The Effect of Low-dose Corticosteroids and Theophylline on the Risk of Acute Exacerbations of COPD: the TASCS Randomised Clinical Trial
Phase: PHASE4
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: The George Institute

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 1 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
 
 
 
 
 
Low Dose Corticosteroids and Theophylline in the Treatment of 
Chronic Obstructive Pulmonary Disease – the TASCS Study 
(Theophylline and Steroids in COPD Study) 
 
 
 
 
 
Protocol Number: TGI-Resp-01 
 
Protocol Version: 2.0 
 
Date of Protocol:  27 May 2015 
 
 
 
 
 
 
 
 
 
 
 
 
                
 
 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 2 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
TABLE OF CONTENTS 
1. 
Chief Investigators ................................................................. 6 
2. 
Sponsor and Contacts ........................................................... 7 
1. 
Chief Investigator’s Signature ............................................... 8 
2. 
Participating Centre Investigator Signature ......................... 9 
3. 
List of Abbreviations ............................................................ 10 
4. 
Synopsis ............................................................................... 11 
5. 
Schedule of Study Tests, Procedure and Visits................. 14 
6. 
Administrative Structure ..................................................... 15 
6.1 
International Coordinating Centre 
15 
6.2 
Data Management 
15 
6.3 
Clinical Centres 
15 
7. 
Funding and Insurance ........................................................ 15 
8. 
Study Background ............................................................... 16 
8.1 
Burden of Disease 
16 
8.2 
The Global Burden of COPD 
16 
8.3 
Risk Factors for COPD 
17 
8.4 
Treatment for COPD 
17 
8.4.1 
Currently Recommended Pharmacological Treatment for COPD 
17 
8.5 
Rationale for the Proposed Study 
18 
8.6 
Intervention Plan 
19 
9. 
Study Design ........................................................................ 19 
9.1 
Hypothesis and Aims 
19 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 3 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
9.2 
Study Treatments 
20 
9.2.1 
Permitted Concurrent Therapy 
20 
9.2.2 
Non-Permitted Concurrent Therapy 
20 
9.3 
Study Outcomes 
20 
9.3.1 
Primary Outcome 
20 
9.3.2 
Secondary Outcomes 
20 
9.3.3 
Study Duration 
21 
9.3.4 
Number of Participants 
21 
10. 
Study Population .................................................................. 21 
10.1 
Participant Recruitment 
21 
10.1.1 
Study Population 
21 
10.1.2 
Participant Inclusion Criteria 
22 
10.1.3 
Participant Exclusion Criteria 
22 
11. 
Assessments and Study Visits ........................................... 22 
11.1 
Brief Study Visits Outline 
22 
11.2 
Participant Consent 
23 
11.3 
Study Visits 
23 
11.3.1 
Screening Visit 
23 
11.3.2 
Baseline Visit & Randomisation 
23 
11.3.3 
6, 18, 30 and 42-Weeks Phone Visit 
23 
11.3.4 
12-Weeks Visit 
23 
11.3.5 
24-Weeks and 36-Weeks Visits 
24 
11.3.6 
48-Weeks Visit 
24 
11.3.7 
50-Weeks Visit 
24 
11.4 
Safety Assessments 
24 
11.5 
Losses to Follow-up 
25 
11.6 
Non-adherence and Deviations from the Protocol 
25 
11.7 
Duration of Subject Participation 
25 
11.8 
Duration of the Study 
25 
11.9 
Screening and Recruitment log 
25 
11.10 
Data Collection 
25 
12. 
Statistics ............................................................................... 26 
12.1 
Power Calculations and Statistical Analysis 
26 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 4 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
12.1.1 
Baseline characteristics 
26 
12.1.2 
Effects of treatment 
26 
12.2 
Randomisation and Allocation of Treatment 
26 
12.3 
Missing Data 
27 
12.4 
Blinding 
27 
12.5 
Final Analysis 
27 
13. 
Termination of Study Treatment ......................................... 27 
14. 
Human Research Ethics Committee Approvals ................. 27 
15. 
Informed Consent ................................................................ 28 
15.1 
Documentation of Consent 
28 
15.2 
Withdrawal of Consent 
28 
16. 
Other therapies ..................................................................... 28 
17. 
Data Safety Monitoring Committee ..................................... 29 
18. 
Assessment of Safety .......................................................... 29 
18.1 
Definitions 
29 
18.1.1 
Adverse Event 
29 
18.1.2 
Serious Adverse Event 
30 
18.1.3 
Timing for Reporting Serious Adverse Events 
32 
18.1.4 
Documentation of Adverse Events and Serious Adverse Events 
32 
19. 
Data Quality Assurance ....................................................... 32 
19.1 
Pre-study Documentation 
32 
19.2 
Declaration of Helsinki 
33 
19.3 
Source Data Documentation 
33 
19.4 
Case Report Forms 
34 
19.5 
Review of Source Records 
34 
19.6 
Monitoring of the Study 
34 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 5 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
19.7 
Protocol Amendments 
35 
19.8 
Change in Investigator 
35 
19.9 
Termination of the Study 
35 
19.9.1 
Termination by the Study Steering Committee 
35 
19.9.2 
Termination by the Investigator 
35 
19.9.3 
Notification of Study Closure 
36 
20. 
Confidentiality ...................................................................... 36 
21. 
Records Retention ............................................................... 36 
22. 
Organisation and Collaboration .......................................... 36 
23. 
Publications and Presentations .......................................... 36 
24. 
References ............................................................................ 37 
 
 
 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 6 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
1. Chief Investigators 
Chief Investigators are members of the Steering Committee.  
 
Prof Norbert Berend 
Prof Christine Jenkins 
Prof Peter Barnes 
Prof Bartolome Celli 
Prof John Seale 
 
 
Responsibilities: 
 
The Chief Investigators are responsible for implementing the study protocol. The Steering 
Committee is responsible for ensuring that study implementation is consistent with the stated 
objectives, procedures and outcomes for a study conducted according to ICH GCP (Good 
Clinical Practice).   
 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 7 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
2. Sponsor and Contacts 
 
Sponsor 
 
The George Institute for Global Health 
Missenden Road 
Camperdown 
NSW 2050 
Australia 
 
 
 
 
 
Chief Investigator 
 
Prof Norbert Berend 
The George Institute for Global Health 
 
Level 13, 321 Kent Street 
Sydney  
NSW 2000 
Australia 
Email: norbert.berend@sydney.edu.au 
 
International Coordinating Centre 
 
Prof Christine Jenkins 
Study Director and Lead Physician 
The George Institute for Global Health 
 
Level 13, 321 Kent Street 
Sydney  
NSW 2000 
Australia 
Email: christine.jenkins@sydney.edu.au 
 
Dr Emma Heeley 
Senior Research Manager 
The George Institute for Global Health 
 
Level 13, 321 Kent Street 
Sydney  
NSW 2000 
Australia 
Email: eheeley@georgeinstitute.org 
 
 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 8 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
1. Chief Investigator’s Signature 
I have read and approve this protocol. I assure that this study will be conducted according to 
all stipulations of the protocol, including all statements regarding confidentiality. 
 
 
Name (print): 
 
 
Professor Norbert Berend 
 
Signature: 
 
 
 
Date of Signature: 
 
27th May 2015 
 
 
 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 9 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
2. Participating Centre Investigator Signature 
I have read this protocol and agree that it contains all necessary details for carrying out the 
study as described. I will conduct this protocol as outlined therein, including all statements 
regarding confidentiality. I will make all reasonable efforts to complete the study within the 
time designated. I will provide copies of the protocol and access to all information furnished 
by the study Steering Committee to study personnel under my supervision. I will discuss this 
material with them to ensure that they are fully informed about the study. I understand that the 
study may be terminated or enrolment suspended at any time by the Steering Committee, with 
or without cause, or by me if it becomes necessary to protect the best interests of the study 
participants.  
I agree to conduct this study in full accordance with all applicable regulations and Good 
Clinical Practice (GCP). 
 
 
Investigator’s Name (print): 
 
 
 
Signature: 
 
 
 
 
Date of Signature: 
 
 
 
 
 
 
 
 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 10 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
3. List of Abbreviations 
Abbreviation     
Term 
ACTH 
Adrenocorticotropic Hormone 
AE  
Adverse Event 
ATS 
American Thoracic Society 
BSQ 
Brief screening questionnaire 
CAT 
COPD Assessment Test 
COPD 
Chronic Obstructive Pulmonary Disease 
DSMC  
Data Safety Monitoring Committee 
e-CRF 
Electronic Case Report Form 
FBC  
Full Blood Count 
FDA 
Food and Drugs Administration 
FEV1 
Forced expiratory volume in 1 second (L) 
FVC 
Forced Vital Capacity (L) 
GCP  
Good Clinical Practice 
GGT 
Gamma - glutamyl transferase 
GOLD  
 
Global Initiative for Obstructive Lung Disease 
HRU 
Health Resource Use 
ICC 
International Coordinating Centre 
ICH 
The International Conference on Harmonization 
ICS 
Inhaled Corticosteroids 
ITT 
Intention To Treat Trial 
LABA 
Long acting beta-2 agonist 
LAMA 
Long acting anti-muscarinic antagonist 
PCA 
Participating Centre Agreement 
RCT 
Randomised Controlled Trial 
SABA 
Short acting beta-2 agonist 
SAE 
Serious Adverse Event  
SGRQ 
St George’s Respiratory Questionnaire 
TGA 
Therapeutic Goods Administration 
 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 11 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
4. Synopsis 
Study Title  
Low dose corticosteroids and theophylline in the treatment of 
COPD – the TASCS Study (Theophylline and Steroids in 
COPD Study) 
Clinical Phase  
IV 
 
Study Rationale 
 
This trial aims to assess the effect of low dose theophylline, 
singly or in combination with low dose oral prednisone, on 
COPD exacerbations, quality of life, and secondary clinical 
outcomes compared with placebo over 48 weeks. The study 
has been designed with clinically important outcomes, in order 
to be feasible in multiple centres in China. The inclusion criteria 
ensure that the results are generalisable to the majority of 
symptomatic patients with COPD. 
 
Trial Design  
This is a multi-centre, double blind, randomised, controlled trial 
comparing low dose theophyline alone or in combination with 
low dose prednisone, versus placebo over 48 weeks in patients 
with COPD.  
 
Study Intervention 
 
This is a trial with a 3-arm blinded, double dummy comparison: 
1. placebo and placebo 
2. low-dose theophylline and placebo 
3. low-dose theophylline and low dose oral prednisone.  
Study Medications & 
Dose 
Prednisone 5 mg daily, slow release theophylline 100mg bd 
and matched placebos 
Intervention Duration  
48 weeks 
Rationale for Number 
of 
Participants 
 
1650 patients are required to detect 20% relative risk reduction 
(80%power, 2-tailed alpha) for comparison of low dose 
theophylline and low dose prednisone  versus placebo (arm 3 
vs arm1) for the primary outcome, number of COPD 
exacerbations per patient over 48 weeks, annualised to 12 
months in a 3-arm trial.  A 20% risk reduction, with baseline of 
1 exacerbation per year, 15% drop out, 12 months follow up 
and 80% power would require 550 patients per arm. In addition, 
low dose theophylline administered alone will be compared with 
placebo (arm 2 vs arm 1). 
Study Endpoints  
 
Primary Outcome 
The primary outcome for this study is the difference between 
the three treatment groups in  
 
COPD exacerbation rate 
 
Secondary Outcomes 
 
Time to first severe exacerbation requiring hospitalisation or 
death 
 
Quality of Life using the St George’s Respiratory 
Questionnaire  

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 12 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
 
COPD Assessment Test (CAT), score out of total 40 
 
Pre-bronchodilator spirometry 
 
Post-bronchodilator spirometry 
 
Analyses will include difference in exacerbation rates between 
the two groups at 12-, 24 and 48 weeks. Quality of life will be 
assessed by the change in quality of life between 
randomisation and 48-weeks visit measured by the SGRQ.  
 
Study specific Adverse Events and Serious Adverse Events 
assessments will be recorded including those recorded in the 
participant diary, phone visits and at 12 weekly study visits, 
serum theophylline levels collected  at baseline, 12- and 48-
weeks in a subgroup of 100 participants will be stored and 
analysed at the end of the participant follow up. In addition, the 
ACTH stimulation test will be performed at  and 50-weeks in 
another subgroup of 100 participants. Symptoms attributable to 
corticosteroid and theophylline toxicity will be recorded at each 
patient visit. 
Medication Adherence 
Medication compliance will be assessed by residual tablet 
count at each study visit. Good compliance is defined as taking 
> 80% of study medication. 
 
Inclusion Criteria  
Patients will be eligible for inclusion if they  
 
Are current or former smokers (> 10 pack years) 
 
40-80 years of age 
 
Have a clinical diagnosis of COPD 
 
Have a post-bronchodilator FEV1 < 70% predicted 
 
Have FEV1/FVC ratio < 70% after bronchodilator 
 
Exclusion criteria 
 
Patients will be excluded if, in the opinion or knowledge of the 
responsible clinician:  
 
Life expectancy of less than 12 months  
 
Exacerbation or respiratory infection within 4 weeks prior to 
randomisation  
 
Patient is taking and requires maintenance oral 
corticosteroids  
 
Patient is on domiciliary oxygen  
 
There has been previous pulmonary resection  
 
Previous sensitivity to, or intolerance of theophylline  
 
Coexistent illness precluding participation in the study 
(epilepsy, chronic liver disease, unstable cardiovascular 
disease, diabetes, active malignancy) 
 
Inability to complete quality of life questionnaire  
 
Concomitant major illness that would interfere with visits, 
assessments and follow-up 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 13 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
 
Have evidence of chronic liver disease, or transaminase or 
GGT elevation > 1.5 x ULN 
 
Random blood glucose level > 8 mmol/L 
 
High chance in the view of the treating physician that the 
patient will not adhere to study treatment and follow up 
 
Current asthma 
 
Pregnancy or breast feeding 
Number of 
Participants 
1650 participants 
Centres 
Centres will be recruited in China  
 
Treatment 
Administration 
 
Patients will be randomized to receive either theophylline and 
placebo 2 tabs twice a day or prednisone and theophylline 2 
tabs twice a day or placebo and placebo 2 tabs twice a day for 
48 weeks. Randomisation will be stratified by smoking status 
and centre. Returned by participant tablets will be counted at 
study visit.  
 
Safety Evaluation  
 
Safety for individual participants will be assessed on an 
ongoing basis by physical examination including vital signs, 
laboratory assessments, and monitoring of adverse events. 
Symptoms attributable to corticosteroid and theophylline 
toxicity will be sought and specifically recorded at each patient 
visit. A subgroup of 100 participants, will have serum 
theophylline measured at baseline, 12- and 48- weeks. Another 
subgroup of 100 participants, , will have the ACTH stimulation 
test performed at 48 weeks. 
Efficacy Evaluation  
Data will be collected from participant visits at baseline, 12, 24, 
36, and 48 weeks.  
 
DSMC Analysis  
 
Safety data will be reviewed at 6-12 month intervals and/ or 
when 25%, 50 %, 75% and 100 % participants have been 
randomised. Thereafter safety data review will be at the 
discretion of the DSMC and/or the Steering Committee. 
 
Ethical Approval 
Application for ethical approval for the conduct of the study will 
be submitted to the Human Research Ethics Committee 
(HREC) of the University of Sydney, followed by submission to 
either HREC at each participating hospital or to a central ethics 
committee (or equivalent) as appropriate in accordance with 
the national and local regulatory and research ethics guidelines 
applicable in China. 
 
 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 14 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
 
5. Schedule of Study Tests, Procedure and Visits 
 
Table 1 Schedule of Study Tests, Procedures and Visits 
Assessment Description 
Screening 
2--4 
weeks 
prior to 
randomis
ation 
Baseline/ 
Randomis
ation 
(Week 0) 
6,18,30, 
42 
weeks 
(phone) 
12 
wee
ks 
24 
weeks 
36 
weeks 
48 
weeks 
50 
weeks 
Informed Consent 
X 
 
 
 
 
 
 
 
Physical Examination incl. blood 
pressure 
X 
 
 
 
 
 
 
 
Spirometry 
X 
X 
 
X 
X 
X 
X 
 
CAT score 
 
X 
 
X 
X 
X 
X 
 
Medications  
X 
X 
 
X 
X 
X 
X 
 
Demographics, Medical History, Vital 
signs 
X 
 
 
 
 
 
 
 
SGRQ 
 
X 
 
 
 
 
X 
 
Routine pathology as listed below1 
X 
 
 
 
 
 
 
 
ACTH stimulation test3 
(100 participants) 
 
 
 
 
 
 
 
X 
Serum theophylline levels 
(100 participants) 
 
X 
 
X 
 
 
X 
 
Plasma storage for subsequent 
analysis4  
 
X 
 
 
 
 
X 
 
Study Medication Dispense and  
Compliance  
 
X 
 
X 
X 
X 
X 
 
Adverse Events/Serious Adverse 
Events2 
 
X 
X 
X 
X 
X 
X 
 
Participant Diary review  
 
 
X 
X 
X 
X 
X 
 
Vital status 
 
X 
X 
X 
X 
X 
X 
 
                                                 
1 Routine pathology collected at screening: 
Haemoglobin, White cell count, Platelets, Potassium, Sodium, Chloride , SGOT, SGPT, LDH, GGT (Gamma 
Glutamic Transpeptidase), neutrophils, lymphocytes, monocytes, eosinophils, basophils, Bicarbonate, Blood 
Urea Nitrogen, Creatinine  
 
2  Study Specific AEs and all SAEs will be collected from randomisation until completing the study or 
withdrawal from the study. This includes the records in the participant diary. 
 
3 The ACTH stimulation test will be performed 2 weeks after completion of 48 weeks study treatment. A visit 
window is not applicable for this test. 
 
4Plasma is collected at selected sites with suitable storage facilities 
Study visits window is ± 2 weeks. 
 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 15 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
6. Administrative Structure 
6.1 International Coordinating Centre 
The International Coordinating Centre (ICC) is based at The George Institute for Global 
Health. The ICC has responsibility for the overall management of the study including the 
following: assistance with HREC applications, management of study budget, liaison with 
funding bodies; funding applications; liaison with Coordinating Centre staff, Steering 
Committee and Data Safety Monitoring Committee (DSMC), case report form design; 
preparation and completion of Investigator contracts; management of regulatory affairs; study 
set up, monitoring and study close out at the participating centre; training of Investigators and 
Study Coordinators; organisation of Investigator meetings; liaison with Independent Data and 
Safety Monitoring Committee; data analysis and collaboration on publications. 
6.2 Data Management 
Data management will be provided by The George Institute for Global Health and the principle 
means of data collection and data processing will be electronic via the Internet.  All 
computerised forms will be electronically signed by the authorised study staff and all changes 
made following the electronic signing will have an electronic audit trail with a signature and 
date. Quality control of spirometry will be managed using software standardized for EasyOne 
spirometers used in the Burden of Obstructive Lung Disease Study, and overseen by 
Professor Norbert Berend, Chief Investigator. 
6.3 Clinical Centres 
Individual clinical centres will manage the study at their own centre in accordance with the 
study protocol.  Additionally, the individual centres will manage: 
 
protocol education of staff members involved in the study,  
 
participant recruitment,  
 
data collection, storage and data transfer 
 
spirometry training, documentation and quality  
 
data query resolution at their centre  
 
liaison with local ethics committee regarding adherence to local ethics committee 
guidelines and reporting requirements,  
 
adverse event reporting to ethics committee and the international/regional 
coordinating centre.  
 
7. Funding and Insurance  
The study is funded by a National Health and Medical Research Council of Australia Project 
Grant and by seeding grants from The George Institute for Global Health and the George 
Foundation. 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 16 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
The study was designed by the Principal Investigators, and initiated at the George Institute for 
Global Health. The study design, protocol and procedures have been finalised in collaboration 
with The George Institute for Global Health.  
The George Institute for Global Health certifies that it has taken out a liability insurance policy. 
This insurance policy is in accordance with local laws and requirements. The insurance of The 
George Institute for Global Health does not relieve the Investigator or manufacturers of the 
study interventions of any obligation to maintain their own liability insurance policy as required 
by applicable law. Liability and insurance provisions for this study are given in separate clinical 
trial agreements. 
8. Study Background 
8.1   Burden of Disease 
 Chronic obstructive pulmonary disease (COPD) accounts for a large proportion of the global 
burden of death and disability and is projected to rise even further over the next few decades. 
Strategies for the prevention of COPD, such as tobacco control and reduction in indoor smoke 
pollution, are critical components of the necessary public health response. However, in the 
short to medium term, prevention alone will not be enough to deal with the huge burden of 
largely irreversible lung disease that is now unavoidable. Therefore affordable treatment 
strategies that improve symptoms and quality of life are also an essential component of the 
public health response. In combination, anti-inflammatory drugs and long acting 
bronchodilators, while having a doubtful effect on progression of disease or reducing mortality, 
are effective in reducing exacerbations, improving lung function and quality of life. However, 
these medications are expensive and unaffordable for many patients, particularly in low-
income countries, where the prevalence of COPD is particularly high and is increasing most 
rapidly. Oral corticosteroids and theophylline are available at much lower cost and there is 
compelling new evidence that suggests that when given at low doses in combination, they will 
act synergistically to confer worthwhile benefits. If proven effective, such therapy will offer the 
first affordable treatment option for many patients with COPD in resource-poor settings around 
the world. Furthermore, oral drugs are easier to administer and may have an advantage over 
inhaled medication in targeting the peripheral lung which is the main site of disease activity.  
8.2   The Global Burden of COPD  
In recent studies using standardised methodology including spirometry, the prevalence rates 
across the world for Global Initiative for Obstructive Lung Disease (GOLD) stage II to IV 
ranged from 6-19% of the population 2-3. The morbidity of COPD is considerable. Estimates 
of the years of living with disability (YLD) for COPD of 1.7 YLD per thousand represents about 
1.8% of all YLDs. The economic cost of COPD is huge. A telling figure is that the annual cost 
of healthcare per capita in the United States for people with COPD is approximately 2.5 times 
the expenditure for people without COPD 2. The social burden of COPD as measured by 
Disability-Adjusted Life Years (DALYs) ranked 12th in the world in 1990 and is estimated to 
become the 5th leading cause of DALYs by 2020 3. The mortality of COPD is increasing with 
deaths attributed to COPD ranking sixth in 1990 and COPD projected to be the third leading 
cause of death by 2020 3 . Reasons for the increase include greater longevity of the 

 
 
 
 
Low dose corticosteroids and theophylline in the treatment of COPD – the TASCS Study (Theophylline and 
Steroids in COPD Study) 
 
Protocol Number: TGI-Resp-01 
___________________________________________________________________________________________________ 
Confidential                                                       Page 17 of 39                    TASCS Study Protocol Version 2.0 dated 27 May 2015 
population, allowing people to develop COPD later in life, and continuing exposure to noxious 
agents which cause COPD.  
8.3   Risk Factors for COPD 
Cigarette smoking and exposure to smoke from combustion of biomass fuels are the most 
common causes of COPD. While cigarette smoking is the most common cause in Western 
countries, both causes are common in Asia and the developing world4. Whilst the prevalence 
of smoking in women in most Asian countries is < 5% 5, women and children have significant 
exposure to indoor air pollution due to combustion of unprocessed biomass (wood, dung, coal 
and crop residues) for cooking, heating and lighting in developing countries. It has been 
estimated that up to 3 billion people world-wide and 90% of rural households are exposed to 
open fires or poorly functioning and unflued stoves and heaters6, including China and India 
7,8. Women are at particularly high risk because of longer periods of exposure in the home 9, 
8. One study in China has demonstrated a greater prevalence of COPD in rural women 
exposed to biomass smoke than in cigarette smoking city women 8. In China the prevalence 
of COPD in men is 12.4% whereas in women it is 5.1% 10. Therefore, although the main cause 
of COPD in women in China appears to be biomass smoke exposure, passive smoking is also 
an important cause of COPD amongst non-smokers in China. The overall prevalence of 
COPD in Chinese non-smokers is 5.2%11. In summary, throughout the Asia Pacific region and 
in other developing parts of the world, cigarette smoking is much more prevalent in men than 
in women and most of the COPD in women appears to be caused by biomass smoke 
exposure.  
8.4   Treatment for COPD  
Treatment for COPD involves a number of modalities including pharmacological treatment 
(bronchodilators and anti-inflammatory agents), pulmonary rehabilitation, vaccination against 
influenza, and domiciliary oxygen and lung volume reduction surgery for severe and end-
stage disease 1.  
8.4.1 Currently Recommended Pharmacological Treatment for COPD  
The mainstay of pharmacological treatment is the early and sustained use of bronchodilators, 
and the later introduction of inhaled corticosteroids. The current GOLD evidence -based 
guidelines for COPD1  recommend short and long acting bronchodilators (beta agonists and 
muscarinic antagonists) alone or in combination for symptomatic mild to moderate COPD 
(GOLD stage 1 and 2). Theophylline is also of benefit but due to its potential toxicity when 
used in bronchodilating doses is regarded as a second-line drug. The addition of inhaled 
corticosteroids (ICS) is recommended for severe to very severe COPD (FEV1 ≤ 50% pred, 
GOLD stage 3 and 4) with frequent exacerbations12,13. Combination ICS and long acting 
bronchodilator is usually given as ICS/LABA combination in a single inhaler. There is 
emerging evidence that the addition of a long acting antimuscarinic (LAMA) to the ICS/LABA 
combination offers additional benefit14 .  
 

 
 
 
 
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8.4.1.1 Limitations of Current Pharmacological Treatment  
Short-acting beta agonists, LABAs and LAMAs are effective in reducing airway smooth muscle 
tone and offer relief of breathlessness, improve quality of life and reduce exacerbations. 
However, COPD is an inflammatory disease of the lungs with extra-pulmonary inflammatory 
manifestations15-18. The anti-inflammatory agents used in COPD are ICS but, in contrast to 
asthma where they have potent anti-inflammatory effects and markedly reduce clinical 
morbidity, they have disappointingly limited efficacy in improving inflammation in COPD 19,20.  
 
8.4.1.2 The High Cost of Current Pharmacological Treatment  
Tiotropium and combination therapies of ICS and LABAs are expensive and impose a large 
financial burden on patients in low-income countries and on governments in countries which 
provide full or partial cover for the cost of medications. In Australia, the total cost of COPD is 
estimated to be ~$A8.8 billion 6, with the health system shouldering ~$0.9billion of this cost. 
After the cost of hospitalisation ($473M or 63%), pharmaceuticals make up the next highest 
share ($147M or 20%). In China the annual cost for a patient with COPD treated with 
tiotropium is RMB 6132 ($A907) and with high dose Seretide RMB 5076 ($A 761). There is 
therefore an urgent need for an effective low-cost treatment option.  
 
8.5   Rationale for the Proposed Study  
ICS have very limited efficacy in COPD and hence there is a large effort by the pharmaceutical 
industry to find more effective agents. Even if these efforts bear fruit it is highly likely that the 
new agents will be expensive and will continue to impose a large financial burden and, in the 
worst case, will totally deny patients access to these drugs. There is now a large body of 
evidence from studies carried out in vitro and in vivo that corticosteroids and theophylline, 
both in low dosage, have synergistic and clinically useful anti-inflammatory effects in COPD 
21-29. The molecular mechanisms for this effect have been elucidated and a proof of concept 
clinical study has been published. A large clinical trial is now required to more clearly define 
the magnitude of the clinical benefit. Such a study will not be funded by the pharmaceutical 
industry as these drugs are off patent and cheap. The impact of a positive study outcome will 
be immense throughout the developing world. In China, the annual cost to a patient of low 
dose prednisone (RMB 11, $A 1.70) in addition to theophylline (RMB 146, $A 22) is 
approximately 1.4% of the cost of the inhaler combination of fluticasone and salmeterol 
(Seretide™). 
 
Apart from the efficacy and cost advantage of the proposed regimen and lack of increased 
systemic steroid exposure, other compelling arguments can be made in favour of oral therapy 
in COPD. Although both fluticasone and budesonide have high topical activity, when given by 
inhalation they may not be distributed uniformly to the small airways where the functionally 
important airway inflammatory and fibrotic changes are located in COPD30,31. The most 
severely affected airways are minimally ventilated and will receive little drug 31. Giving both 
prednisone and theophylline orally will ensure good penetration to the peripheral airways via 
the systemic and pulmonary circulation 32. In addition, oral therapy will abolish the risk of 
laryngeal side-effects seen with ICS 33,34. This is particularly the case in older patients in whom 

 
 
 
 
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difficulties with co-ordination and correct device use can markedly affect pulmonary 
deposition35. 
 
Adherence to prescribed medication is problematic in chronic disease. In COPD the causes 
of low adherence have been investigated and are found to be complex and include race/ethnic 
and cultural differences 35. There is evidence that adherence to inhaled medication is lower 
than to oral therapy of the same class of drug 36, 37. Cost-related non-adherence is highly 
prevalent in asthma and COPD (31% in a recent study) even in the United States. Similarly, 
cost was a cause of non-adherence in the Asia-Pacific region in 37% of surveyed patients 37. 
In addition, correct inhaler use is a major issue whereby even adherent patients may receive 
inadequate dosing unless adequate instruction is given initially with repeated follow-up. Even 
in developed countries inadequate inhaler technique is seen in nearly half of all patients 38,39. 
 
8.6   Intervention Plan 
This study will assess the efficacy of two relatively inexpensive treatment options already 
widely available around the world: oral theophylline and oral corticosteroids (prednisone). The 
study will test low dose theophylline administered in combination with low dose prednisone, 
compared to placebo over 48 weeks.  
 
The study has been designed with clinically important endpoints in order to be feasible in 
centres in China. The wide inclusion criteria ensure that the results are generalisable to the 
majority of symptomatic patients with COPD.  
 
This randomised clinical trial will be conducted with a 3-arm blinded, double dummy 
comparison:  
Arm 1.  
 
Placebo (1 tablet twice a day) + placebo (1 tablet once a day) 
Arm 2.  
 
Low-dose theophylline (100mg slow release) (1 tablet twice a day) + 
placebo (1 tablet once a day) 
Arm 3.  
 
Low-dose theophylline (100mg slow release) (1 tablet twice a day) + 
low dose oral prednisone (5mg) (1 tablet once a day) 
 
9. Study Design  
9.1   Hypothesis and Aims  
We hypothesise that patients with COPD will have beneficial responses to combination of low 
dose theophylline and low dose prednisone, superior to placebo reflected by a range of 
clinically important outcomes.  
Further we hypothesise that there will be no significant increase in serious adverse events 
and study specific adverse events in patients receiving both prednisone and theophylline, 
compared to placebo. 
The primary efficacy comparison aims to demonstrate that treatment with low dose oral 
prednisone and low dose, slow release theophylline compared to placebo will reduce COPD 
exacerbations over 48 weeks. 

 
 
 
 
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9.2   Study Treatments 
This randomised clinical trial will be conducted with a 3-arm blinded, double dummy 
comparison:  
 
Arm 1. Placebo (twice a day) + placebo (once a day)  
Arm 2. Theophylline 100mgs (twice a day)  and placebo (once a day) 
Arm 3. Theophylline 100mgs (twice a day)  and prednisone 5 mgs (once a day) 
 
9.2.1 Permitted Concurrent Therapy  
Patients may continue on the following: 
 
 
regular inhaled LAMA or LABA therapy  
 
short acting anticholinergic inhaled medication  
 
short acting beta agonist (SABA) inhaled rescue medication 
9.2.2 Non-Permitted Concurrent Therapy 
The following maintenance medications are not permitted during the study: 
 
 
Inhaled corticosteroids, except at exacerbation for maximum seven (7) days 
 
Daily oral corticosteroids in addition to study medication 
 
Parenteral corticosteroids 
 
Oral syrups or other formulations containing theophylline  
 
9.3   Study Outcomes 
9.3.1    Primary Outcome 
Number of COPD exacerbations per participant in 48 weeks 
 
Definition of a severe COPD exacerbation – symptomatic deterioration in COPD symptoms 
(cough, sputum production or dyspnea) requiring treatment with antibiotics, increase in the 
dose of oral corticosteroids, hospitalisation or a combination of these.  
9.3.2 Secondary Outcomes  
 
Time to first severe exacerbation leading to hospitalisation or death  
 
Quality of Life using the St George’s Respiratory Questionnaire  
 
COPD Assessment Test (CAT), score out of total 40 
 
Pre-bronchodilator spirometry: FEV1, FVC, FEV1/FVC 
 
Post-bronchodilator spirometry: FEV1, FVC, FEV1/FVC 

 
 
 
 
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 
Mild, moderate and severe exacerbations. Exacerbations are defined as worsening for at 
least two consecutive days of two or more of the major symptoms (dyspnoea, sputum 
volume or sputum purulence) or worsening of any one major symptom together with any 
one minor symptom (sore throat, colds (nasal discharge or nasal congestion), fever 
without other cause, cough or wheeze). Severity grades:   
 
Mild : exacerbations requiring symptomatic treatment with inhaled bronchodilators 
only 
 
Moderate exacerbations are those managed with antibiotics and/or oral 
corticosteroids;  
 
Severe exacerbations are those that resulted in emergency department presentation 
hospitalization. 
9.3.3 Study Duration  
48 weeks of study treatment  
9.3.4 Number of Participants  
Total of 1650 randomised participants, with 550 in each treatment arm  
 
10. Study Population  
10.1   Participant Recruitment  
10.1.1 Study Population  
The definition of COPD adopted by the Global Initiative for Chronic Obstructive Lung Disease 
(GOLD)1 is generally accepted world-wide. COPD is a preventable and treatable disease 
characterised by persistent airflow limitation that is usually progressive and associated with 
an enhanced chronic inflammatory response in the airways or lung to noxious inhaled particles 
or gases. Exacerbations and comorbidities contribute to the overall severity in individual 
patients.  
A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic 
cough or sputum production and /or a history of exposure to risk factors for the disease. 
Spirometry is required to make the diagnosis in this context. A post-bronchodilator FEV1/FVC 
ratio < 0.7 confirms the presence of airflow limitation and thus the diagnosis of COPD.  
This is the definition that will define the patient population in this trial. GOLD defines severity 
of COPD in terms of post-bronchodilator spirometry, performed according to ATS standards 
after administration of 400mcgs salbutamol. Four stages are recognised:  
GOLD 1 - Mild - FEV1/FVC< 0.7, FEV1≥ 80% predicted  
GOLD 2 - Moderate - FEV1/FVC < 0.7, 50% ≤ FEV1 <  80% predicted  
GOLD 3 – Severe - FEV1/FVC< 0.7, 30% ≤ FEV1 < 50% predicted 
GOLD 4 – Very severe – FEV1/FVC < 0.7, FEV1 <  30% predicted  
Although there is imperfect correlation between classification of severity by spirometry and 
symptoms, using inclusion criteria of FEV1/FVC < 0.7 and FEV1< 70% predicted will include 
most patients with symptomatic COPD. 

 
 
 
 
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10.1.2 Participant Inclusion Criteria  
Participants are eligible for INCLUSION in the study if ALL the following criteria are met:  
 
Current or former smokers (> 10 pack years) or biomass exposure  
 
40 – 80 years of age  
 
Clinical diagnosis of COPD  
 
Post-bronchodilator FEV1 < 70% predicted  
 
Post bronchodilator FEV1/FVC ratio < 70% 
10.1.3 Participant Exclusion Criteria  
 
Patients will be EXCLUDED from the study if, in the opinion or knowledge of the 
responsible clinician any of the following criterion is present:  
 
Life expectancy of less than 12 months  
 
Exacerbation or respiratory infection within 4 weeks prior to randomisation  
 
Patient is taking and requires maintenance oral corticosteroids  
 
Patient is on domiciliary oxygen  
 
There has been previous pulmonary resection  
 
Previous sensitivity to, or intolerance of theophylline  
 
Coexistent illness precluding participation in the study (epilepsy, chronic liver 
disease, unstable cardiovascular disease, diabetes, active malignancy) 
 
Inability to complete quality of life questionnaire  
 
Concomitant major illness that would interfere with visits, assessments and follow-up 
 
Have evidence of chronic liver disease, or transaminase or GGT elevation > 1.5 x 
ULN 
 
Random blood glucose level > 8mmol/L 
 
High chance in the view of the treating physician that the patient will not adhere to 
study treatment and follow up.  
 
Current asthma 
 
Pregnancy or breast feeding 
 
11. Assessments and Study Visits  
11.1   Brief Study Visits Outline 
Patients with COPD and considered eligible will undertake a screening visit, two to four 
weeks before the randomisation visit (Baseline, Week 0). During the four week run-in, all 
prohibited medications, specifically any theophylline containing medications and ICS will be 
ceased. LABA, LAMA and SABA may be continued. The patient’s usual supply of SABA will 
be used as rescue medication throughout the study.   
Spirometry before and after bronchodilator, according to ATS criteria will be performed at the 
screening visit to confirm eligibility. Patients will be randomised to treatment groups and 
provided with blinded medication at the baseline visit. The study visits will take place at 12 
week intervals for 48 weeks. At each visit study medication will be dispensed to the participant 
to ensure supply for the following 12 weeks. In summary, the information that will be sought 

 
 
 
 
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from all the participants is outlined in Table 1 - Schedule of Study Tests, Procedures and 
Visits. All visits have a window is 2 ± week. 
 
11.2   Participant Consent 
Prior to any study related procedures being performed informed consent is to be obtained 
from each participant.  
 
11.3   Study Visits 
11.3.1 Screening Visit 
The purposes of the screening evaluation are to identify patients for study enrolment, provide 
potentially eligible patients with information regarding the study, obtaining the informed 
consent for participation in this study. Assessment at this visit will include spirometry and 
gathering information on the type of medication a potential participant is using for their COPD 
treatment. If a participant wishes to participate they will be asked to withdraw the inhaled 
corticosteroids or theophylline before being randomised to one of the three study groups. 
Study staff at the centre will also estimate patient’s ability to adhere to study treatment and 
clinic visits, and also their capacity to complete participant diary. Participants who smoke will 
be encouraged to stop smoking. 
 
11.3.2 Baseline Visit & Randomisation 
At baseline visit the following baseline characteristics and clinical assessments will be made: 
vital signs, spirometry, CAT score, medical history including bone fracture, medication, 
demographics, routine pathology, SGRQ. In addition, blood will be collected for the plasma 
storage (selected sites only), and also for the theophylline levels in 100 randomly selected 
participants. Adverse Events will be recorded and study medication will be dispensed. 
Participants will also be provided with the Participant Diary to record all events that occur 
between study visits.   
 
11.3.3 6, 18, 30 and 42-Weeks Phone Visit 
Participants will be phoned up in between clinic visits to review the Participants Diary card, 
vital status and record any Adverse Events.  All information will be recorded directly into the 
eCRF. 
11.3.4 12-Weeks Visit 
The following assessments will be performed during this visit: spirometry, CAT score, 
medication, if applicable, blood collection for the theophylline levels in 100 randomly selected 
participants. Adverse Events will be recorded, Participant’s Diary will be reviewed and study 

 
 
 
 
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medication will be dispensed. Accountability for the returned study medication will be 
performed. 
 
11.3.5 24-Weeks and 36-Weeks Visits 
The following will be performed during this visit: spirometry, CAT score and medication, if 
applicable. Adverse Events will be recorded, Participant’s Diary will be reviewed and study 
medication will be dispensed. Accountability for the returned study medication will be 
performed. 
 
11.3.6 48-Weeks Visit 
The following assessments will be performed during this visit: spirometry,CAT score and 
medication, if applicable, and SGRQ, In addition, blood will be collected for the plasma storage 
(selected sites only), for the theophylline levels in 100 randomly selected participants. Adverse 
Events will be recorded and Participant’s Diary will be reviewed. Accountability for the returned 
study medication will be performed. 
 
11.3.7 50-Weeks Visit 
The ACTH stimulation test to be undertaken 2 weeks after completion of 48 weeks’ study 
treatment in 100 randomly selected participants. 
 
11.4   Safety Assessments 
Symptoms attributable to corticosteroid and theophylline toxicity will be sought and specifically 
recorded at each patient visit. These will be classified as: 
  
Severe – convulsions 
Moderate – stomach discomfort, headache, insomnia, palpitations, weight gain, bruising 
Routine adverse event data will be collected according to ICH GCP. 
Participants will be specifically asked about respiratory tract infections in the previous 12 
weeks and whether bone fractures have occurred.  
In a subgroup of 100 patients blood samples will be taken at 12 and 48 weeks, serum 
theophylline will be analysed in a central laboratory, investigators will be informed of the 
results after the participant has completed the study follow up. Serum cortisol and ACTH 
suppression tests will be performed in a subgroup of 100 patients at 50 weeks. The 50 week 
time point (2 weeks following completion of the 48 week study drug administration) was 
chosen to assess the safety of long term administration40. The 250mg ACTH stimulation test 
will specifically assess adrenal suppression and recovery two weeks after completion of 48 
weeks’ administration of low dose prednisone and theophylline. All adverse event data will be 
reviewed by the Data Safety Monitoring Committee (DSMC). The DSMC will include 6 
members with experience in clinical trials conduct and oversight, not associated with the 
conduct of the trial.  

 
 
 
 
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11.5   Losses to Follow-up 
Efforts will be made to follow all randomised subjects for 48 weeks, irrespective of their 
adherence to the randomised therapy.  All losses to follow-up with reason will be reported to 
the ICC and reviewed by the Steering Committee. 
11.6   Non-adherence and Deviations from the Protocol 
All participants will be strongly encouraged throughout the study to adhere to the randomised 
therapy. Participants will continue to be followed for all data collection, irrespective of their 
adherence to the randomised therapy (intent to treat analysis).  
11.7   Duration of Subject Participation 
Individual participants will participate in the 48 weeks treatment phase of the study until the 
earliest of: 
 
completion of the intervention period at 48 weeks, 
 
withdrawal of consent, by the participant or 
 
participant death  
 
All participants will attend all scheduled three-monthly follow-up visits for 48 weeks.  
11.8   Duration of the Study 
The expected timelines for the study:  
June 2014 
 
TASCS first patient randomised 
December 2016 
Recruitment complete (n=1650) 
December 2017 
TASCS last patient visit 
Jan – March 2018 
Site close out activities 
April – May 2018 
Statistical analyses and publication preparation  
 
11.9   Screening and Recruitment log 
The screening and randomisation logs are designed to monitor patient recruitment at the 
individual study centre. 
11.10  Data Collection 
 
Streamlined data collection instruments and procedures will be used to minimise the work in 
collaborating centres.  The George Institute for Global Health will take responsibility for the 
randomisation and data management of the study.  This includes programming and data 
management support of the randomisation system and the database during the study.  

 
 
 
 
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12. Statistics  
12.1   Power Calculations and Statistical Analysis  
All analyses will be performed on an intention to treat basis (ITT). The primary endpoint of this 
study is the event rate of exacerbations of COPD. Randomisation of 1650 participants (550 in 
each arm) will provide 80% power (alpha=0.05) to detect a 20% relative risk reduction in the 
primary endpoint in each intervention group compared with the control group. The 
assumptions inherent in this calculation are: (a) event rates of 1 per person per year for the 
primary endpoint in control group; (b) 15% drop out -  but all patients will be followed up even 
if they drop out of treatment; (c) assuming the exacerbation event rates follow negative 
binomial distribution which is robust to handle the problem of over-dispersion. Number of 
exacerbations will vary with severity of disease from about 0.6 to 1.6 but an overall baseline 
exacerbation rate of 1 is conservative. 41,42. A comparison of the theophylline and placebo 
arms will also be undertaken for the primary outcome, number of exacerbations, although the 
study is not powered for this probably smaller effect 43. 
This is a multi-centre, randomized, three-arm blinded clinical trial to investigate the clinical 
benefit of combination of low-dose theophylline plus low dose oral prednisone for patients with 
COPD. The full Statistical Analysis Plan (SAP) will be developed separately. This will be 
finalized prior to locking the trial database. The SAP will give a detailed description of the data 
summaries and analyses that will be performed.  
12.1.1 Baseline characteristics 
All analyses will be performed on an intention-to-treat basis. Baseline comparability of the 
intervention and control groups will be assessed via descriptive analyses in terms of age, 
gender, medical history, etc. Descriptive demographic and baseline clinical characteristics 
statistics will be used for the total population. 
12.1.2 Effects of treatment 
For the primary efficacy analysis, the events rate of exacerbations of COPD will be analysed 
using Negative Binomial regression. Time to first severe exacerbation will be analysed using 
a Cox models Kaplan-Meier plot. Analysis of other secondary outcomes will be conducted 
using standard statistical procedures applicable to categorical or continuous data as 
appropriate. 
12.2   Randomisation and Allocation of Treatment  
Treatment randomisation will be stratified by smoking status and centre. The randomisation 
process will be centrally administered. . Details of the randomisation schedule will remain 
confidential and known by a limited number of persons including the unblinded statistician 
working on the study. This will be done in agreement with the GI standard operating 
procedures (SOP) on randomisation.  Randomisation will occur using a secure web based 
randomisation system developed and maintained by The George Institute for Global Health. 

 
 
 
 
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Randomisation will be achieved using a minimisation algorithm stratified by study centre via 
a password-protected encrypted website interface. 
12.3   Missing Data 
Efforts to minimise missing data will be made and will include data monitoring and feedback, 
the collection of data from individuals after termination of randomised therapy and 
rescheduling visits if a participant is hospitalised or unavailable. Methods for handling missing 
data at the analysis stage will be detailed in the statistical analysis plan. 
12.4   Blinding 
Key clinical endpoints will be collected in a fashion that will allow bias to be minimised as 
much as possible. Both, participants and investigators will be fully blinded to the treatment 
allocation. Similarly, the endpoints will be collected by study personnel unaware of treatment 
allocation. The only personnel with access to the randomisation during the study conduct will 
be the IT person(s) who will have an access to the secure web-based randomisation module 
and the unblinded statistician(s) responsible for providing the reports to the DSMC. The GI 
SOP on blinding/unblinding will be followed by personnel involved in these procedures. 
12.5   Final Analysis 
Enrolment will be terminated when 1650 participants have been randomised into the study. 
When all participants have completed their 48 weeks assessment the main analysis will be 
conducted for all endpoints and safety.  
13. Termination of Study Treatment 
Study treatment prior to 48 weeks will cease if or when any of the following criteria are met: 
 
Participant withdraws consent for study treatment, or 
 
Participant dies, or 
 
The treating clinicians consider it is clearly in the participant’s best interest to 
receive treatment other than the randomised therapy, or 
 
The DSMC advises study termination 
 
Following completion of the study further treatment will be prescribed at the discretion of the 
caring physician. 
Participants withdrawn from the randomised treatment for any reason will be followed up and 
analysed according to the intention-to-treat-principle.  
14. Human Research Ethics Committee Approvals  
An application requesting approval to conduct this study will be submitted to the Human 
Research Ethics Committee (HREC) of the University of Sydney (central HREC), followed by 
the HREC application at each of the participating regional centres or hospitals and/or at a 
central ethics committee where applicable. Each application will be submitted according to 

 
 
 
 
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the requirements of each hospital ethics committee, all of which have been formed and are 
conducted in accordance with the national and local guidelines applicable in China. The 
content and format of the Participant Information Statements and Consent Forms will be 
approved by each ethics committee and formatted in accordance with their own guidelines 
and requirements notwithstanding the requirements of the central Ethics Committee.  
Each Principal Investigator will be responsible for preparation of annual status reports, serious 
adverse event reports, and any other required documentation to the local HREC in 
accordance with their guidelines. Any amendments or additions to the study protocol and 
material will be notified to the HREC by the Chief Investigator.  
It is the responsibility of the Principal Investigator at each participating hospital or study centre 
to maintain up to date records of all correspondence and applicable documentation with the 
local HREC and the regulatory authorities. The Template of the Informed Consent Form and 
Participant Information Statements that are to be used at each hospital or study centre, 
together with a copy of all signed Informed Consent Forms and any other consent related 
correspondence will also be kept in a separate file for audit purposes. All study records and 
documents will be stored for a minimum of 15 years from the end of the study or for a period 
as required by the individual HREC or central Ethics Committee. 
15.  Informed Consent  
A copy of each participating centre’s proposed informed consent document should be 
submitted to the George Institute for Global Health for review and comment before submission 
to the relevant ethics committee. The study should not begin until the document has been 
approved by the ethics committee. Copies of the regulations relating to informed consent and 
the protection of human subjects in clinical studies are available from the George Institute for 
Global Health. Nothing in these regulations is intended to limit the authority of a physician to 
provide emergency medical care under applicable regulations. The participant information 
sheet will be provided to the participant, to make an informed decision concerning continued 
participation in the study.   
15.1   Documentation of Consent  
A copy of the signed participant consent and participant information statement will be given to 
the participant who has provided the informed consent.  The original copy of the signed 
informed consent will be filed in the participant’s study related records and kept in a locked 
room or cabinet in the centre research office. 
15.2   Withdrawal of Consent  
At any time during the study, the participant may withdraw consent to participate in the study. 
This is documented in the informed consent form and participant information statement.   
16.  Other therapies 
All participants will receive routine care as delivered in their usual context of clinical care.  

 
 
 
 
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17.  Data Safety Monitoring Committee 
An independent Data Safety Monitoring Committee (DSMC), independent from the 
investigators participating in the study, will perform an ongoing review of predefined safety 
parameters and overall study conduct. The DSMC will be comprised of experts in clinical trials, 
bio-statistics and respiratory medicine. The committee will review unblinded data on 
participant characteristics and adverse events at regular intervals during the study. The 
committee will be charged with monitoring total mortality, serious adverse events and making 
recommendations based on other outcomes such as cause specific death or serious non-fatal 
adverse events. They will principally monitor safety and adverse events without including any 
formal testing of a treatment effect. In addition, the DSMC will monitor the operational progress 
of the study. The DSMC will autonomously determine the timing of their meetings, the 
information required from the nature of their analyses. The Steering Committee may request 
various analyses from the DSMC from time to time. 
Safety analyses presented at DSMC meetings will include summary reports of frequency and 
differences between treatment groups for each of the following: 
i. 
deaths 
ii. 
hospitalizations 
iii. 
exacerbations and other SAEs 
iv. 
fractures 
18.  Assessment of Safety 
The investigator agrees to record all study specific AEs. Furthermore, the investigator is 
responsible for ensuring that any co-investigator or sub-investigator brings SAEs to the 
attention of the investigator, and then the investigator notifies the national medical leader 
according to GCP – i.e. within 24 hours of any SAE onset or notification to the investigator. 
The investigator is also responsible for informing their local HREC of any SAE’s. 
18.1   Definitions 
The term “adverse event,” as used here, is synonymous with the term “adverse experience,” 
which is used by the TGA.  
18.1.1  Adverse Event 
An Adverse Event (AE) is any untoward, undesired, unplanned clinical event in the form of 
signs, symptoms, disease, or laboratory or physiological observations occurring in a human 
being participating in a clinical study with a sponsor treatment, regardless of causal 
relationship.  

 
 
 
 
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A pre-existing condition is a clinical condition (including a condition being treated) that is 
diagnosed before the subject signs the informed consent form or is documented as part of the 
subject’s medical history. 
The active phase of the study begins at the time of the first commencement of study 
intervention. 
18.1.1.1 Recording of Adverse Events 
The collection of study specific adverse events should be limited to: 
i. 
Weight gain (>5kgs since baseline) 
ii. 
Fractures 
iii. 
Pneumonia 
iv. 
Other infections 
v. 
A new diagnosis of diabetes or hypertension 
vi. 
Stomach discomfort 
vii. 
Epileptic fits 
18.1.2 Serious Adverse Event 
A Serious Adverse Event (SAE) is any AE that meets 1 or more of the following criteria: 
 
Results in death; 
 
Is life-threatening; 
 
Requires in-patient hospitalisation or prolongation of existing hospitalisation; 
 
Results in persistent or significant disability/incapacity; 
 
Results in a congenital anomaly/birth defect. 
 
Is a medically important event or reaction 
A life threatening adverse event is any AE that places the subject at immediate risk of death 
from the event as it occurred. A life-threatening event does not include an event that might 
have caused death had it occurred in a more severe form but that did not create an immediate 
risk of death as it actually occurred. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening, even though drug-induced 
hepatitis of a more severe nature can be fatal. 
Hospitalisation is identified by an official admission. Hospitalisation or prolongation of a 
hospitalisation is a criterion for considering an AE to be serious. In the absence of an SAE, 
the participating investigator should not report hospitalisation or prolongation of 
hospitalisation. This is the case in the following situations: 
 
Hospitalisation or prolongation of hospitalisation is part of a routine procedure followed 
by the study centre. This should be recorded in the study file. 
 
Hospitalisation is for an elective, unrelated procedure and no SAE occurs 
 
Hospitalisation for survey visits or annual physicals fall in the same category. 

 
 
 
 
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In addition, a hospitalisation planned before the start of the study for a pre-existing condition 
that has not worsened does not constitute an SAE (e.g., elective hospitalization for a total 
knee replacement due to a pre-existing condition of osteoarthritis of the knee that has not 
worsened during the study). 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions.  
If there is any doubt whether the information constitutes the SAE, please report the event. 
18.1.2.1 Recording of Serious Adverse events 
At each required study visit, all SAEs that have occurred since the previous visit must be 
recorded. The following SAE information must be included (when applicable): the specific 
condition or event; the dates and times of occurrence; severity; causal relationship to 
treatment; action taken; and outcome. 
The causal relationship between an SAE and the treatment will be determined by the 
investigator on the basis of his or her clinical judgment and the following definitions: 
 
Definitely related: Event can be fully explained by administration of the treatment. 
 
Probably related: Event is most likely to be explained by administration of the treatment 
rather than the subject’s clinical state or other agents/therapies. 
 
Possibly related: Event may be explained by administration of the treatment or by the 
subject’s clinical state or other agents/therapies. 
 
Probably not related: Event is most likely to be explained by the subject’s clinical state 
or other agents/therapies, rather than the treatment. 
 
Definitely not related: Event can be fully explained by the subject’s clinical state or 
other agents/therapies. 
When assessing the relationship between the protocol and/or administration of a treatment 
and an SAE, the following should be considered: 
 
Temporal relationship between the protocol and/or administration of the treatment and 
the SAE 
 
Biological plausibility of relationship 
 
Participant’s underlying clinical state or concomitant agents and/or therapies 
 
When applicable, whether the SAE abates on discontinuation of the treatment (de-
challenge) 
 
When applicable, whether the SAE reappears on repeat exposure to the treatment 
(rechallenge) 
SAEs that are not treatment related may nevertheless be considered by the participating 
investigator or the medical monitor (or designee) to be related to the conduct of the clinical 
study, i.e. to a subject’s participation in the study. For example, a protocol-related SAE may 

 
 
 
 
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be an event that occurs during a washout period or that is related to a procedure required by 
the protocol. 
18.1.3 Timing for Reporting Serious Adverse Events 
All SAEs should be reported using the eCRF within the required timeframe after the site staff 
becomes aware of the SAE. Compliance with this requirement is essential so that the study 
team is aware of any safety signals and thus complies with local regulatory obligations. Where 
applicable all follow-up information relating to an SAE must be reported, as detailed above, 
within 24 hours of receipt by the investigator via eCRF or by faxing a completed serious 
adverse event form. The participant should be observed and monitored carefully until the 
condition resolves or stabilises or its cause is identified. 
18.1.4 Documentation of Adverse Events and Serious Adverse Events 
Study specific AEs and all SAEs will be reported on the eCRFs after randomisation. The AEs 
and SAEs must be documented in the source documents. The study centre investigator has 
to follow up all SAEs until the event has subsided or values have returned to baseline, or in 
case of permanent impairment, until the condition stabilises. If requested, the investigator will 
provide all supporting documentation pertaining to the event (e.g., additional laboratory tests, 
consultation reports, post mortem reports, etc.) to the George Institute for Global Health in a 
timely manner. Reports relative to the participant’s subsequent course must be submitted to 
the George Institute for Global Health until the event has subsided or, in case of permanent 
impairment, until the condition stabilises. 
19. Data Quality Assurance 
A qualified representative of the George Institute for Global Health will monitor the conduct of 
the study by visiting the centre and by contacting the centre by telephone and email. During 
the visits, information recorded on the CRFs will be verified against source documents. Quality 
control of spirometry will occur at each centre through a predetermined constant review, using 
standardised software, and will be overseen by the Chief Investigator, Professor Norbert 
Berend.  
A random sample of patients will be phoned at various intervals through the study by an 
independent person under the supervision of Professor Fuqiang Wen from West China 
Hospital of Sichuan University hospital as a quality assurance measure to ascertain the 
complete collection of the exacerbation data. 
 
19.1   Pre-study Documentation 
The investigator must provide The George Institute for Global Health with the following 
documents BEFORE enrolling any participants: 
 
Current signed and dated curricula vitae for the investigator, sub-investigators, and all 
key personnel listed on the clinical study information form. 
 
Copy of the Institutional Ethics Committee (HREC) approval letter for the protocol. 

 
 
 
 
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 
Copy of the Institutional Ethics Committee (HREC) approval letter for the informed 
consent(s). 
 
Copy of the Institutional Ethics Committee (HREC) approval letter for the participant 
diary 
 
Centre Investigator Signed Protocol page. 
 
Laboratory Normal / Reference Ranges 
 
Laboratory Certification / Accreditation 
 
Participating Centres Agreement, containing confidentiality and indemnity clauses. 
 
EC membership list or letter of assurance.  
On an ongoing basis the investigator must provide The George Institute for Global Health with 
written assurance of continuing approval (at least annually) as well as a copy of the annual 
progress report submitted to the HREC. The investigator must also promptly report any 
changes in this study or unanticipated problems involving risks to the participants to the 
HREC. An investigator must not make any changes in a study without HREC and Study 
Steering Committee approval from The George Institute for Global Health except when 
necessary to eliminate apparent immediate hazards to the participants in which case the 
HREC and The George Institute for Global Health are to be notified immediately. All protocol 
amendments must be submitted to the HREC and approved. 
 
19.2   Declaration of Helsinki 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with good clinical practice (GCP) and the 
applicable local regulatory requirements. 
19.3   Source Data Documentation 
The purpose of source documents is to document the existence of the participant and 
substantiate the integrity of the study data collected. Adequate and accurate source 
documents allow the investigator and the centre monitor to verify the reliability and authenticity 
of data recorded on the electronic CRFs and ultimately to validate that the clinical study was 
carried out in accordance with the protocol. Source data documentation includes original 
documents related to the study, medical treatment, and to the medical history of the 
participant. Source data constitute the original documents, certified copies, data and records 
necessary for the reconstruction and evaluation of the study.  Examples of source documents 
include hospital records, patient notes, participant diary, X-rays, electrocardiography (ECG) 
reports, magnetic resonance imaging (MRI) reports, laboratory reports, pharmacy dispensing 
records, letters, emails and electronic records.  In case of electronic records the readable 
copies must be generated and validated.  

 
 
 
 
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19.4   Case Report Forms 
All data will be recorded in the CRFs. Information recorded in the CRF should accurately 
reflect participant’s medical/hospital notes. Information must be completed in the case report 
form as soon as it is made available for recording. The intent of this process is to improve the 
quality of the clinical study by providing prompt feedback to the investigators on the progress 
of the data submitted and to enhance the ability to collect early safety information in a more 
timely fashion to fully comply with the intent of GCP requirements.  
19.5   Review of Source Records 
During and after this study qualified representatives of The George Institute for Global Health 
will conduct inspections, audit and review medical records pertinent to the clinical study as 
permitted by the regulations. Participants will not be identified by name, and confidentiality of 
information in medical records will be preserved. The confidentiality of the participant will be 
maintained unless disclosure is required by regulations.  
Accordingly, the following statement (or similar statement) will be included in the informed 
consent document: 
‘Representatives of regulatory agencies, HRECs, The George Institute for Global Health, the 
study manager and your personal physician may review your medical records and information 
related to this study as permitted by law. Identifying information will not appear on any record 
other than the medical record. Your identity will remain confidential unless disclosure is 
required by law in accordance with the Privacy of Information act.’ 
19.6   Monitoring of the Study 
This study will be monitored by a representative of The George Institute for Global Health. 
Centre monitoring visits will be performed in regular intervals. Communication by telephone 
and mail and e-mail may be used as needed to supplement centre visits. The investigator and 
study personnel will assist the monitoring staff by providing all appropriate documentation, 
and being available to discuss the study. The purpose of the centre visits is to verify the 
following: 
a. Adherence to the protocol. (The investigator should document and explain any 
deviation from the approved protocol.) 
b. The completeness and accuracy of the CRFs and source documentation. (Adequate 
time and space for these visits should be allocated by the investigator.) 
c. Compliance with regulations. The verification will require comparison of the source 
documents with the CRF data entry. 
The source document verification (SDV) is to verify the data recorded in the electronic case 
report form (eCRF) against the source document.  In other words, it is a process of checking 
the accuracy, consistency and completeness of data entered in the eCRF with the source 
data.  
 

 
 
 
 
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19.7   Protocol Amendments 
Any significant change in the study protocol will require an amendment. The investigator and 
an appropriate representative of the Steering Committee will indicate their approval by signing 
the approval page of the amendment. Once the Steering Committee has approved a protocol 
amendment, the investigator will need to submit it to the HREC or centralised Ethics 
Committee for written approval. The approval letter, signed by the HREC chair, must refer 
specifically to the investigator, the protocol number, the protocol title, the protocol amendment 
number, and the date of the protocol amendment. The protocol amendment may be 
implemented only after it has been approved by the HREC.  A protocol change intended to 
eliminate an apparent immediate hazard to participants may be implemented immediately, but 
the change must then be documented in an amendment, reported to the HREC and the 
International Coordinating Centre within 5 working days.  
19.8   Change in Investigator 
If any investigator retires, relocates, or otherwise withdraws from conducting a study, the 
responsibility for maintaining records may be transferred to The George Institute for Global 
Health, HREC, or other investigator. The George Institute for Global Health must be notified 
of and agree to the change. All associated documentation must also be updated.  
19.9   Termination of the Study 
19.9.1 Termination by the Study Steering Committee 
The Study Steering Committee may terminate the entire study or terminate the study at a 
particular centre at any time for any of the following reasons: 
 
Failure to enroll participants. 
 
Protocol violations. 
 
Inaccurate or incomplete data. 
 
Unsafe or unethical practices. 
 
Questionable safety of the treatment. 
 
Suspected lack of efficacy of the treatment. 
 
Lack of treatment safety 
 
Administrative decision. 
19.9.2 Termination by the Investigator 
If the investigator terminates the study prematurely, the investigator will do the following: 
 
Return all study materials to The George Institute for Global Health. 
 
Provide the HREC and The George Institute for Global Health with a written statement 
describing why the study was terminated prematurely.  
All discontinuations of therapy will be reviewed by the Steering Committee. 

 
 
 
 
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19.9.3 Notification of Study Closure 
The investigator completes a report notifying the HREC of the conclusion of the clinical study. 
This report should be made within 3 months of completion or termination of the study. The 
final report sent to the HREC is also sent to The George Institute for Global Health. 
20.  Confidentiality 
All unpublished information that The Steering Committee forwards to the investigator shall be 
kept confidential and should not be published or disclosed to a third party without the prior 
written consent of The Steering Committee. 
 
21. Records Retention 
The investigator shall retain and preserve one copy of all data generated in the course of the 
study, specifically including but not limited to those documents defined by GCP as essential 
documents, for 15 years following study closure. At the end of such period, the investigator 
shall notify in writing The International Coordinating Centre of its intent to destroy all such 
study material. The International Coordinating Centre shall have 30 days to respond to the 
investigator’s notice, and The International Coordinating Centre shall have a further 
opportunity to retain such materials at The George Institute for Global Health’s expense. 
22. Organisation and Collaboration  
The study will be conducted under the auspices of The George Institute for Global Health, 
University of Sydney. It will be overseen by the Steering Committee.  
23. Publications and Presentations  
The main reports from the study will be published in the name of “The TASCS Study 
Investigators” as requested by the publishing journal with credit assigned as determined by 
the Steering Committee to the appropriate investigators. Presentations of the study findings 
will be made at national and international meetings. 

 
 
 
 
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