loss reported in the left and right ear as two separate AEs but 
with overlapping start and stop dates will be reported in analyses as one AE of bilateral 
hearing loss at the maximum grade of the two unilateral events. 
 
 


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6 ANALYSIS OF PRIMARY OUTCOMES 
6.1 Primary efficacy analyses 
 
6.1.1 Modelling technique used in analysis 
For the primary efficacy analysis the difference in proportions of favourable outcome 
between Regimen B (Bmox and Blev combined) and Regimen C with corresponding 95% 
confidence intervals and p-values will be estimated using a stratified analysis of the risk 
difference from each stratum using Cochran-Mantel-Haenszel weights.5  The analysis will be 
stratified by randomisation protocol and HIV status (as defined in Section 1.6).  
 
6.1.2 Non-inferiority of Regimen C compared to Regimen B at Week 76 
Non-inferiority will be shown if the upper bound of the 95% confidence interval of the 
difference in proportion of favourable outcomes at Week 76 between Regimens B and C is 
less than the 10% margin of non-inferiority; this must be shown in both the mITT and PP 
populations.  An sensitivity analysis will be undertaken using the mPP population. 
 
6.1.3 Superiority of Regimen C compared to Regimen B at Week 76 
If non-inferiority is demonstrated, then superiority of Regimen C compared to Regimen B 
will be declared if the upper bound of the 95% confidence interval of the difference in 
proportion of favourable outcomes at Week 76 between Regimens B and C is less than 
zero,.  For this analysis, the mITT population will be primary and the PP and mPP 
populations will be sensitivity analyses. 
 
Secondary analyses will repeat the primary analysis but compare Regimen Blev and Regimen 
C, Regimen Bmox and Regimen C, and Regimen B and Regimen D, restricting the population in 
each case to include only concurrent controls within site.  For this analysis, the mITT 
population will be primary and the PP population will be sensitivity analyses. Comparisons of 
Regimen C and Regimen D were carried out at the time of the primary analysis but considered 
exploratory. 
6.2 Tabulation of primary endpoint classification 
Since the primary endpoint is a composite of various components, the actual reason 
(component) for outcome will also be tabulated by treatment arm.  Patients will be classified 
by the first event that made the patient unfavourable (see section 3.2) and further sub-
classified by whether their outcome is deemed to be bacteriologically related or not, based on 
a review of all data up to the time that the outcome occurred (see Section 6.2.1).  
6.3 Subgroup analyses 
This primary efficacy analysis will be repeated (in both mITT and PP analysis populations) in 
subgroups according to the following baseline characteristics: 
 
 
HIV infection status 
 
baseline drug resistance patterns (i.e. resistance to pyrazinamide and isoniazid) 
 
albumin levels (by severity grade) 
 
BMI (<16.0 kg/m2, 16.0-18.4 kg/m2, 18.5-24.9 kg/m2, >25 kg/m2) 
 
cavitation (presence, absence) 
 
study centre/country 
 
age (<25, 25-<45,  ≥45) 


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24 
 
sex 
 
Smoking history (current, ex, never) 
 
Smear grade 
 
Weight band (<33kg, 33-50kg, >50kg) 
 
Race. 
 
6.4 Sensitivity analyses 
The primary efficacy analysis will be repeated: 
 
A. Unadjusted for any covariates except randomisation protocol. 
B. Adjusted for randomisation stratification factors HIV status and centre. Small strata 
with fewer than 10 patients will be combined within geographical regions within 
country. 
C. Adjusted for randomisation stratification factors and any additional important 
covariate such as cavitation at baseline, baseline bacillary load or adherence.  
 
D. Ignoring substitutions of levofloxacin for moxifloxicin and vice versa when counting 
the number of drug substitutions within the definition of unfavourable outcome. 
E. Ignoring starting linezolid alone as a criterion for an unfavourable outcome. 
F. Reclassifying any participants with reinfection (based on genotype or DST) as “non-
assessable” rather than unfavourable. 
G. Reclassifying any participants who died as a result of trauma (as adjudicated by 
independent review) as “non-assessable” rather than unfavourable. 
H. Reclassifying any participants with missing Week 76 culture results because of 
COVID-19 as “non-assessable” rather than unfavourable. 
I. Reclassifying any participants with missing Week 76 culture results because of 
COVID-19 as favourable if they meet the definition of favourable, with the latest of 
the 2 negative culture results being within the Week 68 window, unfavourable 
otherwise. 
J. Requiring a 25 day delay between the last 2 negative culture results in participants 
classified as favourable. A participant’s outcome will be unfavourable if previously 
classified as favourable but not meeting this definition. . .  
 
K. In the ITT analysis population 
L. In the safety analysis population 
 
Analyses D to J will be repeated adjusted only for randomisation protocol. 
6.5 Bayesian analysis of non-inferiority 
An exploratory Bayesian analysis of non-inferiority provides an estimate of the probability 
that Regimen B has efficacy not much worse than Regimen C for different thresholds of 
what might be considered ‘not much worse’.  
 
Following methods described previously6, we will use Bayesian binomial regression to 
estimate the distribution of the (unadjusted) difference in the proportion of favourable 
outcomes between regimens B and C. Gaussian Normal priors will be placed on the intercept 
term (mean = 0.0 and variance = 100) and on the difference in proportion between 
regimens (Flat: mean = 0.0 and variance = 100, Sceptical: mean = 0.02 and variance 0.05, 
and Expected: mean = -0.02 and variance 0.05). The Flat prior is an uninformative prior 


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25
with very large variance centred around zero representing weak prior information, the 
Sceptical prior is centred around an absolute 2% increase in proportion of favourable in  
Regimen B with a smaller variance, and the Expected prior represents the assumptions used 
in the sample size calculations representing an absolute 2% increase in the proportion of 
favourable outcomes in regimen C. Initial values for the Markov Chain Monte Carlo algorithm 
came from estimates from the frequentist binomial regression model. This analysis will be on 
the mITT population. 
 
7 ANALYSIS OF SECONDARY OUTCOMES 
7.1  Efficacy outcomes 
Secondary efficacy analyses will be carried out on i) data censored at Week 76, and ii) data 
from all visits occurring on or before the projected Week 96 visit of the last patient 
randomised i.e. approximately end of November 2021 (long-term efficacy data).  A 
participant’s scheduled last efficacy visit will be their latest scheduled trial visit on or before 
this date. In addition to the comparisons detailed below, analyses of the long-term efficacy 
data will include comparisons of Regimen C with Regimen D. Comparisons of Regimen C and 
Regimen D using data up to Week 76 were carried out at the time of the primary analysis 
but considered exploratory. 
 
Secondary efficacy outcomes will be analysed on the mITT analysis population with the 
exception of the analysis of favourable outcome at Week 132 to determine the non-inferiority 
of Regimen C to Regimen B which will be analysed on the mITT, PP and mPP populations. 
 
7.1.1 Time to sputum smear and culture conversion 
Time to sputum smear conversion is defined as the time from randomisation to the first of 
two consecutive negative sputum results, collected on separate days. All patients in the 
analysis population will be included in this analysis, except those with no positive smear 
result at screening and randomisation.  Patients that never achieve smear conversion will be 
censored at the date of collection of sputum that yielded their last smear result. 
 
Time to sputum culture conversion is defined as the time from randomisation to the first of 
two consecutive negative culture results, collected on separate days. Patients that never 
achieve culture conversion will be censored at the date of collection of sputum that yielded 
their last culture result. 
 
Median time to sputum smear and culture conversion will be calculated for Regimen B, 
Regimen C, and Regimen D using the Kaplan-Meier estimator. 
 
A hazard ratio with corresponding two-sided 95% confidence intervals and p-value will be 
estimated for the comparison of Regimen B with Regimen C, and Regimen B with Regimen 
D.A Cox Proportional Hazards model will be used, adjusted for randomisation protocol (as 
defined in Section 1.6) and the stratification factor HIV status with the three categories of: 
HIV negative; HIV positive with CD4 count ≥350 cells/mm3; and HIV positive with CD4 
count <350 cells/mm3.   
 
The equality of survivor functions for time to sputum conversion for Regimen B and 
Regimen C, and Regimen B and Regimen D, will each be tested using a Log rank test, 
stratified by randomisation protocol (as defined in Section 1 .6) and the randomisation 


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26 
stratification factor HIV status with the three categories of: HIV negative; HIV positive with 
CD4 count ≥350 cells/mm3; and HIV positive with CD4 count <350 cells/mm3.   
 
The assumption of proportional hazards between the two comparisons will be tested using 
the proportional hazards test based on the Schoenfeld residuals after fitting the Cox 
Proportional Hazards models. In the case where there is adequate evidence that the 
proportional hazard assumptions are violated at the 5% level (i.e. p<0.05), methods where 
proportional hazards is not a necessary assumption will be used, such as the Wilcoxon test 
of equality of survivor functions and restricted mean survival time. 
 
These analyses of time to sputum smear conversion and time to sputum culture conversion 
will be repeated with the alternative definition as time from randomisation to the first 
negative culture or smear result respectively (without the need for a second negative culture 
or smear result to confirm).  These analyses will only be carried out on data up to Week 76. 
 
7.1.2 Time to unfavourable efficacy outcome 
Time to unfavourable efficacy outcome is defined as the time from randomisation to the first 
event that results in the definition of an unfavourable efficacy outcome for that patient (as 
defined in Section 3.2).  Patients that do not culture convert during the treatment and 
follow-up phases (i.e. fail to have 2 consecutive culture negative results), and have not 
otherwise been called unfavourable, will be called unfavourable at the date of the last visit 
when a culture positive result was obtained.  Patients classified as favourable or not 
assessable will be censored in this analysis at the date of collection of sputum that yielded 
their last negative culture result. 
 
Median time to unfavourable efficacy outcome will be calculated for Regimen B, Regimen C, 
and Regimen D using the Kaplan-Meier estimator. 
 
A hazard ratio with corresponding two-sided 95% confidence intervals and p-value will be 
estimated for the comparison of Regimen B with Regimen C, and Regimen B with Regimen 
D. A Cox Proportional Hazards model will be used, adjusted for randomisation protocol (as 
defined in Section 1.6) and the stratification factor HIV status with the three categories of: 
HIV negative; HIV positive with CD4 count ≥350 cells/mm3; and HIV positive with CD4 
count <350 cells/mm3.   
 
The equality of survivor functions for time to unfavourable efficacy outcome for Regimen B 
and Regimen C, and Regimen B and Regimen D, will each be tested using a Log rank test, 
stratified by randomisation protocol (as defined in Section 1.6) and the randomisation 
stratification factor HIV status with the three categories of: HIV negative; HIV positive with 
CD4 count ≥350 cells/mm3; and HIV positive with CD4 count <350 cells/mm3.   
 
The assumption of proportional hazards between the two comparisons will be tested using 
the proportional hazards test based on the Schoenfeld residuals after fitting the Cox 
Proportional Hazards models.  In the case where there is adequate evidence that the 
proportional hazard assumptions are violated at the 5% level (i.e. p<0.05), methods where 
proportional hazards is not a necessary assumption will be used, such as the Wilcoxon test 
of equality of survivor functions and restricted mean survival time. 
 


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27
7.1.3 Time to failure or recurrence 
Favourable outcome for each participant will be re-classified according to the likelihood that 
it was a Failure or Recurrence (FoR) event on a five-point Likert scale: Definite, Probable, 
Possible, Unlikely, and Highly Unlikely7.  
 
An event will be considered Highly Unlikely to be a FoR event only if there is evidence of 
durable cure; i.e. the primary outcome classification of favourable which required completion 
of follow-up with negative cultures. A Definite FoR event requires clear bacteriological 
evidence of failure or recurrence (excluding a proven reinfection with exogenous strain of M. 
tuberculosis), a Probable FoR event requires some evidence for failure or recurrence 
(clinical, bacteriological, or radiological) in the absence of clear bacteriology. The remaining 
participants will be classified as possible or unlikely based on their data. Time of the FoR 
event/censoring is the same as defined in the time to unfavourable outcome analysis (see 
Section 7.1.2).The FoR classification will reviewed by an independent clinician, blinded to 
treatment.  
 
In the time to FoR analyses, the main groups of interest are those classified as having a 
Definite or Probable FoR event, with censoring of Possible, Unlikely and Highly Unlikely 
events at the time of the censoring event which met criteria for Unfavourable or Not 
Assessable in the primary analysis.   
 
Median time to FoR will be calculated for Regimen B, Regimen C, and Regimen D using the 
Kaplan-Meier estimator. 
 
A hazard ratio with corresponding two-sided 95% confidence intervals and p-value will be 
estimated for the comparison of Regimen B with Regimen C, and Regimen B with Regimen 
D. A Cox Proportional Hazards model will be used, adjusted for randomisation protocol (as 
defined in Section 1.6) and the stratification factor HIV status with the three categories of: 
HIV negative; HIV positive with CD4 count ≥350 cells/mm3; and HIV positive with CD4 
count <350 cells/mm3.   
 
The equality of survivor functions for time to failure or recurrence for Regimen B and 
Regimen C, and Regimen B and Regimen D, will each be tested using a Log rank test, 
stratified by randomisation protocol (as defined in Section 1.6) and the randomisation 
stratification factor HIV status with the three categories of: HIV negative; HIV positive with 
CD4 count ≥350 cells/mm3; and HIV positive with CD4 count <350 cells/mm3.   
 
The assumption of proportional hazards between the two comparisons will be tested using 
the proportional hazards test based on the Schoenfeld residuals after fitting the Cox 
Proportional Hazards models.  In the case where there is adequate evidence that the 
proportional hazard assumptions are violated at the 5% level (i.e. p<0.05), methods where 
proportional hazards is not a necessary assumption will be used, such as the Wilcoxon test 
of equality of survivor functions and restricted mean survival time. 
 
Sensitivity analyses will be conducted i) considering different dichotomies of the 5 point 
scale and ii) assessing the assumption of independent or non-informative censoring (i.e. that 
the likelihood of an FoR event at the time of censoring is assumed to be the same as for 
those in whom no censoring occurred) using inverse probability of censoring weights 
(IPCW)8 and multiple imputation(MI)9 respectively. 
 
This failure or recurrence analysis will be repeated in subgroups according to baseline 
characteristics as described in Section 6.3. 


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28 
 
7.1.4 Favourable outcome at Week 132 
A patient’s outcome will be classified as favourable if their last two sputum culture results 
are negative, unless they have previously been classified as unfavourable.  These two 
sputum results must be from samples taken at separate visits; the latest must be no more 
than six weeks before their scheduled last efficacy visit (see Section 7.1). 
 
A patient’s outcome at their scheduled last efficacy visit will be classified as unfavourable if: 
• They are unfavourable at Week 76 
• They start any MDR-TB treatment between their Week 76 and scheduled last efficacy 
visits  
• They die between their Week 76 and scheduled last efficacy visits 
• At least one of their last two culture results, from specimens taken on separate occasions, 
is positive. 
 
A patient who does not have a culture result within the window for their scheduled last 
efficacy visit, having not otherwise been classified as unfavourable, will be regarded as non-
assessable if their last two cultures, from specimens taken on separate occasions, are 
negative.  All other patients who do not have a culture result within the window for their 
scheduled last efficacy visit and do not meet this definition of non-assessable will be 
classified as unfavourable. 
 
The secondary non-inferiority outcome at Week 132 for Regimen B compared to Regimen C 
will be analysed using time to unfavourable outcome, thereby using information on all 
participants.  Data from participants whose scheduled last efficacy visit is before Week 132 
will be censored at the time of their last visit, unless they have already become 
unfavourable.  Non-assessable participants will be included in the time to event analysis and 
censored at the time of their last visit. 
 
The survival curve for each combination of strata (randomised protocol and HIV status) will 
be calculated using a Cox model adjusting for stratification factors and randomised group. 
The average survival curve for each randomised group will be estimated as a weighted 
average of the corresponding stratum-specific survival curves, with weights proportional to 
the number of individuals in each stratum in the randomised group at baseline.  The mean 
of these differences at week 132 is the point estimate for the difference in overall survival 
function between Regimen C and Regimen B. A two sided bias-corrected 95% CI for the 
difference in proportion (Regimen C – Regimen B) will be calculated with bootstrap standard 
errors. Bootstrap standard errors for the risk difference will be used so that the CI of the risk 
difference (estimated by the risk difference ±1.96se assuming the bootstrap distribution is 
approximately Normal) is bounded between -1 and 1. The bootstrapping will sample 1000 
times and be stratified by stratification factors. The seed for the bootstrap simulations will 
be stored to enable replication of results. 
 
Non-inferiority will be shown if the upper bound of the 95% confidence interval of the 
difference in proportion of favourable outcomes at Week 132 between Regimens B and C is 
less than the 10% margin of non-inferiority; this must be shown in both the mITT and PP 
populations.  If non-inferiority is demonstrated, then superiority of Regimen C compared to 
Regimen B will be declared if the upper bound of the 95% confidence interval of the 
difference in proportion of favourable outcomes at Week 132 between Regimens B and C is 
less than zero.  For this analysis, the mITT population will be primary and the PP and mPP 
populations will be sensitivity analyses. 
 


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29
A sensitivity analysis will estimate the proportion unfavourable at Week 132 on the subset of 
participants randomised at least 132 weeks on or before 30 November 2021 (see Section 
6.1.1). For this analysis, non-assessable participants will be excluded. The mITT population 
will be primary and the PP and mPP populations will be sensitivity analyses.  
 
The above analyses will be repeated for the following comparisons, restricting the 
population in each case to include only concurrent controls within sites: Regimen Blev and 
Regimen C, Regimen Bmox and Regimen C, Regimen D and Regimen B, Regimen B and 
Regimen A, Regimen C and Regimen A, Regimen D and Regimen A. The analysis will also be 
repeated (in both mITT and PP analysis populations) in subgroups according to HIV status. 
 
 
7.2 Safety outcomes  
Safety outcomes will be analysed using the safety analysis population. 
   
7.2.1 Placement of events by study phases 
Adverse events are placed in study phases (see Section 5.2 for definitions) based on the 
start date.  
In case of partial start dates, the following approach is used: 
 
Missing day only: The event is placed in the earliest phase that overlaps the given 
month and year for the event, excluding any phases that start after the end date of the 
AE (if specified). 
 
Missing day and month only: The event is placed in the earliest phase that overlaps 
the given year for the event, excluding any phases that start after the end date of the 
AE (if specified). 
 
Missing start date: The event is placed in the treatment phase, unless the end date 
of the AE is specified and is before randomisation, in which case the event is placed in 
the screening phase.  
 
7.2.2 All-cause mortality during treatment or follow-up 
All-cause mortality is defined as a patient who has died from any-cause (both TB- or non-
TB-related) while in the trial either during treatment or during follow-up.  
 
The number of patients who die during treatment and follow-up will be tabulated by treatment 
arm.  Mortality rates, stratified by randomisation protocol and HIV status, will be calculated 
for the individual treatment arms and treatment group differences in mortality rates will be 
calculated together with a 95% confidence interval. For patients that do not die, time will be 
censored at their final visit.   
 
The difference in proportion of patients dying during treatment and follow-up, between 
Regimen B and Regimen C, between Regimen Bmox and Regimen C, between Regimen Blev and 
Regimen C,  between Regimen B and Regimen D, and between Regimen B and Regimen A, 
with corresponding two-sided 95% confidence intervals and p-values will be estimated (see 
Section 6.1.1).  The analysis will be stratified by randomisation protocol (as defined in Section 
1.6) and HIV status with three strata: HIV negative, HIV positive with CD4 count less than 
350 cells/mm3, and HIV positive with CD4 count more than or equal to 350 cells/mm3.   
 
Survival analysis will be conducted for time to death.  A hazard ratio with corresponding 
two-sided 95% confidence intervals and p-value will be estimated for the comparison of 


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30 
Regimen B with Regimen C, and Regimen B with Regimen D, using a Cox Proportional 
Hazards model stratified by randomisation protocol (as defined in Section 1.6) and the 
randomisation stratification factor HIV status with the three categories of: HIV negative; HIV 
positive with CD4 count ≥350 cells/mm3; and HIV positive with CD4 count <350 cells/mm3.    
 
The equality of survivor functions for time to death for Regimen B and Regimen C, and 
Regimen B and Regimen D, will each be tested using a Log rank test, stratified by 
randomisation protocol (as defined in Section 1.6) and the randomisation stratification factor 
HIV status with the three categories of: HIV negative; HIV positive with CD4 count ≥350 
cells/mm3; and HIV positive with CD4 count <350 cells/mm3.   
 
This analysis will be conducted on the whole study period, and separately for follow-up 
censored at Week 76. It will also be repeated comparing bedaquiline and non-bedaquiline 
regimens (Regimens A and B vs C and D) and comparing Regimen Bmox and Regimen C, and 
Regimen Blev and Regimen C.  A descriptive analysis will consider deaths by cause, as 
adjudicated by an independent review committee. In addition to the comparisons detailed 
above, analyses of the whole study period (up to Week 132) will include comparisons of 
Regimen C with Regimen D.  Comparisons of Regimen C and Regimen D using data up to 
Week 76 were carried out at the time of the primary analysis but considered exploratory. 
 
 
7.2.3 Proportion of patients experiencing a grade 3 or greater adverse event, as 
defined by the DAIDS criteria, during treatment and follow-up 
The difference in proportion of patients experiencing a grade 3 or greater adverse event, as 
defined by the DAIDS criteria10, during treatment and follow-up, between Regimen B and 
Regimen C, between Regimen Bmox and Regimen C, between Regimen Blev and Regimen C,  
between Regimen B and Regimen D, and between Regimen B and Regimen A, with 
corresponding two-sided 95% confidence intervals and p-values will be estimated (see Section 
6.1.1).  The analysis will be stratified by randomisation protocol (as defined in Section 1.6) 
and HIV status with three strata: HIV negative, HIV positive with CD4 count less than 350 
cells/mm3, and HIV positive with CD4 count more than or equal to 350 cells/mm3.   
 
This analysis will be conducted on the whole study period, the study period censored at Week 
76, and separately for each phase (Treatment censored at Week 76, and Allocated treatment).  
 
Comparisons will be repeated in subgroups according to HIV infection status.  In addition the 
proportion of participants with cardiac events, hearing loss and hepatotoxicity by Week 76 
and Week 132 in Regimen C and Regimen D will be compared to Regimen B. 
 
In addition to the comparisons detailed above, analyses of the whole study period (up to Week 
132) will include comparisons of Regimen C with Regimen D. Comparisons of Regimen C and 
Regimen D using data up to Week 76 were carried out at the time of the primary analysis but 
considered exploratory. 
 
7.2.4 Change of regimen for adverse events 
A change of regimen for an adverse event is defined as when a patient’s regimen is modified 
in any way (including stopping a drug, changing the dose of a drug or starting a new drug) 
with the reason being an adverse event. 
  


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The difference in proportion of patients who have a change of regimen for adverse events 
between Regimen B and Regimen C, between Regimen Bmox and Regimen C, between 
Regimen Blev and Regimen C, and between Regimen B and Regimen D, will be calculated.   
 
The MedDRA SOC/SMQ or preferred term of the adverse event and the type of treatment 
change, will be described by arm. 
 
7.2.5 Pharmacokinetics/Pharmacodynamics 
At a number of visits throughout the trial, a single blood sample is taken to determine the 
bedaquiline (BDQ) and M2 plasma concentrations. The BDQ plasma concentrations are used 
by a qualified vendor to estimate Ctrough, Cmax and AUC using empirical Bayes’ estimation based 
on a population pharmacokinetic model. Individual ART plasma concentrations (LPV, RTV and 
NVP) and 4β-hydroxycholesterol/cholesterol ratio (as a measure of cytochrome P450 3A 
(CYP3A) activity) are also measured. 
 
Participants randomised to Regimen C or Regimen D with PK data available, will be classified 
into 5 subgroups based on their HIV status and HIV drugs taken immediately before the PK 
blood draw: 
 
HIV Neg: HIV negative at baseline 
 
HIV Pos, LPV/r : HIV positive at baseline having received Liponavir/Ritonavir (but not 
Nevirapine) immediately before the PK blood draw. 
 
HIV Pos, NVP: HIV positive at baseline having received Nevirapine (but not 
Liponavir/Ritonavir) immediately before the PK blood draw. 
 
HIV Pos, other ARV : HIV positive at baseline having received ART (but not 
Liponavir/Ritonavir or Nevirapine) immediately before the PK blood draw.  
 
HIV Pos, not taking ARV: HIV positive at baseline but not receiving ART immediately before 
the PK blood draw. 
Individual plasma concentrations will be listed and descriptive statistics generated at each 
sampling time, by treatment group and separately for the above defined subgroups.  
 
Further details of the analyses of PK/PD will be described in the STREAM Stage 2 Extensive 
SAP. 
7.3 Health Economics  
In selected sites, acceptability of Regimens A, B, C and D to stakeholders will be analysed in 
terms of: 
 
Costs to the health system 
 
Household costs 
 
Patient treatment and support experiences 
 
Health worker experiences. 
 
The analyses of health and household costs and patient and health worker experiences will 
be described in a separate document. 
7.4 Testing multiple outcomes  
We will make no adjustment to p-values or confidence intervals to allow for testing multiple 
secondary outcomes. 
 
The STREAM primary outcome is a composite outcome of bacteriological failure, treatment 
failure for any reason (clinical, bacteriological, intolerance) and death. The primary analysis 
is non-inferiority of Regimen C versus Regimen B. If the 95% CI for the treatment effect 


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32 
(difference in proportion unfavourable by 76 weeks (C-B)) lies below the non-inferiority 
margin, then we will also test for superiority; because this is a closed test procedure there is 
no issue of multiplicity. 
 
Secondary outcomes are divided in the protocol into efficacy outcomes, safety outcomes and 
acceptability outcomes. For safety outcomes it is appropriate to test each independently 
since it is important to identify any risks associated with Regimen C. The secondary efficacy 
outcomes are mostly components of the primary outcome or very closely related to the 
primary outcome (bacteriological and clinical outcomes). We will not adjust for multiple 
testing for these since they are correlated with the primary outcome (so standard 
adjustments are conservative).  
 
We will report significance tests for differences between treatment arms for acceptability 
outcomes, but if we have failed to demonstrate non-inferiority of Regimen C versus Regimen 
B for the primary outcome, we will not use significance tests for these acceptability 
outcomes to conclude superiority. 
 
 
8 ADDITIONAL EXPLORATORY ANALYSES 
The following analyses will all be completed after the last participant has reached Week 132 
on the mITT population unless otherwise stated. 
8.1 Time to cessation of clinical symptoms based on PI assessment 
In stage 2 of STREAM, the presence of a productive cough, fever, and night sweats was only 
solicited at the randomisation visit. During follow-up these symptoms were recorded on the 
AE log if reported by the participant.  There is concern that these events have been under 
reported.  Therefore, the proportion of people reporting these symptoms in Regimen B will 
be compared to the proportion reported in stage 1 (when they were solicited at each visit).  
If this proportion is <80% of that seen in stage 1, the following analyses will not be 
conducted. 
 
Time to cessation of clinical symptoms is defined as the time from randomisation to the first 
of two consecutive visits where cessation of all three of the TB symptoms: a productive 
cough, fever, and night sweats, as reported by the patient. Patients with none of the TB 
symptoms at screening and baseline with be excluded from this analysis. This definition 
matches the definition of time to culture conversion as the first of two consecutive 
symptom-free months. For patients who do not cease clinical symptoms, cessation of clinical 
symptoms will be censored at the patients’ last visit up to and including week 76.    
 
Median time to cessation of clinical symptoms will be calculated for Regimen B, Regimen C, 
and Regimen D. 
 
A hazard ratio with corresponding two-sided 95% confidence intervals and p-value will be 
estimated for the comparison of Regimen B with Regimen C, and Regimen B with Regimen 
D. A Cox Proportional Hazards model will be used, adjusted for randomisation protocol (as 
defined in Section 1.6) and the stratification factor HIV status with the three categories of: 
HIV negative; HIV positive with CD4 count ≥350 cells/mm3; and HIV positive with CD4 
count <350 cells/mm3.   
 
The equality of survivor functions for time to cessation of clinical symptoms for Regimen B 
and Regimen C, and Regimen B and Regimen D, will each be compared using a (Wilcoxon) 


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33
Log rank test, stratified by randomisation protocol (as defined in Section 1.6) and the 
randomisation stratification factor HIV status with the three categories of: HIV negative; HIV 
positive with CD4 count ≥350 cells/mm3; and HIV positive with CD4 count <350 cells/mm3.   
 
The assumption of proportional hazards between the two comparisons will be tested using 
the proportional hazards test based on the Schoenfeld residuals after fitting the Cox 
Proportional Hazards models. In the case where there is adequate evidence that the 
proportional hazard assumptions are violated at the 5% level (i.e. p<0.05), methods where 
proportional hazards is not a necessary assumption will be used, such as restricted mean 
survival time. 
8.2 WHO classification of outcome 
TB outcome at the end of treatment will be determined using the WHO DR-TB treatment 
outcomes definition11. Participants will be classified as cured, treatment completed, 
treatment failed, died, lost to follow-up or not evaluated, with the first two categories 
considered together as treatment success.  
 
The modified WHO DR-TB treatment outcome definition will also be applied; this includes an 
additional category of relapse after treatment success, defined as bacteriological relapse 
after end of treatment cure4,12. 
 
The most recent WHO DR-TB treatment outcome definition13 will also be applied; this moves 
away from bacteriological status and focuses more on the completion of treatment or 
reasons for incompletion. 
 
Each classification will be tabulated by treatment arm and the unadjusted difference in 
treatment success comparing Regimen B with Regimen C, Regimen B with Regimen D and 
Regimen C with Regimen D calculated with 95% confidence intervals.  
8.3 TB outcome irrespective of treatment changes at Week 132 
This analysis will exclude all participants whose scheduled last efficacy visit is before Week 
132. 
 
TB outcome will be classified according to the patients’ culture status at week 132 
regardless of treatment changes or intermediate culture results – similar to a simplistic 
intention-to-treat analysis.  
 
A participant is defined as “cured at Week 132” if the last two cultures were negative with 
the last no earlier than the Week 132 analysis window; other categories include death prior 
to Week 132, last culture positive at Week 132, last culture negative prior to Week 132, last 
culture positive prior to Week 132, or no cultures after baseline. 
 
This classification will be tabulated by treatment arm, and the difference in proportion cured 
reported comparing Regimen B with Regimen C, Regimen B with Regimen D and Regimen C 
with Regimen D calculated with 95% confidence intervals, stratifying for randomisation 
protocol and HIV status.   
8.4 Lung surgery 
The proportion of participants having undergone lung surgery (resection or 
pneumonectomy) by Week 76 and Week 132 in Regimen C and Regimen D will be compared 
to Regimen B using Fisher’s exact test on the safety population. 
 


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34 
 
9 DATA SUMMARIES 
9.1 Recruitment and baseline characteristics 
 
9.1.1 Recruitment, screening, & eligibility 
The number of patients screened, randomised, and treated will be tabulated by centre and 
treatment arm. The number of patients who failed screening, and the reasons for ineligibility 
will be presented by randomised group. 
 
9.1.2 Exclusions from analysis  
The number of patients excluded from the mITT and PP analysis populations will be 
tabulated by treatment arm and by reason for exclusion. 
 
9.1.3 Baseline characteristics 
All eligible patients randomised will be included in tables of baseline comparisons by 
treatment group. Characteristics will include sex, age, race, height, weight, BMI, albumin 
levels, and laboratory parameters such as, HIV status, CD4 count (if applicable), smear and 
culture status, and drug susceptibility status for a number of TB drug types. The baseline 
characteristics table will be repeated for each of the ITT, safety, PP and mITT populations.  
9.2 Efficacy and adherence 
Each analysis will be carried out using the mITT analysis population. 
 
9.2.1 Sputum smear and culture 
Sputum smear and culture results (positive or negative) will be tabulated by visit and 
treatment arm. 
 
9.2.2 Adherence 
Adherence will be summarised by treatment arm as the percentage of each of the intensive 
and continuation phase doses completed and overall across both phases.  
 
9.2.3 Drug resistance 
All drug resistance analyses will be based on phenotypic DST results unless unavailable 
when genotypic results will be used. 
 
Drug resistance at screening or baseline will be tabulated by treatment arm.  
 
Acquired resistance to any drugs will also be described and tabulated by treatment arm 
using i) the last available DST result for each drug for each patient, and ii) all available post-
randomisation DST result (i.e. classifying as resistant if any result is resistant) for each drug 
for each patient ignoring isolated resistance unless it is the last result prior to the point of 
analysis. The proportion of participants developing resistance, especially resistance leading 
to the development of pre-XDR or XDR strains of TB in Regimen C and Regimen D will be 
compared to that in Regimen B for data up to Week 76, and for the Allocated treatment 
phase only (i.e. up to the point of starting a salvage regimen).  


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35
9.3 Safety 
 
All the following analyses will be on the safety population. 
 
9.3.1 ECG 
Time to first QT/QTcF over 450ms and first QT/QTcF over 500ms and QTcF increase from 
baseline by 30ms and by 60ms analyses will be conducted.  The proportion of participants 
experiencing of each of these events (ie whether a threshold was exceed or not) will be 
tabulated by treatment arm and country. Hazard ratios with corresponding two-sided 95% 
confidence intervals will be estimated for the comparison of Regimen B with Regimen C, 
Regimen Bmox with Regimen C, Regimen Blev with Regimen C, and Regimen B with Regimen 
D. A Cox Proportional Hazards model will be used, adjusted for randomisation protocol (as 
defined in Section 1.6) and the stratification factor HIV status with the three categories of: 
HIV negative; HIV positive with CD4 count ≥350 cells/mm3; and HIV positive with CD4 
count <350 cells/mm3.The outcomes will be censored at the patients’ last visit.    
 
The equality of survivor functions for time to QTcF over 450ms and over 500ms and QTcF 
increase from baseline by 30ms and by 60ms for Regimen B and Regimen C, and Regimen B 
and Regimen D, will each be tested using a Log rank test, stratified by randomisation 
protocol (as defined in Section 1.6) and the randomisation stratification factor HIV status 
with the three categories of: HIV negative; HIV positive with CD4 count ≥350 cells/mm3; 
and HIV positive with CD4 count <350 cells/mm3. 
 
The assumption of proportional hazards will be tested using the proportional hazards test 
based on the Schoenfeld residuals after fitting the Cox Proportional Hazards models. In the 
case where there is adequate evidence that the proportional hazard assumptions are 
violated at the 5% level (i.e. p<0.05), methods where proportional hazards is not a 
necessary assumption will be used, such as using the Kaplan-Meier estimator restricted 
mean survival time. 
 
QTcF will be estimated by visit and by treatment arm using a linear mixed model, adjusted 
for the stratification factors.  Estimates with 95% confidence intervals will be plotted by visit 
and treatment arm.  This will be repeated for change in QTcF from baseline. 
 
It is likely that treatment and dose changes will impact on QTcF and so this analysis will be 
repeated ignoring any results after discontinuation or change of dose of any drug. 
Exploratory analyses will investigate the relationship between changes in QTcF and ART use.  
 
9.3.2 Liver function 
Bilirubin, ALT, and AST will be tabulated by DAIDS grade, visit and treatment arm. Mean 
(and SE) bilirubin, ALT, and AST will be presented by visit and treatment arm.  The number 
of patients experiencing more than or equal to five times above the upper normal limit will 
be tabulated by arm. 
 
9.3.3 Hearing impairment  
The proportion of patients experiencing significant hearing loss (unilateral or bilateral) based 
on Brock’s Criterion applied to Shoebox data, during treatment and follow-up will be 
tabulated by treatment arm. Significant hearing loss will be defined as hearing loss that 
persists such that it is still present at the last visit of the follow-up period being considered 
(Week 76 or last efficacy visit) and is grade 3 or higher. 


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36 
 
9.3.4 Weight gain 
Patient weight will be tabulated by treatment arm and visit in addition to change from 
baseline weight by visit and treatment arm.  
 
9.3.5 SAE/NE/AE 
SAEs and grade 3 or higher AEs will be tabulated by MedDRA System Organ Class (SOC) / 
Standardised MedDRA queries (SMQ) and Preferred Term and treatment arm. NEs will be 
tabulated by event type and treatment arm. The total number of events and the number of 
participants with at least one event will be given.   SAEs will also be tabulated by event 
relatedness to study drugs and treatment arm. Pregnancy outcomes will be reported by 
treatment arm. 
 
Grade 3 and 4 laboratory AEs will be tabulated by laboratory marker and treatment arm. 
This will be presented for results from the central laboratory alone. 
 
These analyses will be conducted on the whole study period, and separately for each phase 
(Treatment censored at Week 76, and Allocated treatment).  
 
9.3.6 HIV infection  
HIV viral load (VL) and CD4 actual values and changes from baseline will be tabulated by visit 
and treatment arm. VL response, defined as <50 copies/mL, between 50 and less than 400 
copies/mL, and ≥400 copies/mL, will be tabulated by visit and treatment arm, overall and by 
baseline VL. This analysis will be restricted to HIV positive patients and repeated by patient 
on/off ARV therapy at baseline. 
 
10 
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