Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: Chronic Obstructive Pulmonary Disease (COPD)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 144
Healthy volunteers: no

Brief summary:
This study investigates the effects of targeted re-treatment of patients who do not recover from an exacerbation of COPD. Half of the patients will receive ciprofloxacin while the other half will receive a placebo.

Detailed description:
COPD is a long term lung condition where patients suffer recurrent symptom flare-ups, called 'exacerbations'. Patients who have lots of exacerbations have a worse quality of life, poorer ability to breath, and may die earlier than those who don't. Previous research by our group has shown that patients who have an exacerbation and have not completely recovered two weeks after the start of treatment are more likely to suffer another one early than those who completely recover.

This study aims to test whether we can prevent this early re-exacerbation by giving an extra course of antibiotics, compared to a placebo. Patients who experience an exacerbation of COPD and are treated with antibiotics will, two weeks after the start of their treatment, be invited to attend a screening visit. Patients will be eligible for the study if they have not fully recovered at this visit (i.e. if they either still have symptoms or if blood tests show there is still inflammation present) and fulfil other diagnostic measures for COPD. Patients will be allocated to the treatment groups at random, and if eligible will be treated with a further 1 week of ciprofloxacin 500mg twice daily or a placebo.

Patients will then be followed up in the study for a further 3 months, and the primary study outcome will be the time to the next exacerbation.

Arms:
arm 1: 500 mg, twice daily for 1 week (oral). arm 2: one capsule, twice daily for 1 week.

Interventions: intervention 1: Ciprofloxacin intervention 2: Placebo
Intervention descriptions: intervention 1: 500 mg, twice daily for 1 week (oral) intervention 2: One capsule, twice daily for 1 week

Protocol document:
Prot_000.pdf: 
NIHR Programme Work Package 4: Targeted retreatment of COPD exacerbations 
 
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Full title of trial: 
 
Targeted retreatment of incompletely recovered 
COPD exacerbations with ciprofloxacin: a double-
blind, randomised, placebo-controlled, multicentre 
Phase III trial 
Short title: 
Targeted retreatment of COPD exacerbations  
Version and date of protocol: 
Version  5.1 20.07.2015 
Sponsor: 
Imperial College London 
Sponsor protocol number: 
 
Funder (s): 
NIHR 
EudraCT no: 
2012-002198-72 
ACTIVE IMP(s): 
Ciprofloxacin 
PLACEBO IMP(s): 
Placebo 
Phase of trial: 
Phase III 
Sites(s): 
Multi-Site  
Chief investigator: 
 
Professor JA Wedzicha 
COPD Group 
Airway Disease Section  
National Heart and Lung Institute (NHLI)  
Guy Scadding Building 
Dovehouse Street 
London  
SW3 6LY 
+44 (0)207 59 47959  
 
Sponsor Representative: 
 
Ms Tharani Thurairajah 
 
AHSC Joint Research Compliance Office 
Imperial College London and 
Imperial College Healthcare NHS Trust 
510C 
Fifth Floor 
Lab Block 
Charing Cross Hospital 
London 
W6 8RF 
Tel:  020 3311 0213 
E-mail:  t.thurairajah@imperial.ac.uk 
 
 


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Signatures 
The Chief Investigator and the Sponsor have discussed this protocol. The investigators agree to 
perform the investigations and to abide by this protocol. 
 
The investigator agrees to conduct the trial in compliance with the approved protocol, EU GCP and 
UK Regulations for CTIMPs (SI 2004/1031; as amended), the UK Data Protection Act (1998), the Trust 
Information Governance Policy (or other local equivalent), the Research Governance Framework 
(2005’ 2nd Edition; as amended), the Sponsor’s SOPs, and other regulatory requirements as amended. 
 
Chief investigator 
Wisia Wedzicha 
 
 
 
Signature 
Date 
 
 
 
Sponsor Representative 
Tharani Thurairajah 
 
 
 
Signature 
Date 
 
 


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Table of contents 
Signatures 
2 
Table of contents 
3 
List of abbreviations 
6 
1 
Trial personnel 
9 
2 
Summary 
11 
3 
Introduction 
13 
3.1 
Background 
13 
3.2 
Clinical data, Rationale and Risks/Benefits 
13 
3.3 
Preclinical data (as per SmPC) 
14 
3.4 
Assessment and management of risk 
15 
4 
Objectives 
18 
4.1 
Primary objective 
18 
4.2 
Secondary objectives 
18 
5 
Trial design 
19 
5.1 
Overall Design 
19 
5.2 
Justification of trial design, participants and follow up 
19 
6 
Selection of Subjects 
19 
6.1 
Inclusion criteria 
19 
6.2  
Exclusion criteria 
19 
7 
Recruitment 
21 
8 
Study procedures and schedule of assessments 
22 
8.1  
Informed consent procedure 
22 
8.2 
Randomisation procedures 
23 
8.3  
Unblinding Procedures 
23 
8.4  
Screening Assessment (Visit 1) 
24 
8.5  
Treatment procedures 
25 
8.6  
Follow-up visits (V2 & V3) 
25 
8.7  
Follow-up telephone call 
26 
8.8  
Ongoing study monitoring 
26 
8.9  
Exacerbation visits (if applicable) 
26 


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8.10  
End of Study Visit (V4) 
27 
8.11  
Flowchart of study assessments 
27 
8.12  
Clinical Procedures and Data collection 
27 
8.13  
Laboratory Procedures 
28 
8.14  
Definition of end of trial 
28 
8.15  
Discontinuation/withdrawal of participants and ‘stopping rules’ 
28 
9 
Investigational Medicinal Product 
29 
9.1  
Name and description of investigational medicinal product(s) 
29 
9.2  
Name and description of each NIMP 
29 
9.3  
Concomitant medication 
29 
9.4  
Description and justification of route of administration and dosage 
30 
9.5  
Preparation and labelling of Investigational Medicinal Product 
30 
9.6  
Drug accountability 
30 
9.7  
Source of IMPs including placebo 
30 
9.8  
Assessment of compliance 
31 
9.8.1 
Compliance to the IMP 
31 
9.8.2 
Compliance to the Protocol 
31 
9.9  
Post-trial IMP arrangements 
31 
10 
Recording and reporting of adverse events and reactions 
31 
10.1  
Definitions 
31 
10.2  
Recording adverse events 
32 
10.3  
Assessments of Adverse Events 
33 
10.4  
Procedures for recording and reporting Serious Adverse Events 
34 
10.6  
Notification of deaths 
35 
10.7  
Reporting SUSARs 
35 
10.8  
Development Safety Update Reports 
35 
10.9  
Annual progress reports 
36 
10.10  
Pregnancy (If applicable) 
36 
10.11  
Overdose: 
36 
10.12  
Reporting Urgent Safety Measures 
36 
10.13  
The type and duration of the follow-up of subjects after adverse events 
37 
10.14  
Notification of Serious Breaches to GCP and/or the protocol  
37 


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11 
Data management and quality assurance 
37 
11.1  
Confidentiality 
37 
11.2  
Data collection tools and source document identification 
37 
11.3  
Data handling and analysis 
39 
11.4  
Record keeping and archiving 
40 
12 
Statistical Considerations 
41 
12.1  
Outcomes 
41 
12.1.1  
Primary outcome 
41 
12.1.2  
Secondary outcomes 
42 
12.2  
Sample size and recruitment 
42 
12.2.1  
Sample size calculation 
42 
12.3  
Statistical analysis plan 
43 
12.3.1  
Summary of baseline data and flow of patients 
43 
12.3.2  
Primary outcome analysis 
43 
12.3.3  
Secondary outcome analysis 
44 
12.4  
Randomisation methods 
45 
12.5  
Interim analysis 
45 
12.6  
Other statistical considerations 
45 
13 
Name of Committees involved in trial 
46 
14 
Direct Access to Source Data/Documents 
46 
15 
Ethics and regulatory requirements 
46 
16 
Monitoring requirement for the trial 
46 
17 
Finance 
46 
18 
Insurance 
46 
19 
Publication policy 
47 
20 
Statement of compliance 
47 
21 
References 
47 
22 
Schedule of Study Visits 
49 
 


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List of abbreviations 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
APR 
Annual Progress Report 
AR 
Adverse Reaction 
CA 
Competent Authority 
CFU 
Colony Forming Unit 
CI 
Chief Investigator 
COPD 
Chronic Obstructive Pulmonary Disease 
CLRN 
Comprehensive Local Research Network 
CRF 
Case Report Form 
CRO  
Contract Research Organisation 
CRP 
C-reactive protein, serum 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Reports 
EC 
European Commission 
ECG 
Electrocardiogram  
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
EQ5D 
A 5-point standardised measure of health outcome 
FEV1 
Forced Expiratory Volme in 1 second 
FVC 
Forced Vital Capacity 
GAfREC 
Governance Arrangements for NHS Research Ethics 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
GP 
General Practitioner  


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HCU 
Health Care Utilisation 
HES 
Hospital Episode Statistics 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IUD 
Intrauterine Device 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised   
MA 
Marketing Authorisation             
Main REC 
Main Research Ethics Committee 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MRC 
Medical Research Council 
MS 
Member State 
UK MIA IMP 
United Kingdom Manufacturer's Authorisation for 
Investigational Medicinal Products 
N/A 
Not Applicable 
NIHR 
National Institute for Health Research  
NHS R&D 
National Health Service Research & Development   
 
 
NIMP Non Investigational Medicinal Product 
PCR 
Polymerase Chain Reaction  
PCRN 
Primary Care Research Network 
PCRN-GL 
Primary Care Research Network Greater London  
Ph Eur 
European Pharmacopoeia 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person for release of trial drug 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
RFH 
Royal Free Hospital 


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SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SD 
Standard Deviation  
SDV 
Source Document Verification 
SGRQ  
St George’s Respiratory Questionnaire 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SSA 
Site Specific Assessment 
SSAR 
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TC 
Trial Coordinator  
TB 
Tuberculosis 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
WP 
Work Package  
 
 
 
 
 
 
 
 
 
 
 
 


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1 
Trial personnel 
 
Chief Investigator (CI)  
Prof Jadwiga Wedzicha 
COPD Group 
Airway Disease Section  
National Heart and Lung Institute (NHLI)  
Guy ScaddingBuilding 
DovehouseRoad 
London  
SW3 6LY 
+44 (0)207 59 47959  
 
IMPERIAL COLLEGE LONDON 
Royal Brompton Hospital 
Principal Investigator (PI) in London: 
Dr John Hurst 
Centre for Respiratory Medicine  
UCL Medical School 
Royal Free Hospital 
Rowland Hill Street 
London NW3 2QG 
E-mail: j.hurst@ucl.ac.uk  
Tel:  020 7472 6260 
Fax: 020 7472 6141 
 
Principle Investigator (PI) in Liverpool  
Dr Paul Walker 
Respiratory Research Department 
University Hospital Aintree 
Longmoor Lane 
Liverpool L9 7AL 
Telephone: 0151 529 5886 
E-mail: pmacal@liverpool.ac.uk 
 
Sponsor’s representative 
 
Ms Tharani Thurairajah 
  
AHSC Joint Research Compliance Office 
Imperial College London and 
Imperial College Healthcare NHS Trust 
510C 
Fifth Floor 
Lab Block 
Charing Cross Hospital 
London 
W6 8RF 
Tel:  020 3311 0213 
E-mail:  t.thurairajah@imperial.ac.uk 
   
 
Statisticians 
Dr Daniel Jackson Senior statistician) 
MRC Biostatistics Unit 
Institute of Public Health 
University Forvie Site 
Robinson Way 
Cambridge CB2 0SR 
Tel: 01223 330374 
Fax: 01223 760729 
Email: dan@mrc-bsu.cam.ac.uk 
 
Mr Martin Law  
MRC Biostatistics Unit 
Institute of Public Health 
University Forvie Site 
Robinson Way 
Cambridge CB2 0SR 
Tel: 01223 768257 
Fax: 01223 760729 
Email: martin.law@mrc-bsu.cam.ac.uk 
 
Routine Local laboratories: 
 
 
 
Clinical Research Fellow in Liverpool 
Dr Ben Vlies  
Respiratory Research Department 
University Hospital Aintree 
Longmoor Lane 
Liverpool L9 7AL 
 
Clinical Research Fellow in London  
Dr Simon Brill 
COPD Group 
Airway Disease Section  
National Heart and Lung Institute (NHLI)  
Guy Scadding Building 
Dovehouse Street 
London 
SW3 6LY 
Tel: 0207 59 47771 
Email: s.brill@imperial.ac.uk 
 
 
 


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Trial Co-ordinator  
Miss Luana Alves Moreira 
COPD Group 
Airway Disease Section  
National Heart and Lung Institute (NHLI)  
Guy Scadding Building 
Dovehouse Street 
London 
SW3 6LY 
Tel: 0207 59 479 
Email:  l.alves-moreira@imperial.ac.uk 
 
Professor Emma Baker (PI) 
Mailpoint J1A 
Division of Biomedical Sciences 
Jenner Wing, Corridor 10 
St George’s, University of London 
Cranmer Terrace 
London SW17 0RE 
Tel: 02087255383Email: ebaker@sgul.ac.uk 
 
 
Mr Michael Tumilty 
Respiratory Research Coordinator 
St George's University of London 
Mailpoint J1A 
Jenner Wing, Corridor 10 
Cranmer Terrace, London, SW17 0RE 
T: 020 8725 5658 
Email: mtumilty@sgul.ac.uk 
 
 
Dr Patrick Mallia (PI) 
National Heart & Lung Institute 
356 Medical School, St Mary’s Campus 
T:020 7594 3751 
Email: p.mallia@imperial.ac.uk 
 
 
 
 
 
 
 


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2 
Summary 
Title: 
Targeted 
retreatment 
of 
incompletely 
recovered 
COPD 
exacerbations with ciprofloxacin: a double-blind, randomised, 
placebo-controlled, multicentre Phase III trial  
Short title: 
Targeted retreatment of COPD exacerbations  
Trial medication: 
Ciprofloxacin 
Phase of trial: 
Phase III 
Objectives: 
The primary outcome will be the time to the next COPD 
exacerbation following targeted retreatment with the IMP or 
placebo. 
 
Secondary endpoints will include duration of the initial 
exacerbation, adverse events, changes in lung function and 
health status, bacterial load and resistance, and hospital 
readmission.  
Type of trial: 
Phase 
III, 
double-blind, 
randomised, 
placebo 
controlled, 
multicentre trial. 
Trial design and methods: 
A 90 day, double-blind, randomised, placebo controlled, 
multicentre clinical trial investigating the effects of targeted 
retreatment of COPD exacerbations with antibiotics. 
 
Patients who experience an exacerbation of COPD treated with 
antibiotics will attend, two weeks after the start of initial 
treatment, for a screening visit. Patients will be eligible for the 
study if they have not fully recovered at this visit (either 
persistent symptoms or a raised C-reactive protein [CRP]) and 
fulfil diagnostic and spirometric criteria for COPD.  
 
Eligible participants will be treated with 1 week of ciprofloxacin 
500mg BD or placebo. Follow-up will be for a further 3 months, 
and the primary study endpoint will be the time to the next 
exacerbation. 
Trial duration per 
participant: 
90 days  
Estimated total trial 
duration: 
2 years  
Planned trial sites: 
Multi-Site 
Total number of 
participants planned: 
144 
Main inclusion/exclusion 
criteria (summary; see 
section 6.1 & 6.2): 
Main Inclusion Criteria:  
- 
Diagnosis of COPD confirmed spirometrically at screening 
- 
COPD exacerbation with treatment commenced 14 days 
prior to study enrolment and treated with 5-14 days of a 
non-quinolone antibiotic. Exacerbation here will be defined 
as an episode of symptomatic worsening of COPD that was 
treated by the patient’s attending clinician. Confirmation of 


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the initial exacerbation diagnosis will be provided from the 
case notes, referral letter, or directly from the treating 
clinician, and will be documented in the CRF.  
- 
Age: ≥ 45 years of age at screening. 
- 
Persistent symptoms and/or a CRP≥8mg/L when assessed 2 
weeks after exacerbation onset 
- 
Able to complete questionnaires for health status and 
symptoms and keep written diary cards 
- 
Severity of disease: Patients with a measured FEV1<80% of 
predicted normal values at 2 weeks post exacerbation  
- 
Able and willing to give signed and dated written informed 
consent to participate 
 
Main Exclusion Criteria:  
- 
Other clinically predominant chronic respiratory disease.  
- 
Intubated and receiving mechanical ventilation  
- 
Patients with known hypersensitivity to the antibiotic under 
evaluation, to other quinolones or any excipients of the 
IMP/placebo. 
- 
Patients with a prior history of tendonopathy or tendon 
rupture 
- 
Elderly patients taking long term systemic corticosteroids 
- 
Patients on long term antibiotics for other conditions 
- 
Patient too unwell for randomisation, i.e. requiring 
retreatment in the judgment of the study doctor 
- 
Female patients who are pregnant or planning on becoming 
pregnant during the study, or are breastfeeding.   
- 
Patient 
taking 
clinically 
significant 
contraindicated 
medication as per the SmPC s, such as use of concomitant 
tizanidine or methotrexate. 
 
Statistical methodology 
and analysis: 
 
The impact of ciprofloxacin use on the probability of experiencing 
a recurrent exacerbation will be assessed using survival analysis 
of time to next exacerbation. A Cox proportional hazards model 
will be used to adjust for baseline characteristics, including 
possible centre effects. 
 
 


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3 
Introduction 
3.1 
Background 
COPD (Chronic Obstructive Pulmonary Disease) is a chronic, ongoing, progressive disease of the 
lower respiratory tract in the lungs. The hallmark of the disease is difficulty with breathing that 
slowly gets worse over time. Airway bacteria are present in the lower airways of COPD patients and 
airway infection is related to airway inflammation, lung function decline (1) and exacerbation 
frequency (2). COPD is a major cause of mortality and hospital admission with a large unmet need for 
novel therapeutic approaches. The over-arching aim of this NIHR (National Institute of Health 
Research) programme is to validate innovative antibiotic strategies to reduce exacerbations, hospital 
admissions and improve quality of life whilst minimising any bacterial resistance. Bacterial infection is 
important in COPD pathogenesis in both stable disease and at exacerbation. After understanding 
how antibiotics are currently used in COPD and developing an optimal regime for treating stable 
patients, we will evaluate the effect on exacerbations of antibiotic regimes in (i) stable COPD in 
primary care and (ii) at follow up in high-risk COPD patients to treat non-recovery and prevent 
recurrence.  
 
This protocol is part of a 6 work programme grant and aims to addresses Aim 4 of programme grant; 
namely whether optimal antibiotic therapy at exacerbation follow-up speeds exacerbation recovery 
and prevents recurrent events in COPD. 
3.2 
Clinical data, Rationale and Risks/Benefits  
COPD exacerbations are episodes of increased respiratory symptoms such as increased shortness of 
breath, increased sputum purulence and increased sputum volume (3). Oral corticosteroids are 
prescribed if exacerbations are associated with adverse effects on daily activities (4, 5). Antibiotics 
are normally used to treat COPD exacerbations in the event of associated sputum purulence or 
increased sputum volume and are associated with faster resolution of the exacerbation and delayed 
time to the next exacerbation (6). 
 
A recent study has shown that treating a single exacerbation prolongs the time to onset of 
subsequent exacerbations and reduces mortality (7).  
 
We have shown that following a first exacerbation, 27% of COPD patients will have another 
exacerbation within 8 weeks (8). In this study we also showed that it is these recurrent exacerbations 
that drive exacerbation frequency and thus there is a need to prevent their occurrence. The 
importance of recurrent exacerbations is highlighted by the finding that once a COPD patient is 
discharged from hospital they are at 34% risk of subsequent exacerbations in the following three 
months, with significantly increased mortality (9). This indicates an urgent need to validate 
interventions in this high-risk period after the initial exacerbation to reduce the likelihood of a 
second exacerbation. 
 
We also reported that a raised serum C-Reactive Protein (CRP) concentration measured 14 days after 
a first exacerbation is predictive of a second exacerbation within 50 days, suggesting that failure to 
normalise the inflammatory response may predispose to another (recurrent) exacerbation (10). 
 
Following an exacerbation, patients are often not regularly assessed for non-recovery or recurrence 
and this may contribute to the high morbidity and readmission rates after exacerbations. At present, 
there are no studies investigating further treatment for patients after a first exacerbation who have 


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failed to recover and/or normalise the inflammatory response, and are therefore at heightened risk 
of a subsequent event. Our aim in this study is to address this question in high-risk patients and test a 
novel approach to reducing the risk of subsequent exacerbation and speeding recovery.  
 
Patients who suffer an exacerbation of COPD will be treated with antibiotics and/or corticosteroids in 
the usual way. We shall then closely follow up these patients, randomising them at 14 days to re-
treatment or placebo if symptoms have not returned to stable levels and/or the systemic 
inflammatory response (CRP) has not normalised. The antibiotic to be used for this study is 
ciprofloxacin (see section 3.4 Rationale /risks benefits). 
 
The formal hypothesis for this study is that re-treatment with ciprofloxacin at day 14 after an 
exacerbation of COPD, in patients who have not fully recovered (either by persistence of symptoms 
or inflammation), will lengthen the time to the next exacerbation. 
 
Ciprofloxacin was the IMP of choice for this study based on the following:  
- 
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the European 
Respiratory Society guidelines for the management of adult lower respiratory tract infections, 
and the Canadian guidelines for the management of acute exacerbations of chronic bronchitis, 
ciprofloxacin is the antibiotic of choice for the treatment of patients with severe exacerbations 
of COPD (11, 12, 13, 14). 
- 
Based on the findings from WP1, ciprofloxacin, as a second line treatment, was found to be one 
of 5 most commonly used antibiotics amongst GP practices for the treatment of COPD in the UK 
- 
Ciprofloxacin is non-penicillin, therefore patients who meet the eligibility criteria for the trial but 
are allergic to penicillin, can also be recruited.  
3.3 
Preclinical data (as per SmPC)  
Non-clinical data reveal no special hazards for humans using ciprofloxacin based on conventional 
studies of single dose toxicity, repeated dose toxicity, carcinogenic potential, or toxicity to 
reproduction. 
 
Like a number of other quinolones, ciprofloxacin is phototoxic in animals at clinically relevant 
exposure levels. 
 
Data on photomutagenicity/photocarcinogenicity show a weak photomutagenic or phototumorigenic 
effect of ciprofloxacin in-vitro and in animal experiments. This effect was comparable to that of other 
gyrase inhibitors. 
 
Like other gyrase inhibitors, ciprofloxacin may induce joint damage during the growth phase of 
juvenile animals. The extent of the cartilage damage varies according to age, species and dose; the 
damage can be reduced by taking the weight off the joints. Studies with mature animals (rat, dog) 
revealed no evidence of cartilage lesions. In a study in young beagle dogs, ciprofloxacin caused 
severe articular changes at therapeutic doses after two weeks of treatment, which were still 
observed after 5 months.  
 
Other preclinical effects were observed only at exposures sufficiently in excess of the maximum 
human exposure that concern for human safety is negligible with regard to the animal data. 


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3.4 
Assessment and management of risk 
Patients will be treated with ciprofloxacin 500 mg twice daily for 1 week and followed for 90 days 
post treatment. This dose has been chosen as it is the standard dose when this drug is used for the 
treatment of lower respiratory tract infections and exacerbations of COPD in clinical practice, and 
tablets of this strength are routinely available. In all patients, the concomitant medications will be 
recorded and carefully checked by the study doctor for drug interactions before ciprofloxacin is 
prescribed. Patients who are taking tizanidine or methotrexate will be excluded from the trial as 
concomitant use of these is not recommended.  
 
Prior to taking the IMP, patients will be counselled by a suitably qualified member of the study team 
who is familiar with the drug and the SmPC and has received suitable training in its use. As per the 
SmPC, specific advice for patients will include: 
 
- 
Not to take the drug at the same time as dairy products or mineral fortified fruit juice 
- 
Not to take the drug at the same time as iron, zinc, polymeric phosphate binders (eg. 
sevelamer), sucralfate, antacids or highly buffered pharmaceuticals, containing magnesium, 
aluminium or calcium. These may reduce the absorption of ciprofloxacin. Ciprofloxacin should 
be taken 1-2 hours before or four hours after administration of these medications. 
- 
To avoid exposure to extensive sunlight or ultraviolet radiation during the period of treatment, 
to avoid photosensitive reactions 
 
Certain concomitant medications may be affected by concurrent ciprofloxacin administration, and in 
these patients extra monitoring, including monitoring of the INR (in the case of warfarin) or serum 
drug levels, may be initiated according to the study doctor. These medications include theophyllines, 
cyclosporin, warfarin, glibenclamide, phenytoin, ropinirole and clozapine. 
 
Patients will be asked to complete daily diary cards for changes in symptoms. These will be collected 
from the patient at the end of the trial. These diaries will note symptoms, any adverse events, 
adherence to treatment or need for further therapy. Participants will be able to discuss and report 
symptoms to the study team by telephone and may be asked to attend the hospital or local GP if 
required.  
 
The table below lists the potential risks associated with all study procedures above standard care: 
 
Intervention 
Potential risk 
Risk Management 
Spirometry/Lung 
function testing 
Patients report that this can be 
strenuous. 
The procedure can cause coughing, 
and some patients feel slightly faint 
afterwards 
 
Advise patients not to over-exert 
themselves during the procedure 
Allow sufficient time between 
attempts for full recovery. 
Blood tests 
Minor bleeding and bruising at the 
site where the needle is inserted 
Small 
risk 
of 
superficial 
skin 
infections. 
Slight pain/discomfort during the 
procedure. 
Bruising will be minimised by 
direct pressure on the site for at 
least 
30 
seconds 
following 
venepuncture. 
Infection will be minimised by 
thorough aseptic technique during 
the procedure.  
Administration of 
No excess risk associated with this 
N/A 


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symptom 
questionnaires 
intervention 
Measurement of 
observations (BP, pulse, 
oxygen saturations) and 
clinical examination 
The blood pressure cuff tightens and 
can be transiently uncomfortable. 
No other excess risks are associated 
with this intervention 
Inform patient prior to BP 
measurement. 
 
The table below summarises those risks that are expected to be associated with taking the IMP, and 
the expected management of these. 
 
Potential risks as per SmPC 
Frequency 
Risk Management 
Mycotic superinfections 
Uncommon 
Treat as necessary with antifungal agents 
Discontinue IMP if necessary 
Antibiotic associated colitis 
Rare/very rare 
Discontinue IMP 
Review and treat as appropriate 
Blood dyscrasias, including 
eosinophilia,leukopenia, 
anaemia, neutropenia, 
leukocytosis, thrombocythaemia, 
thrombocytopaenia  
Rare 
Discontinue IMP 
Review and treat as appropriate  
Allergic reaction, including 
allergic oedema and angioedema 
Rare 
Discontinue IMP 
Further management as appropriate 
Anaphylactic reaction including 
life-threatening anaphylactic 
shock 
Very rare 
Discontinue IMP 
Initiate management of anaphylactic shock 
Immediate transfer to emergency department 
for further assessment and treatment 
Anorexia 
Uncommon 
Review and treat as appropriate 
Hyperglycaemia 
Rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Psychomotor disturbance, 
including agitation, confusion, 
anxiety, abnormal dreams, 
depression, hallucinations, 
psychotic reactions 
Uncommon – 
very rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Nervous system disorders, 
including headache, dizziness, 
sleep disorders, para/dis/hypo-
aesthesiae, tremor, seizures, 
vertigo, gait disturbance, 
intracranial hypertension, 
peripheral neuropathy 
Uncommon – 
very rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Eye disorders including visual 
disturbances and colour 
distortions 
Rare - very 
rare   
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Ear and labyrinth disorders 
including tinnitus and hearing 
impairment 
Rare – very 
rare  
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Tachycardia  
Rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Life-threatening cardiac 
arrhythmia including ventricular 
Frequency 
unknown 
Discontinue IMP 
Initiate management of cardiac arrhythmia 


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arrhythmia and torsades de 
points 
Immediate transfer to emergency department 
for further assessment and treatment 
Vascular disorders including 
vasodilatation, hypotension, 
syncope and vasculitis 
Rare – very 
rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Dyspnoea  
Rare 
Review and treat as appropriate 
Discontinue IMP if causality suspected 
Nausea 
Diarrhoea 
Common 
Review and treat as appropriate 
Consider IMP discontinuation if severe 
Vomiting 
Abdominal pain 
Dyspepsia 
Flatulence 
Uncommon 
Review and treat as appropriate 
Consider IMP discontinuation if severe 
Pseudomembranous colitis 
 
Rare 
Discontinue IMP 
Review and treat as appropriate 
Pancreatitis 
Very rare 
Discontinue IMP 
Review and treat as appropriate 
Increase in liver transaminases 
Increased bilirubin 
Uncommon 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Liver impairment,  
Cholestatic icterus (jaundice) 
Hepatitis 
Rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Liver necrosis +/- life-threatening 
hepatic failure 
Very rare 
Discontinue IMP 
Immediate transfer to emergency department 
for further assessment and treatment  
Rash 
Pruritis 
Urticaria 
Uncommon 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Photosensitivity reactions 
Rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Petechiae 
Erythema multiforme 
Erythema nodosum 
Stevens-Johnson syndrome +/- 
toxic epidermal necrolysis (may 
be life-threatening) 
Very rare 
Discontinue IMP 
Review and treat as appropriate 
Immediate transfer to emergency department 
for further assessment and treatment if 
indicated 
Musculoskeletal pain 
Arthralgia 
Uncommon 
Review and treat as appropriate 
Consider IMP discontinuation if severe 
Myalgia 
Arthritis 
Increased muscle tone and 
cramp 
Rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Muscular weakness 
Tendinitis 
Tendon rupture 
Exacerbation of symptoms of 
myasthenia gravis 
Very rare 
Discontinue IMP if suspected 
Review and treat as appropriate 
Avoid future quinolone use if diagnosis 
confirmed 
Renal impairment 
Rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 
Renal failure 
Haematuria 
Rare 
Review and treat as appropriate 
Discontinue IMP until causality excluded 


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Crystalluria 
Tubulo-interstitial nephritis 
Fever 
Rare 
Review and treat as appropriate 
Consider discontinuation of IMP if causality 
suspected 
Oedema 
Hyperhidrosis/excess sweating 
Very rare 
Review and treat as appropriate 
Consider discontinuation of IMP if causality 
suspected 
Increased serum alkaline 
phosphatise 
Abnormal prothrombin level 
Increased amylse. 
Rare 
Review and treat as appropriate 
Consider discontinuation of IMP if causality 
suspected 
 
The trial risk based approach has been assessed and classified this trial as a Type B trial, on the basis 
that this is a phase III trial using an IMP that is licensed in human use with a good safety profile but 
not currently used for this indication in this patient population. 
4 
Objectives 
4.1 
Primary objective   
To assess the effect of antibiotic retreatment by comparing the use of ciprofloxacin to a placebo, on 
the time to onset of the next exacerbation (from the start of retreatment with the IMP and up to a 
maximum follow-up period of 90 days).  Exacerbation is fully defined in section 12.1.1 (‘Primary 
Outcome’).  
4.2 
Secondary objectives 
Secondary objectives will include: 
 
- 
Duration of (first) exacerbation recovery (from point of retreatment V1) based on diary card 
symptoms 
- 
Treatment-related adverse events 
- 
Exacerbation frequency (rate) during follow-up 
- 
Total number of antibiotic courses received during 90 day follow-up 
- 
(Re)admission/re-attendance to hospital during 90 day follow-up 
- 
Changes in respiratory healthcare status, assessed using SGRQ and CAT 
- 
Change in lung function from study entry to 90 days  
- 
Change in CRP from study entry to 90 days 
- 
Changes in bacterial resistance to ciprofloxacin as assessed by standard culture and sensitivity 
methods at trial beginning and end (in those patients in whom sputum is spontaneously 
expectorated)  
- 
Change in bacterial load from trial beginning to end (in those patients in whom sputum is 
spontaneously expectorated) 
- 
To collect further data on cost-effectiveness which will be analysed in a future study (Work 
Package 5 of the NIHR grant programme) 


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5 
Trial design 
This is a Phase III, randomised, placebo controlled, double-blind trial. Patients and investigators will 
be blinded to treatment group by over- encapsulating the active IMP and placebo.  
5.1 
Overall Design 
This is a Phase III, randomised, placebo controlled, double-blind trial. Patients and investigators will 
be blinded to treatment group by over- encapsulating the active IMP and placebo.  
5.2 
Justification of trial design, participants and follow up 
The three months following an exacerbation has been identified as a high-risk period in patients with 
COPD, with high rates of re-exacerbation. This trial is designed to assess whether the intervention 
prevents further exacerbations in these patients within this time frame. Participants will therefore 
have COPD and have had a recent exacerbation, and will be followed up for 90 days. The intervention 
is targeted at those patients who have not fully recovered, and in order to provide adequate 
retreatment a further full course of antibiotics will be given (one week, which is a standard length, at 
a standard dose of 500mg twice daily).  
 
A schematic diagram of the overall trial design can be found in section 22 ‘Schedule of Study Visits’ 
6 
Selection of Subjects 
6.1 
Inclusion criteria 
Patients eligible for enrolment in the study must meet all the following criteria: 
- 
Pre-existing diagnosis of COPD confirmed by post-bronchodilator FEV1/FVC ratio of <0.7 at 
screening 
- 
Severity of disease: Patients with a measured FEV1<80% of predicted normal values  
- 
Evidence of COPD exacerbation treated 14 days prior to study enrolment (as defined by an 
episode of treated symptomatic worsening of COPD which is documented in the case notes or 
referral letter and/or confirmed with the treating clinician) with 5-14 days of non-quinolone 
antibiotics   
- 
Age: ≥ 45 years of age at screening. 
- 
Measured CRP (C-reactive protein) ≥8mg/L AND/OR persistence of one or more major symptom 
at the screening visit as assessed using a standardised short questionnaire. The individual ‘major 
symptoms’ are dyspnoea, increased sputum purulence and increased sputum volume. 
- 
Able to complete questionnaires for health status and symptoms and to keep written diary cards 
- 
Patients must be able to give consent to participate in writing 
6.2  
Exclusion criteria 
Patients meeting any of the following criteria must not be enrolled in this study:  
- 
Patients with other clinically predominant chronic respiratory disease. Patients with other 
respiratory diagnoses may be enrolled if COPD is the predominant condition (in the judgment of 


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the study doctor) and if the additional diagnosis will not affect the safety of the patient or 
validity of their results. 
- 
Intubated patients receiving invasive positive-pressure ventilation. Patients receiving non-
invasive ventilation and/or oxygen therapy may be included if they otherwise fulfil the inclusion 
and exclusion criteria. 
- 
Patients with known hypersensitivity to ciprofloxacin, to other quinolones or any of the 
excipients used in its manufacture or that of the placebo. 
- 
Patients with prior history of tendinopathy or tendon rupture. 
- 
Elderly patients (≥80 years) on long-term (>6 weeks) systemic corticosteroids at a dose of 
≥5mg/day prednisolone or equivalent. 
- 
Patients on long term antibiotics for other conditions 
- 
Patients already retreated with antibiotics for the current exacerbation (i.e. between day -14 
and the screening visit)  
- 
Patients who at the screening visit are too unwell for randomisation and/or fulfil one or more of 
the following criteria: 
 SaO2 <88% on air (OR ≥5% less than their usual known baseline saturation level on their 
usual oxygen dose if using long-term oxygen therapy) 
 Systolic blood pressure <90mmHg or >200 mmHg 
 Resting tachypnoea >28 breaths/minute  
 Resting tachycardia >120 beats/minute 
 Drowsy or confused 
 Clinical examination suggesting pneumonia or complications (e.g. parapneumonic 
effusion/empyema) 
 Further antibiotic treatment required in the judgment of the study doctor and therefore 
would be at risk if randomised to the placebo arm 
- 
Female patients who are pregnant or planning on becoming pregnant during the study, or are 
breastfeeding.   
- 
Clinically relevant abnormal laboratory values available at the screening assessment that could 
interfere with the objectives of the trial or safety of the volunteer. 
- 
Patient taking clinically significant contraindicated medication, as per the SmPCs, in particular 
tizanidine and methotrexate. 
- 
Patients who are actively enrolled in another interventional clinical trial (i.e. taking another 
IMP). Patients enrolled in observational COPD research (e.g. the London COPD Cohort Study [a 
recruitment source for this study] or COPDMAP) may continue as long as a) this study does not 
adversely impact on the scientific validity of the other study, and b) simultaneous participation 
is not unduly onerous for the patient. See section 8.8. 
- 
Patients with glucose-6-phosphate dehydrogenase deficiency 
- 
Patients with any other condition precluding enrolment in the trial, according to the assessment 
of the study doctor. This will be documented at screening. 
 
Females of childbearing potential must be willing to use an effective method of contraception from 
the time consent is signed until (6 weeks) after treatment discontinuation. These include:  
- 
Complete abstinence from screening to final visit 
- 
Male partner is sterile (vasectomy with documentation of azoospermia) prior to female subject 
entry into the study, and this male partner is the sole partner for the subject 


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- 
Implants of levonorgestral inserted for at least 1 month prior to the study medication 
administration but not beyond the third successive year following insertion 
- 
Injectable progestogen administered for at least 1 month prior to study medication 
administration 
- 
Oral contraception (combined or progestogen only) administrated for at least one monthly cycle 
prior to study medication administration.  
- 
Double barrier methods: condoms or occlusive cap (diaphragm or cervical/vault caps) plus 
spermicidal agent (foam/get/film/cream/suppository) 
- 
An intrauterine device (IUD), inserted by a qualified physician, with published data showing that 
the highest expected failure rate is less than 1% per year 
- 
Estrogenic vaginal ring 
- 
Percutaneous contraceptive patches.  
  
Females of childbearing potential must have a negative pregnancy test within 7 days prior to being 
registered for trial treatment.   
 
NOTE:  Subjects are considered not of childbearing potential if they are surgically sterile (i.e. they 
have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are 
postmenopausal.  
7 
Recruitment 
Study recruitment, in both sites, will take place by any of the following means:  
 
- 
Hospital recruitment via: 
 Inpatients admitted with COPD exacerbation 
 Outpatient clinics if patients have COPD and/or have recently suffered an exacerbation 
 Patients identified as suitable by their treating clinician will be asked if they are happy to 
speak to the study team and will be contacted directly if they agree. 
- 
Recruitment from the London COPD cohort, a research cohort of over 200 COPD patients who 
are under close longitudinal follow-up at the ROYAL BROMPTON and Harefield NHS Foundation 
Trustin London and who attend with exacerbations 
- 
Community recruitment via:  
 Community COPD services in the local and surrounding areas (any suitable patients known to 
the community team, particularly those with recent treated exacerbations) 
 British Lung Foundation or other charity support groups. Representatives of our research 
group frequently attend meetings of patient groups such as these, and patients may 
express interest in participating in research. These patients may be contacted directly by 
the study team once they have given their permission and contact details. If they 
subsequently experience an exacerbation they may be recruited in the normal way. 
 Pulmonary rehabilitation services – patients identified by letter or directly (for example 
patients experiencing exacerbations during their rehabilitation course)  
 Advertisements containing information about the study placed in local journals/newspapers 
for patients to contact the research team. Posters may also be placed in GP practices.  
 GP surgeries, for example when patients attend for treatment of a COPD exacerbation. 
 Via community pharmacies who agree to act as PICs. Trial information packs containing an 
invitation letter and PIS will be included with COPD-specific medication (e.g. prescriptions 
of Tiotropium [Spiriva] or Seretide) and a week’s course of steroids and antibiotics 


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dispensed to patients ≥ 45 years of age. Patients expressing an interest in the study will be 
invited to reply directly to the study team. 
- 
Any other patient interested in the study and who has given agreement for the study team to 
contact them. 
 
Where applicable, patients’ details will only be passed on to the study team once patients have given 
their permission to their treating clinician. 
 
Recruitment will take place to ensure the required patient sample size is achievable within the 
estimated recruitment period of 18 months. Any patient with COPD exacerbation  will be approached 
by the research team after they have given permission via their treating clinician. Participants will be 
given or sent a patient information sheet (PIS) describing the study in detail. Patients expressing an 
interest in participation will be contacted by the study team and invited to a screening appointment 
(V1) at the hospital 14 days after the onset of treatment for their exacerbation (henceforth defined as 
day zero).  
 
Patient recruitment at each site will only be done when each trial site has been initiated by the 
sponsor or delegate and issued with an ‘Open to Recruitment letter.  
8 
Study procedures and schedule of assessments 
8.1  
Informed consent procedure 
All individuals working on the trial will have to review the protocol and the PROTOCOL TRAINING 
LOG. 
 
The Informed consent discussion will take place at the approved sites. The delegated individuals (as 
documented in the delegation log at sites) will be GCP trained, suitably qualified and experienced. 
 
When patients present with an exacerbation and are treated with standard antibiotics, the patient’s 
treating clinician will briefly discuss the study with the patient and obtain the patient’s permission for 
the study team to approach them. This will be documented in the patient’s medical records or source 
document. The study team will then contact the patient, discuss the study in more detail, give or 
send the patient a PIS and ensure they have a minimum of 24 hours to consider this information 
before agreeing to take part. Patients expressing an interest in participation will be offered a 
screening appointment at the hospital 2 weeks after the start of treatment for the initial exacerbation 
 
Prior to obtaining written consent at the screening visit, the delegated research staff will explain of 
the aims, methods, anticipated benefits and potential hazards of the study and give the patient 
opportunity to ask questions. It will also be explained to the patient that they are under no 
obligation to enter the trial and that they can withdraw at any time from the trial, without having to 
give a reason and without impact upon their usual clinical care. 
 
Written informed consent will include consent for all trial related procedures, access to all written 
and electronic medical records and databases, and contact with the patient’s usual medical team and 
general practitioner. A copy of the signed informed consent will be given to the participant.  The 
original signed form will be retained at the study sites and placed in the TMF/SMF; a third copy will 
be kept with the paper CRF.  
 
If new safety information results in significant changes in the risk/benefit assessment, the consent 
form will be reviewed and updated as necessary and subjects will be re-consented as appropriate. 


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No clinical screening or trial procedures will be conducted prior to taking consent from the 
participant. Consent will not denote enrolment into trial.  All patients screened will be recorded on 
the screening log, along with a screening number. Those patients who are enrolled into the trial will 
be allocated a formal trial identifier at the point of randomisation, and this will be the study number 
used to identify them for all subsequent study procedures. 
8.2 
Randomisation procedures 
- 
Randomisation will take place according to the trial specific randomisation SOP.  
- 
Sealed EnvelopeTM (www.sealedenvelope.com) will be responsible for the randomisation 
process including production of the randomisation list. The randomisation list will be held by 
Sealed EnvelopeTM until data lock.  
- 
Randomisation of patients will be conducted by delegated member of the research team at the 
sites using an internet randomisation service provided by Sealed Envelope, at visit 1 (screening 
visit) (if patient is eligible for the study following assessment of results), and after the patient 
has provided informed consent and baseline data (Class A method of randomisation).  
- 
Patients will be randomised equally into the treatment (ciprofloxacin) or control (placebo) group 
(1:1 randomisation) using a computer-generated permuted block system of variable sizes, 
stratified by site and presence or absence of symptoms (as defined by any one or more of 
persisting breathlessness, increased sputum volume, increased sputum colour. This will be 
assessed by the standardised symptom questionnaire detailed in section 8.4). 
- 
Subjects who cease taking their randomised treatment (non-compliers) will continue to be 
followed up at the end of study visit (day 90). They will not be “replaced” with a further 
randomised patient (i.e. intention to treat analysis). 
- 
Upon randomisation, patients will be allocated a trial number and will be given a study specific 
patient card, which will have the study title, IMP details, patient trial number and the contact 
details of the PI/CI/research team and out of hours contact details in cases of emergency. 
- 
Randomisation details will also be entered on to the trial subject log held in the site file.  
- 
Following the randomisation process and the generation of a randomisation number, pharmacy 
at the research sites will be notified by an automatic email. The research fellow will give the 
study medication to the patient at the screening visit.  
8.3  
Unblinding Procedures 
- 
Unblinding will take place through a web based service provided by Sealed Envelope.  
- 
An authorised member of the research team at each site will have administrative rights to the 
unblinding system and a nominated individual will be available 24 hours a day.  
- 
Unblinding will only take place when the patient’s health is compromised or an SAE has 
occurred that requires unblinding for treatment to be delivered. 
- 
In the event that unblinding is required a formal request will be made by the Investigator or 
treating health care professional to an authorised individual.  
- 
If the person requiring the unblinding is not the CI/PI then that health care professional will 
notify the Investigating team (via the 24 hour number telephone number on the patient contact 
card) that unblinding is required for a trial subject and prompt unblinding will be carried out, in 
consultation with the clinical and research teams where possible. 


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- 
Authorised individuals will break the blind by providing the unique randomisation number, via 
number or other identifier used for the trial medication, and will be immediately notified of the 
unblinded treatment allocation. 
- 
On receipt of the treatment allocation details the CI/PI or treating health care professional will 
treat the participant’s medical emergency as appropriate.  
- 
The CI/PI will document the code break and the reasons for doing so on the CRF, in the site file 
and medical notes. All code breaks will be included in the final study report and/or statistical 
report. 
- 
The CI/Investigating team will notify the Sponsor in writing as soon as possible following the 
code break detailing the necessity of the code break.  
- 
Trial Committees, where required within their charters will also be notified.  
- 
Subject always to clinical need, and where possible, other members of the research team will 
remain blinded. 
- 
The written information will be disseminated to the Data Safety Monitoring Committee for 
review in accordance with the DMC Charter.  
- 
The following procedure will be used to unblind for the submission of a SUSAR report to the 
regulatory agencies: 
 An authorised member of the sponsor’s office will unblind in the event of a SUSAR report and 
will therefore, hold administration rights to the unblinding system 
 The Sponsor will follow the procedures described in the SOP. 
 The Sponsor will provide the unblinded information on the e-SUSAR website 
 Unblinded information in SUSAR reports will not be forwarded to the trial team and shall be 
kept in the sponsor files 
 SUSAR reports will be disseminated to Investigators at sites, but the report will remain 
blinded. 
8.4  
Screening Assessment (Visit 1)  
This visit will take place 14 +/- 3 days after the start of treatment for the initial exacerbation. This will 
be defined as day zero, with the date of treatment onset for the initial exacerbation thereafter 
defined as day -14. The following procedures will take place: 
- 
Informed consent 
- 
A screening medical history will be taken, including: 
 Previous medical and surgical history including number of COPD exacerbations suffered in 
previous year and details of COPD diagnosis and treatment 
 Smoking history of cigarettes and any other recreational drug use 
 Concomitant medications 
- Assessment of medication sensitivities, particularly to antibiotics or the excipients of the IMP and 
placebo 
- A full physical examination, including:  
 height and weight,  
 blood pressure, pulse rate, respiratory rate, oxygen saturations, and  
 chest examination 
- 
A post-bronchodilator spirometry assessment (3 readings) Urine pregnancy test (females of 
childbearing potential). 


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- 
Standardised screening trial-specific questionnaire as described in section 8.12. 
- 
Blood test for CRP (see section 8.13) 
- 
Confirmation of Eligibility Criteria and enrollment to the trial. If the patient is too unwell for 
randomisation (as defined in the exclusion criteria) then further investigation and/or 
treatment may be started at this point according to the judgment of the study doctor. The 
patient will not be enrolled into the trial. 
- 
EQ5D, SGRQ (assessing symptoms over the previous 4-week time frame) and CAT questionnaires 
(to be done before after eligibility has been confirmed and before the IMP is dispensed). 
- 
treatment allocation and issue of patient trial number  
- 
Study prescription. 
- 
A blood sample will be collected for laboratory CRP levels as described in section 8.13. (results 
do not need to be available before the patient commences treatment);  
- 
Serum sample for future laboratory analysis (See section 8.13).  
- 
Where patients are able to spontaneously expectorate sputum, a sample will be taken (see 
section 8.13) 
- 
The patient will be given diary cards for the duration of the study period, along with a symptom 
code card, and asked to record their symptoms daily (see section 8.12). 
- 
The patient will also be given a trial contact card and will be asked to show this to any other 
healthcare professionals they may see during the study period, and request those healthcare 
professionals to contact us with any queries regarding the study. The patient will also be asked 
to contact us if they have any worsening respiratory symptoms, suspected side effects, or other 
medical problems during the study period, so that these can be recorded and discussed. 
- 
IMP dispensing and and patient instructed on precautions and how to take the study 
medication.  
- 
An appointment will be made for 7 days after the screening visit. If the patient provided a 
sputum sample at screening then a sputum pot will be given to the patient in case they are able 
to expectorate and bring a sample on the morning of the appointment. Patients will also be 
asked to bring any unused medication with them to this visit. 
8.5  
Treatment procedures  
- 
Ciprofloxacin:  500 mg, twice daily for 1 week (oral) 
- 
Placebo: one capsule, twice daily for 1 week.  
Patients will commence the study medication on the day of screening (visit 1)  
8.6  
Follow-up visits (V2 & V3) 
Patients will return to the hospital at 7 (+3) days (V2) and 28 (+/-3) days (V3) after V1 for follow up 
appointments. The following procedures will be carried out: 
- 
The occurrence of AE/SAE and exacerbations will be checked and recorded. 
- 
Diary cards will be checked and the patients reminded/re-educated on how to fill these in 
correctly (see section 8.12). 
- 
Changes to concomitant medications will be recorded including start and stop dates of any 
modified treatments. 


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- 
Blood sample for CRP analysis (see section 8.13) 
- 
Serum sample for future laboratory analysis (see section 8.13) 
- 
Spirometry (see 8.12). 
- 
Where spontaneously expectorated, sputum will be collected and subsequently analysed for 
bacterial load and antibiotic resistance  
- 
CAT symptom questionnaire. 
- 
At V2 (at 7 days) a pill count will be performed and any unused medication collected to check 
adherence to the IMP. 
- 
Further investigation and treatment may be organised if indicated in the opinion of the study 
doctor. This will fall outside the usual study procedures but will be fully documented in the CRF.  
8.7  
Follow-up telephone call 
The patient will be contacted by telephone between days 50-60 for a telephone review. The 
following will be carried out and documented in the CRF: 
- 
Telephone consultation and assessment for AE/SAE and any exacerbations  
- 
Reminder to fill in diary cards 
- 
General discussion and identification of any problems 
8.8  
Ongoing study monitoring 
Patients who are participating in other observational research studies (for example the London COPD 
Cohort, COPDMAP or the ECLIPSE legacy study) may continue their usual monitoring procedures 
during this study. Patients enrolled in other interventional research studies (i.e. receiving another 
IMP) will not be recruited to the current study. 
8.9  
Exacerbation visits (if applicable) 
Patients will be asked to contact the study team by telephone if they develop worsening respiratory 
symptoms at any point during the study period. If the patient is able to they will be asked to attend 
to see the study team on the same day. Where the patient is hospitalised on site, and well enough to 
carry out study procedures, the study team may visit the patient in hospital for this. If the patient is 
too unwell or unwilling to attend for a study visit then they will seek treatment for the exacerbation 
in their usual way. They will still be asked to inform the study team and this will be recorded in the 
CRF.  
 
The following will be carried out: 
- 
Review of symptoms and diary cards to confirm exacerbation 
- 
Clinical examination and recording of pulse, oximetry, blood pressure, heart rate and respiratory 
rate 
- 
Spirometry to assess FEV1 and FVC (see 8.12) 
- 
 CAT symptom questionnaire  
- 
A blood sample for CRP analysis (see section 8.13) 
- 
serum sample (see section 8.13)  


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- 
Sputum sample will be collected if spontaneously expectorated. (see section 8.13) 
- 
Treatment for the exacerbation will be dispensed as needed via the hospital pharmacy and 
recorded as concomitant medication. 
- 
Further investigation (e.g. chest radiograph) and treatment may be organised if indicated in the 
opinion of the study doctor. This will fall outside the usual study procedures but will be fully 
documented in the CRF.  
8.10  
End of Study Visit (V4)  
Patients will return to the hospital 90 (+/- 3) days after IMP issue, and the following assessments will 
be made: 
- 
The occurrence of AE/SAE or exacerbations will be checked and recorded. 
- 
Spirometry will be performed to assess FEV1 and FVC (see section 8.12).   
- 
Diary cards will be collected by the investigator.  
- 
SGRQ (4 week version) and CAT questionnaires.   
- 
EQ5D. 
- 
A sputum sample will be taken from the patient (See section 8.13). 
- 
Any changes to the concomitant medications will be recorded including start and stop dates of 
any modified treatments. 
- 
A blood sample will be collected for CRP analysis (See section 8.13). 
- 
Serum sample for future work (see section 8.13.  
- 
Further investigations (e.g. chest radiograph) and treatment may be organised if indicated in the 
opinion of the study doctor. This will fall outside the usual study procedures but will be fully 
documented in the CRF. If the patient requires ongoing clinical follow-up this will be organised 
via local NHS services and the patient’s general practitioner. 
8.11  
Flowchart of study assessments 
This can be found in section 22. 
8.12  
Clinical Procedures and Data collection 
- 
Post-bronchodilator Spirometry: to assess FEV1 and FVC. A minimum of three spirometry 
readings will be taken to assess FEV1 and FVC. The highest individual FEV1 and FVC readings will 
be used to calculate the FEV1/FVC ratio and for comparison with the predicted normal value. 
The spirometry will be considered post-bronchodilator if the patient has taken their usual long-
acting bronchodilator medication OR if they have had a short-acting bronchodilator 
administered in clinic 10-15 minutes prior to spirometry testing. Spirometry will be performed 
according to the standardised ATS/ERS Consensus statement [Miller et al., ERJ, 2005]. 
- 
Diary Cards: These cards will be used to measure changes in symptoms/side effects, as well as in 
defining exacerbations for the primary endpoint, and therefore will be carefully explained to the 
patient at this time. 
- 
Basic physiological measurements and clinical examination: These include blood pressure, 
oxygen saturations, pulse oximetry, respiratory rate, pulse rate, height and weight. These will all 
be performed in the usual manner. 


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- 
Questionnaires (study specific symptom questionnaire, EQ5D, CAT, SGRQ) will be given to the 
patient to complete while in the clinic room. The study doctor will be on hand to answer any 
questions and give any necessary assistance.  
- 
Blood sampling will be carried out in the usual manner. Laboratory procedures are detailed 
below. 
8.13  
Laboratory Procedures 
Samples will be collected by delegated research staff at sites.  
- 
CRP Blood samples: will be analysed from study visits via the routine NHS biochemistry 
laboratory for CRP levels using a point-of-care testing CRP analyser.  
- 
Serum Samples: will be processed according to a standardised SOP and stored at -80C or future 
analysis of inflammatory markers.  
- 
Sputum samples: will be collected from patients and processed as clinical samples in the 
hospital  Microbiology laboratories for:  
 
Analysis for bacterial numbers by quantitative culture methods.  
 
Evaluation of any bacterial resistance by susceptibility testing +/- gene sequencing.  
 
Sputum samples will be processed according to a standard SOP and stored at -80C at sites and will be 
transferred in batches to the main laboratory at ROYAL BROMPTON and Harefield NHS Foundation 
Trust for storage and further analysis. Quantitative PCR bacterial detection will subsequently be 
carried out according to the relevant protocol/SOP. 
 
All Stored Sample tubes will be labelled with the unique subject number and date of collection and 
logged at the study site and receiving laboratory. Consent for the collection and storage for future 
studies will be obtained at study entry, and all storage and sample and analysis will take place in 
appropriately equipped and licensed facilities either in the Dept of Medical Microbiology at the RFH 
London or at the COPD Unit at the NHLI . If data from the analysis is to be transferred outside of the 
EU, consent for this will be obtained separately. 
8.14  
Definition of end of trial 
The end of the trial will be defined as the date of the last hospital visit by the last study participant. 
 8.15  
Discontinuation/withdrawal of participants and ‘stopping rules’  
Patients will be discontinued from the study when one or more of the following takes place:  
- 
When patients drop out of the study, with reasons recorded wherever possible. 
- 
SUSAR 
- 
AE/SAE of any type which prevents continued participation in the study, with reasons recorded. 
- 
Patient commenced on medication that is contraindicated with the IMP (e.g. tizanidine). In this 
case the IMP will be discontinued and the patient will continue study procedures as per 
intention-to-treat protocol. 
 
In all cases, when patients are discontinued from study medication, the following minimum 
information will be recorded in the CRF by the research fellow:  
- 
Date of discontinuation  


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- 
Date last study medication taken  
- 
Pill count/drug count 
- 
A sputum sample taken if possible 
- 
Any SAE/AE 
 
Subjects who cease taking their randomised treatment (non-compliers) will continue to be followed 
up at the end of study visit (day 90). They will not be “replaced” with a further randomised patient 
(i.e. intention to treat analysis). 
 
It is thought unlikely that the trial will be stopped prematurely as the study IMP is routinely used for 
a similar duration to that here. However If a number of SAEs occur that in the opinion of the TSC are 
deemed unacceptable (if IMP behaving outside the normal safety profile) then the trial will be 
prematurely stopped. 
9 
Investigational Medicinal Product  
9.1  
Name and description of investigational medicinal product(s)  
Ciprofloxacin is a fluoroquinolone antibacterial agent. Its bactericidal action results from the 
inhibition of both type II topoisomerase (DNA-gyrase) and topoisomerase IV, required for bacterial 
DNA replication, transcription, repair and recombination. 
Placebo is a tablet containing lactose and other pharmacologically inactive substances. 
Ciprofloxacin and placebo will be over-encapsulated to ensure that blinding is maintained for both 
the study team and the patient.  
9.2  
Name and description of each NIMP 
There are no Non Investigation Medicinal Products routinely prescribed for this study. 
9.3  
Concomitant medication 
Patients will continue with their existing concomitant medications. New medication may be 
prescribed for exacerbations or other medical conditions that require treatment during the study 
period, according to the clinical judgment of the study doctor. All medication prescribed will be 
documented in the ‘concomitant medications’ section of the CRF and details of the consultation 
leading to the prescription will be documented in the relevant section (for exacerbation) or in the 
notes section.  
 
Oral corticosteroids will be permitted as treatment for the index exacerbation.  
 
Where the patient is already taking medication that is contraindicated as per the SPC (e.g. tizanidine, 
methotrexate) the patient will not be entered into the trial. If the patient needs to start a 
contraindicated medication during the seven day IMP course, the IMP will be discontinued but the 
patient followed up as per intention-to-treat analysis. See section 8.15. 


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9.4  
Description and justification of route of administration and dosage 
- 
Oral Capsules; this is the standard route of antibiotic therapy for COPD exacerbations unless 
very unwell and requiring hospital admission.  
- 
Ciprofloxacin:  oral dose of 500 mg, twice daily for 1 week or Placebo: one oral capsule twice 
daily for 1 week. There are no dose modifications for this trial. 
- 
Capsules are to be swallowed un-chewed with fluids. They can be taken independent of 
mealtimes however should not be taken with dairy products or mineral-fortified fruit juice. 
9.5  
Preparation and labelling of Investigational Medicinal Product 
Ciprofloxacin is a UK marketed product which will be over encapsulated by a MIA IMP holder in UK. 
Placebo capsules using the same backfill of the active IMP will also be manufactured, under the same 
conditions.  Preparation and labelling of the investigational medicinal products (active and placebo) 
will be carried out by the Manufacturing Unit at the Royal Free hospital. The labels will not disclose 
the active or placebo content to preserve the Blind. The labels will meet Annex 13 of GMP 
requirements and will be approved by the sponsor and regulatory authority 
9.6  
Drug accountability  
RFH manufacturing pharmacy will be responsible for QP release of all IMPs and shipping the IMPs to 
sites via a courier service. IMP shipping arrangement instructions for site pharmacy will be in the 
Summary of Drug Arrangements. Usual procedures for monitoring of temperature and transport 
conditions of the IMP will apply and will be documented on the IMP shipping form. Upon receipt of 
the IMP, the site pharmacy will confirm receipt of the IMPs by posting/faxing back the accompanying 
shipping form to RFH manufacturing pharmacy and copies retained at trial sites. In cases where the 
IMP was damaged or not stored correctly this will warrant an urgent notification to the RFH 
manufacturing pharmacy and a replacement will be arranged.  RFH manufacturing Pharmacy will be 
responsible for dispatching replacement IMPs to pharmacy sites.  Site pharmacy will be responsible 
for logging receipt of the IMPs on the site accountability log within the hospital pharmacy file. Full 
IMP accountability will be conducted during the trial, all IMP will be dispensed and logged in the local 
pharmacy site file. 
 
All used/unused IMPs will be collected from the patients by delegated research staff at both sites, to 
be then forwarded onto the corresponding research site Pharmacy for updating the drug 
accountability log in the hospital pharmacy file in each site. Drug destruction will be conducted, once 
agreed with the sponsor and in accordance to local pharmacy practice, and this will be documented 
in the drug destruction log in the hospital pharmacy file in each site. 
9.7  
Source of IMPs including placebo 
Oral ciprofloxacin tablets will be sourced through pharmacy at the RFH and will be over encapsulated 
by the Manufacturing Unit that holds a valid UK MIA IMP licence. Placebo capsules will be 
manufactured using the same backfill of the Active will also be manufactured under the same 
conditions of the Active. It will then be shipped to site pharmacies. The sourcing arrangements are 
detailed in the Summary of Drug arrangements. 


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9.8  
Assessment of compliance 
9.8.1 
Compliance to the IMP 
- 
Patients will be asked to complete a daily diary card for the whole period of the trial (i.e. 90 
days) to record daily symptoms, patient status, and the need for further therapy. This will also 
include documentation of IMP compliance, and any missed doses of study medication, during 
the week of IMP therapy. 
- 
Patients will be advised to complete the daily diary cards in the morning prior to taking any 
study medication. 
- 
Pill counts will be taken at visit V2 
- 
Compliance to the IMP will be documented in the source data (Case Report Form) 
- 
As this is an intention to treat analysis, there will be no minimum level of compliance to the IMP 
and therefore non-compliance will not result in the withdrawal of the patient. 
 
9.8.2 
Compliance to the Protocol 
Noncompliance to the protocol study procedures will be documented in the Case Report Form and 
on the protocol deviation log by the investigator and reported to the Sponsor as agreed. As this is an 
intention to treat analysis, persistent noncompliance to study procedures by the patient will not 
result in withdrawal from the study and they will continue to be followed up as per protocol 
requirements. 
9.9  
Post-trial IMP arrangements 
Trial IMPs will not be available after the end of trial and patients will revert to standard best practice 
of care post-trial. This will clearly be stated in the patient information sheet.   
10 
Recording and reporting of adverse events and reactions 
10.1  
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial 
subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. 
Adverse Reaction (AR) 
Any untoward and unintended response in a subject to an 
investigational medicinal product which is related to any dose 
administered to that subject.  
This includes medication errors, uses outside of protocol (including 
misuse and abuse of product) 
Serious 
adverse 
event 
(SAE), 
serious 
adverse 
reaction 
(SAR) 
or 
unexpected 
serious 
Any adverse event, adverse reaction or unexpected adverse 
reaction, respectively, that: 
- 
results in death, 


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adverse reaction  
- 
is life-threatening, 
- 
requires 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation, 
- 
results in persistent or significant disability or incapacity, or 
- 
consists of a congenital anomaly or birth defect. 
Important Medical Event 
These events may jeopardise the subject or may require an 
intervention 
to 
prevent 
one 
of 
the 
above 
characteristics/consequences. 
Such 
events 
should 
also 
be 
considered ‘serious’. 
Unexpected adverse 
reaction 
An adverse reaction the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out: 
 (a) in the case of a product with a marketing authorization, in the 
summary of product characteristics for that product,  
(b) in the case of any other investigational medicinal product, in 
the investigator's brochure relating to the trial in question. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
10.2  
Recording adverse events 
Reported symptoms and illnesses will be reviewed by the study doctor and discussed with the PI as 
to causality and expectedness of the event, and a decision made as to whether this qualifies as an 
SAE or SUSAR. Reporting of SAEs and SUSARs will follow established sponsor SOPs and to the 
competent authority and research ethics committee (REC), if applicable. An independent data 
monitoring committee will assess safety data during the course of the trial.  
 
All adverse events will be recorded in the paper CRF (which is the source data), whether believed to 
be related or unrelated to the treatment.  
 
All SERIOUS adverse events must be recorded in the CRF and AE log.  
 
If the investigator suspects that the disease has progressed faster due to the administration of the 
IMP, then she/he will report this as an unexpected adverse event to the sponsor.  
 
Clinically significant abnormalities in the results of objective tests (e.g. ECG) may also be recorded as 
adverse events. If the results are not expected as part of disease or IMP, these will also be recorded 
as unexpected.  
 
All adverse events will be recorded with clinical symptoms and accompanied with a simple, brief 
description of the event, including dates as appropriate.  
 
All adverse events will be reportable to the Sponsor up to 30 days after the last IMP administration. 


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10.3  
Assessments of Adverse Events 
Each adverse event will be assessed for the following criteria: 
10.3.1  Severity  
Category 
Definition 
Mild 
The adverse event does not interfere with the volunteer’s daily routine, and 
does not require intervention; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the volunteer’s routine, or 
requires intervention, but is not damaging to health; it causes moderate 
discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is clearly 
damaging to health 
10.3.2  Causality 
The assessment of relationship of adverse events to the administration of IMP is a clinical decision 
based on all available information at the time of the completion of the case report form.  The 
following categories will be used to define the causality of the adverse event: 
 
Category 
Definition 
Definitely: 
There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. 
Probably: 
There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the 
event occurred 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 events). 
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 
treatments). 
Not related 
There is no evidence of any causal relationship. 
Not Assessable 
Unable to assess on information available. 
10.3.3  Expectedness 


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Category 
Definition 
Expected 
An adverse event that is classed in nature as serious and which is 
consistent with the information about the IMP listed in the SPC or 
clearly defined in this protocol. 
Unexpected 
An adverse event that is classed in nature as serious and which is not 
consistent with the information about the IMP listed in the SPC 
 
The reference document to be used to assess expectedness against the IMP will be the SPC 
appended to the simplified IMPD used by the manufacturer to source and over encapsulate 
Ciprofloxacin for this trial. The protocol will be used as the reference document to assess disease 
related and/or procedural expected events as described in section 10.4 Procedures for recording and 
reporting Serious Adverse Events.  
10.3.4  Seriousness 
Seriousness is defined for an SAE above.  
 
Collection, recording and reporting of adverse events (including serious and non-serious events and 
reactions) to the sponsor will be completed according to the sponsor’s SOP  
10.4  
Procedures for recording and reporting Serious Adverse Events 
- 
All serious adverse events will be recorded in the paper CRF, and the sponsor’s AE log 
by the delegated research staff at site.  The AE log will be reported to the sponsor at least once 
or twice per year.  
- 
All serious adverse events will be reported to the sponsor on a SAE form within 24 
hours, with the exception of COPD exacerbations requiring hospital admission and without 
other complication. Up to 30% of patients discharged from hospital following a treated 
exacerbation of COPD will be readmitted within 90 days and therefore this SAE is likely to occur 
often; it is also an expected end-point of the study. Complicated exacerbations (e.g. pneumonia, 
requiring ventilatory support or other procedures including chest drainage) will be reported to 
the Sponsor. Where there is uncertainty as to whether the admission is complicated or should 
be classified as serious, this will be discussed with the Sponsor within 24 hours of the site 
becoming aware of the event. 
The Research Fellow will complete the sponsor’s serious adverse event form and the form 
will be faxed or emailed to the sponsor [Fax: 0203 311 0203, Email: 
Nabila.Youssouf@imperial.ac.ukinsert fax/email details], within 24 hours of his / her 
becoming aware of the event. The event will be discussed with the Chief or Principal 
Investigator and any SAE queries raised by the sponsor will be responded to as soon as 
possible.  
- 
All SUSARs must be notified to the sponsor immediately (or within 24 hours) according 
to the sponsor’s written SOP. 
 
Exceptions to SAE reporting requirements:  
 


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Symptoms of COPD exacerbations requiring hospital admission and without other complication, such 
as: 
- 
Breathlessness and reduced exercise tolerance 
- 
Increased sputum volume 
- 
Increased sputum purulence 
- 
Upper airway viral symptoms (e.g. runny nose) 
- 
Wheeze or tight chest 
- 
Sore throat 
- 
Increased cough 
- 
Fever 
 
Example: As the IMPs used in this trial are licensed in the UK and used within their marketing 
authorization, EXPECTED SARs (as outlined in the SPCs appended to the simplified IMPD for this trial) 
and listed below will be RECORDED in the CRF.  However, SAE forms will not be completed and sent 
to the sponsor.  
The most commonly reported adverse drug reactions with ciprofloxacin are nausea and diarrhoea. As 
these events are very common with well-established safety data profile, for this protocol, these will 
not be reportable. 
10.5  
Managing serious adverse events in a multi-centre trial 
The PI of each site will send the report to the CI and  the Sponsor concurrently .The PI at each site 
will review the report first before sending to the CI and the Sponsor as soon as received and within 
24 hours. The CI will review the SAE and this will be discussed at the TMG meeting. All SUSARs will be 
reported simultaneously to the sponsor and to other sites. 
 
Sites reporting to the sponsor and CI will be complete the SAE report as per sponsor’s SOP and using 
IMPERIAL COLLEGE LONDON SAE form. 
10.6  
Notification of deaths 
All deaths will be reported to the sponsor irrespective of whether the death is related to disease 
progression, the IMP, or an unrelated event. Notification of death will take place within 1 day.   
10.7  
Reporting SUSARs 
The sponsor will notify the main REC and MHRA of all SUSARs.  SUSARs that are fatal or life-
threatening must be notified to the MHRA and REC within 7 days after the sponsor has learned of 
them.  Other SUSARs must be reported to the REC and MHRA within 15 days after the sponsor has 
learned of them.   
 
The procedure for unblinding in the event of a SUSAR is described in section 6.3 of this protocol.  
10.8  
Development Safety Update Reports 
The sponsor will provide the main REC and the MHRA with Development Safety Update Reports 
(DSUR) which will be written in conjunction with the trial team and the Sponsor’s office. The report 


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will be submitted within 60 days of the Developmental International Birth Date (DIBD) of the trial 
each year until the trial is declared ended. 
 
This will be done in accordance with the sponsor’s SOP  
10.9  
Annual progress reports   
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary date 
on which the favourable opinion was given, and annually until the trial is declared ended. 
 
The chief investigator will supervise the preparation of the APR. 
10.10  Pregnancy (If applicable) 
- 
Female participants in this study are unlikely to be of child-bearing age because of the nature of 
the disease investigated and the minimum age cut-off. However, in the event of a pregnancy 
occurring during the study, this must be reported using a clinical trial pregnancy form. 
- 
To ensure subject’s safety, each pregnancy must be reported to sponsor within 24 hours of 
learning of its occurrence. The pregnancy must be followed to determine outcome (including 
premature termination) and status of mother and child. 
- 
Pregnancy complications and elective terminations for medical reasons must be reported as an 
AE or SAE. Spontaneous abortion must be reported as an SAE to the CI and Sponsor within 24 
hours of learning of its occurrence.  
- 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after 
the subject has completed the study and considered by the investigator as possibly related to 
the investigational product, must be promptly reported to sponsor.   
10.11  Overdose:  
Overdoses of greater than three tablets in a single dose reported by patients will be recorded and 
notified to the sponsor (this information should be placed on the deviation log). As an intention to 
treat (ITT) analysis is planned, patients who overdose will still be included in the final analysis and 
attend for further study procedures where possible.  
 
If an AE/SAE is associated with the overdose the overdose will be fully described in the AE/SAE report 
form. 
10.12  Reporting Urgent Safety Measures  
If any urgent safety measures are taken the PI/Sponsor shall immediately and in any event no later 
than 3 days from the date the measures are taken, give written notice to the MHRA and the relevant 
REC of the measures taken and the circumstances giving rise to those measures. 
Please refer to the following website for details on clinical trials safety reporting: 
http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/Safetyrepor
ting-SUSARSandASRs/index.htm 


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10.13  The type and duration of the follow-up of subjects after adverse events 
All AEs and SAEs must be followed until resolution, until the condition stabilises, until the event is 
otherwise explained, or the subject is lost to follow-up. The investigator is responsible to ensure that 
follow-up includes any supplemental investigations as may be indicated to elucidate as completely as 
practical the nature and/or causality of the AE or SAE. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
 
New or updated information should be recorded on the originally completed SAE CRF with all 
changes signed and dated by the investigator. 
 
Any SUSAR related to the IMP will need to be reported to the Sponsor irrespective of how long after 
IMP administration the reaction has occurred. 
10.14  Notification of Serious Breaches to GCP and/or the protocol  
 A “serious breach” is a breach which is likely to effect to a significant degree:  
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial. 
 
The sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach of  
(a) the conditions and principles of GCP in connection with that trial; or  
(b) the protocol relating to that trial, as amended from time to time, within 7 days of becoming 
aware of that breach. 
The sponsor will be notified immediately of any case where the above definition applies during the 
trial conduct phase.  The sponsor’s SOP on the  will be followed.  
11 
Data management and quality assurance 
11.1  
Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 1998. 
 
The Case Report Forms (CRFs) will not bear the subject’s name or other personal identifiable data.  
The subject’s initials, date of birth and trial identification number, will be used for identification.’ 
11.2  
Data collection tools and source document identification 
The final version will be approved by the sponsor. All data will be entered legibly in black ink with a 
ball-point pen.  If an error is made, the error will be crossed through with a single line in such a way 
that the original entry can still be read.  The correct entry will then be clearly inserted, and the 
alterations will be initialled and dated by the person making the alteration.  Overwriting or use of 
correction fluid will not be permitted. 
 
There will also be an electronic version of the CRF, and all data contained in the paper CRF and any 
other source documentation will be transcribed into this. 
 
The data collection methods for this study will comprise the following: 


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- 
Patient and study-specific data (e.g. medical history, clinical examination) will be collected and 
directly transcribed onto the paper CRF by the research fellow. This will form the main source 
document. 
- 
Symptom and quality of life indices (questionnaires) will be completed by the patients onto 
standard template forms. 
- 
Data will be entered from both sites onto a password protected web based electronic case 
report form collection system (Sealed Envelope) and this will be the trial database. 
 
The following Source Documents will be collected:  
Type 
Paper Case Report Form 
Stand alone document 
Consent form from patient 
Stand alone document 
Date and cause of death (where appropriate) 
Death certificate 
SGRQ  
EQ5D 
CAT 
Stand alone questionnaires 
(completed by patient) 
Daily Diary cards 
Stand alone document 
(completed by patient) 
CRP result – point-of-care testing 
Printed label and/or hand 
transcribed into paper CRF 
Lab results- blood 
Sputum analysis data  
Hospital data base 
Pregnancy test result 
Hospital data base.  
Master Patient List  
Stand alone document 
Record of Initial Contact telephone call and patient details  
Stand alone document 
Hospital discharge summary or other information regarding the 
initial exacerbation (where available only) 
Stand alone document 
 
NOTE: Blood, sputum and pregnancy test results will be transcribed into the paper CRF. Any print out 
hard copies of results will be kept with the paper CRF.  
 
As a minimum, the following will be recorded directly on to the paper CRF (Case Report Form ) which 
will then be transcribed into the electronic CRF: 
- 
Dated statement that the subject has entered the clinical study and that written consent was 
taken prior to the subject’s entry into the study 
- 
A medical history at the screening visit.  
- 
Details of the index exacerbation, including date of treatment onset (day -14) and (if applicable) 
the date that the patient says symptoms returned to normal 
- 
Physical examination findings 
- 
Spirometry 
- 
Inclusion/exclusion criteria 
- 
Confirmation of diagnosis of the disease being treated (COPD) 
- 
Eligibility of patient for the study  


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- 
Initials, sex and date of birth 
- 
Demographic data  
- 
Smoking history  
- 
Exacerbation frequency in previous year (patient recall)  
- 
Randomisation number  
- 
Treatment kit number  
- 
AE/SAEs 
- 
Pill count   
- 
Concomitant medication 
- 
Off study (date off study/last study medication taken, reason off study)  
- 
Subsequent visit dates (including unscheduled visits) 
- 
Start and stop dates of study medication 
 
It will be the responsibility of the investigator to ensure the accuracy of all data entered in the CRFs. 
The delegation log will identify all those personnel with responsibilities for data collection and 
handling, including those who have access to the trial database. Patients who have not returned their 
study questionnaires or missed a scheduled visit will also be telephoned to reschedule a visit or 
request them to post the questionnaire to ensure completion of data.   
11.3  
Data handling and analysis 
A data management SOP will be followed. A web-based database will be programmed by Sealed 
Envelope. The software is Sealed Envelope's own software application with an underlying MySQL 
database for storage. It has been used successfully in other trials over the last five years. 
 
The web-based database will include the following:         
- 
All information recorded in the paper CRF  
- 
Randomisation records 
- 
EQ-5D, CAT and SGRQ questionnaires 
- 
Diary card              
 
The system will also have the following attributes:  
- 
Password protected user accounts for Delegated staff at each  site. 
- 
Single data entry with validation checks and source data verification against the data in the 
database. 
- 
Have the ability to edit data and view history of edits. Only authorised delegated members of 
staff at each site will be able to edit the data from that site. 
- 
Have the ability to add queries to CRFs to assist with follow-up of missing data or other issues. 
- 
Full audit log of all changes to data 
- 
The delegated research staff at both sites and the statisticians in Cambridge will have read-only 
access to the electronic data set (back end access) to download whenever required for data 


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cleaning and/or analysis purposes. Queries can be raised and will be addressed by the 
authorised delegated members of staff at site. 
- 
An audit trail will be maintained of any change or correction to the case report form or the 
electronic database. Data will be generated, recorded and reported in compliance with the 
protocol and with Good Clinical Practice. Free text variables will also be allowed to describe, for 
example, deviations from the protocol. These will also be recorded on the protocol deviation 
log. 
- 
The CRFs are designed for ease of use and to minimise cross-validation errors. Nevertheless, 
data cleaning and monitoring will be conducted by the trial manager and statistician during and 
at the end of the trial. It will be possible to check patient notes with any queries that arise. 
- 
Data will not be double entered. 
- 
Data entries will be checked to ensure they fall within the normal parameters at the time of 
entry- data will also be reviewed by the statistician and members of the steering committee for 
other queries.   
- 
The Authorised delegated members of staff at both sites will complete data entry in the paper 
CRF at the time of seeing the patient. This data will then be entered onto the online database. 
Site staff may insert new records and browse records they have previously entered, but will not 
be able to access records of patients from the other trial site. 
- 
Data entered via the website will not contain personal identifiers.  
- 
Each patient will be given a unique number, which will be linked to a paper record of the 
participants’ names and addresses. This will only be accessible by trial personnel seeing patients 
at the study site. Any patient-identifiable data will be stored securely and separately from 
anonymised documents at each site, and will not be entered onto the electronic database. 
- 
The database will also be accessed centrally by the study statistician and the steering committee 
(on a read only basis) and analysed to assess recruitment and retention levels and for data 
cleaning according to specified SOPs developed by the research team.  
- 
Data analysis for the trial will be done by the trial Statistician who is independent to the person 
entering the data on to the database.  
- 
All data collected will be in adherence to Data Protection Act 1998 , as well as IMPERIAL 
COLLEGE LONDON Information Security Policy and Trust Information Governance Polices. The 
data will be stored in a highly secure data centre owned and operated by Rackspace in the UK 
(www.rackspace.co.uk). The data centre is audited annually under the SAS70 accreditation 
system. Backup is daily to tape on-site (2 week retention) and hourly offsite to a failover server 
with full disk encryption held at Sealed Envelope's offices. In the event of disaster at the main 
data centre online operations can be switched to the failover server. 
11.4  
Record keeping and archiving 
Archiving will be authorised by the Sponsor following submission of the end of study report.  
- 
Site Files and Consent Forms will be securely stored with access restricted to trial authorised 
persons only at participating sites.   
- 
CRF will be securely stored with access restricted to trial authorised persons only at participating 
sites as a hard (paper) copy.   


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- 
All essential documents held at sites (e.g. CRF, Site Files and Consent forms) will be archived at 
site according to local trust policy. These documents will be archived for a minimum of 5 years 
after completion of the trial. 
- 
The electronic trial database, which includes an electronic version of the CRF, will be stored 
electronically on the server of Sealed EnvelopeTM. Authorised staff at the Dept of Respiratory 
Medicine at the ROYAL BROMPTON  and Harefield NHS Foundation Trust, Dept of Clinical 
Sciences, as well as to the study statisticians (Dr Daniel Jackson and Mr Martin Law) at the MRC 
Biostatistics Unit, Cambridge, will be able to access this data as needed.  At the end of the 
analysis, the database will be securely transferred electronically (based on the secure processes 
Sealed Envelope have in place and the arrangements will be detailed in the data management 
SOP) to the Dept of Respiratory Medicine at the ROYAL BROMPTON and Harefield NHS 
Foundation Trust. Only Trial authorised persons will have access to the database. 
- 
Chief Investigator is responsible for the secure archiving of essential trial documents within the 
TMF for the trial and the trial database as per their trust policy. All essential documents will be 
archived for a minimum of 5 years after completion of the trial.  
 
Destruction of essential documents will require authorisation from the Sponsor.   
12 
Statistical Considerations  
Dr Daniel Jackson and Mr Martin Law are the trial statisticians who will be responsible for all 
statistical aspects of the trial from design through to analysis and dissemination.     
12.1  
Outcomes 
12.1.1  Primary outcome 
The primary outcome will be the time in days to the first day of the next exacerbation following IMP 
start (at day 0, 14 days after the initial exacerbation), up to a maximum of 90 days. Exacerbation is 
defined fully below. Patients who do not suffer a recurrent exacerbation will be censored at the end 
of follow-up / time of drop-out. 
 
The onset of the next (recurrent) exacerbation will be defined as either: 
1) The first day of treatment with antibiotics and/or steroids for an exacerbation of COPD (HCU  
definition), or 
2) The first of two or more consecutive days of increased respiratory symptoms recorded on 
the daily diary cards, either: 
a. Two ‘major’ symptoms (increased dyspnoea, increased sputum volume, or increased 
sputum purulence), or 
b. One ‘major’ and one ‘minor’ symptom (cold, wheeze/chest tightness, sore throat, 
cough or fever).  
 
A recurrent exacerbation will only be diagnosed based on diary cards if there are a minimum of five 
symptom-free days after the end of the previous exacerbation. 
The end of the first exacerbation will be defined as the first day of two consecutive symptom-free 
days. 


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12.1.2  Secondary outcomes 
- 
Duration of the initial exacerbation (from point of retreatment V0) based on diary card 
symptoms. The exacerbation will be considered to have ended on the first of two consecutive 
symptom-free days. 
- 
Treatment-related adverse events 
- 
Exacerbation frequency (rate) during follow-up.  
- 
Total number of antibiotic courses received during follow-up 
- 
Rates of (re)admission/re-attendance to hospital during follow-up 
- 
Changes in respiratory healthcare status, during follow-up, assessed using SGRQ and CAT. 
Changes in lung function during follow-up. 
- 
Change in CRP during follow-up. 
- 
Changes in bacterial resistance to ciprofloxacin as assessed by standard culture and sensitivity 
methods at trial beginning and end (in those patients in whom sputum is spontaneously 
expectorated)  
- 
Change in bacterial load from trial beginning to end (in those patients in whom sputum is 
spontaneously expectorated) 
- 
Cost-effectiveness will be assessed as part of a future study (WP5) 
12.2  
Sample size and recruitment 
12.2.1  Sample size calculation  
Over the two centres, based on HES data, we anticipate that a total of 218 hospital admission or 
ambulatory exacerbations will be identified over the 18-month recruitment period 
(http://www.hscic.gov.uk/hes). Based on data from the London COPD Cohort, 33% of exacerbating 
patients have a CRP of 8 or above at 2 weeks.  Furthermore, our pilot data suggest that of patients 
with CRP >8mg/L, at least 60% of patients report symptoms at day 14. Thus, assuming that 90% of 
eligible patients will agree to take part in the study, we expect 218/3 ≈ 73 patients eligible due to CRP 
level, 0.6(218-73) = 87 eligible due to symptoms at day 14, and to randomise 0.9(73+87)=144 
patients in total.  
 
Pilot data from our group suggests that at a level of CRP>10mg/l at 14 days, there will be 36% 
recurrent exacerbations within 50 days. Assuming a constant hazard of exacerbation this translates 
to around a 55% recurrent exacerbation rate at 90 days. A similar proportion of recurrent 
exacerbations are seen in the London COPD cohort (for both CRP>10 and CRP<10).  An observational 
database study by Roede et al. (2008) reported a hazard ratio of 0.62 when antibiotics were given in 
addition to usual treatment. Allowing for a 5% dropout, we will therefore have 80% power at a 5% 
two-sided significance level to detect a 22% absolute reduction in the proportion of exacerbations 
seen at 90 days (from 55% to 32%), using time-to-event (survival) methods. This is equivalent to 
detecting a hazard ratio of 0.48 over the follow-up period. 
 
The recruitment period for this trial is estimated to be 18 months, requiring approximately 8 patients 
per month to be randomised across both sites.  


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12.3  
Statistical analysis plan 
12.3.1  Summary of baseline data and flow of patients 
A CONSORT diagram will be produced to illustrate recruitment and flow of patients through the 
study. (http://www.consort-statement.org/) 
 
The variables to be collected at day zero are:  
- 
Bacterial load: If spontaneously expectorated, sputum samples will be collected and analysed to 
measure bacterial load in the lung. Concentrations will be log transformed and expressed as 
log10 CFU (colony forming units)/ml. Collection of sputum is not a requirement for study entry 
and this will therefore form a subgroup analysis. 
- 
CRP: Blood samples will be collected and analysed for CRP levels to measure presence of 
inflammation in the body. This is measured in milligrams per litre of blood (mg/L) 
- 
Spirometry: A test used to measure lung function.  Specifically the measurement of volume and 
flow of air inhaled and exhaled. The parameters measured will be the Forced vital capacity (FVC) 
and Forced expiratory volume (FEV) at 1 second. The FEV1/FVC ratio and FEV1 as a percentage 
of Predicted Normal value will be computed. 
- 
SGRQ: This is a standardized self-completed questionnaire for measuring impaired health and 
perceived well-being ('quality of life') in airways disease. It has been designed to allow 
comparative measurements of health between patient populations and quantify changes in 
health following therapy. 
- 
EQ5D: This is a standardised instrument for use as a measure of health outcome. It provides a 
simple descriptive profile and a single index value for health status.  Health outcome at 
treatment end will be compared to baseline data to assess change in health status. 
- 
CAT: This is a standardised self-completed symptom questionnaire  
- 
Age and Gender 
- 
Smoking status 
- 
Self-reported exacerbation frequency in the previous year 
 
Summary statistics for all baseline variables will be presented (mean, standard deviation, median, 
interquartile range for continuous variables, percentages for categorical variables), stratified by 
treatment group, site and presence of symptoms to assess baseline comparability. No formal 
statistical tests of these baseline comparisons will be made. 
 
The flow of patients through the trial will be summarised in a CONSORT diagram, showing all 
exclusions including reasons for non-randomisation and drop-outs / lost to follow-up statistics. The 
CONSORT diagram will be stratified by randomised group. 
12.3.2  Primary outcome analysis 
The primary outcome is the time to the next exacerbation within the 90-day study period. This will 
analysed using Cox proportional hazards regression and the estimated hazard ratio between the 
groups will be reported, along with its standard error. A log-rank test will be used to test the primary 
hypothesis. A Kaplan-Meier plot will be produced. Patients who do not suffer a recurrent 
exacerbation during follow-up will be treated as censored observations at their end of follow-up 
time. As analysis is intention to treat, non-compliers will be treated as belonging to the treatment 
group originally randomised to. Where patients withdraw from follow up, every effort will be made 


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to ascertain their primary outcome (i.e. date of next exacerbation OR exacerbation-free survival to 
90 days) by telephone. 
Analysis will be adjusted for a number of important baseline covariates including; sex, exacerbation 
phenotype, level of symptoms (CAT), levels of CRP, disease severity (FEV), baseline exacerbation 
frequency in previous year, hospital admission at initial exacerbation.  
12.3.3  Secondary outcome analysis 
Summary measures of the secondary endpoints will be presented (mean, standard deviation, 
median, interquartile range for continuous variables, percentages for categorical variables) by 
treatment group and for both baseline and end of trial follow-up visits. The percentage of missing 
data will be summarised. 
- 
Time until resolution of first exacerbation will be compared between the active treatment and 
placebo groups, using a log-rank test. Cox regression analysis will also be conducted adjusting 
for important baseline covariates. 
- 
The number of treatment-related adverse events will be analysed by using (over dispersed) 
Poisson regression or a suitable zero-inflated model and adjusted for treatment group and 
important baseline covariates.  
- 
Exacerbation frequency: The rate of exacerbations experienced during the study period will be 
analysed by using (over dispersed) Poisson regression or a suitable zero-inflated model and 
adjusted for treatment group and important baseline covariates and with length of follow-up as 
an offset. 
- 
Frequency of antibiotic courses: The rate of antibiotic courses received for patients in the active 
treatment and placebo groups will be compared using using (over dispersed) Poisson regression 
or a suitable zero-inflated model adjusting for treatment group and important baseline 
covariates. 
- 
The rate of hospital attendances during the study period will be analysed by using (over-
dispersed) Poisson regression or a suitable zero-inflated model and adjusted for treatment 
group and important baseline covariates. 
- 
Changes in respiratory healthcare status, assessed using SGRQ and CAT. SGRQ (score between 0 
and 100) and CAT (score between 0 and 40) from baseline to day 90 will be modelled as a 
normally distributed random variable by using a suitable transformation (e.g. a Box-Cox like 
transformation to remove skewness and possible boundary effects). Any analysis will be 
adjusted for baseline scores, treatment, and other important baseline covariates. Repeated 
measures analysis will be used to assess treatment effects over time during the follow-up 
period. 
- 
Lung function: Changes in FEV1, FEV1 as % predicted, and FEV1/FVC ratio and FVC  at day 90 
from day 0 will be modelled separately as continuous outcomes and assumed to be normally 
distributed (an appropriate transformation will be applied before analysis if required). Analyses 
will be adjusted for baseline values, treatment, and other important baseline covariates. 
Repeated measures analysis will be used to assess treatment effects over time during the 
follow-up period. 
- 
Change in CRP from study entry to 90 days will be modelled as a normally 
distributed random variable by using a suitable transformation (e.g. a Box-Cox like 
transformation to remove skewness and possible boundary effects). Any analysis will be 
adjusted for baseline CRP, treatment, and other important baseline covariates. Repeated 
measures analysis will be used to assess treatment effects over time during the follow-up 
period. 


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- 
Resistance patterns (not resistant, resistant) will be analysed using logistic regression and 
adjusting for treatment group, baseline values and other important baseline covariates.  
- 
The change in bacterial load from trial beginning to end will be analysed using multiple  tobit 
regression and adjusting for baseline values and other relevant baseline covariates. Values 
below limits of detection will be treated as left censored observations in the tobit regression 
analysis. 
- 
Adherence as assessed by pill counts. The number of pills taken over total number dispensed will 
be modelled using logistic regression (Binomial distribution with logit link). The difference in 
percent adherence will be assessed between treatment groups. 
- 
Cost-effectiveness will be assessed as part of a future study (WP5) 
 
This study is not powered to test these secondary outcomes – only the primary outcome. As such, 
analyses of the secondary outcomes will be hypothesis generating only.  
12.4  
Randomisation methods 
Randomisation will be conducted by the research fellow contacting a central randomisation service 
(Sealed EnvelopeTM) after the patient has provided informed consent and baseline data (Class A 
method of randomisation). 
 
Patients will be randomised using a 1:1 ratio from a computer-generated permuted block system of 
variable sizes. Stratification will take place by site and each patient will be randomised to one of the 
two treatment groups on an individual basis.  
Randomisation will further be stratified according to the type of inclusion criteria (persistent 
symptoms or raised CRP). 
12.5  
Interim analysis 
An interim analysis will not be required on the primary end point. The IMP has a well-established 
safety record and is being administered for a short course only; all treatment-related adverse events 
will be reviewed with the PI and trial steering committee during the trial. If there is suspicion that the 
IMP is acting outside its normal safety profile then further analysis will be undertaken.  
 
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, the procedure for an early termination or temporary halt will be arranged after 
consultation by all involved parties. This will be recorded in the CRF and documented in the final 
report. Unblinding at this point is unlikely to be necessary. 
 
The sponsor will submit a written notification to the Regulatory Authority concerned and Ethics 
Committee/Institutional Review Board providing the justification of premature ending or of the 
temporary halt.   
12.6  
Other statistical considerations 
Any deviations from the statistical plan will be discouraged. However, any unforeseen changes will 
be described and justified in the final report, as appropriate.  The sponsor, CI, TSC and or DMC will be 
notified of these deviations. Where required the sponsor and Chief Investigator will notify REC, 
Regulatory Authorities and the funder. 


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13 
Name of Committees involved in trial 
Trial Steering Group (TSC) 
Data Monitoring Committee (DMC)  
 
Each of the above committees will have terms of references described in charters which will be kept 
within the TMF. 
14 
Direct Access to Source Data/Documents 
The investigator(s)/ institution(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents.  Trial participants are 
informed of this during the informed consent discussion.  Participants will consent to provide access 
to their medical notes. 
15 
Ethics and regulatory requirements 
The sponsor will ensure that the trial protocol, patient information sheet, consent form, and 
submitted supporting documents have been approved by the appropriate regulatory body (MHRA in 
UK) and a main research ethics committee, prior to any patient recruitment. The protocol and all 
agreed substantial protocol amendments, as assessed by the sponsor, will be documented and 
submitted for ethical and regulatory approval prior to implementation. 
 
Before the site can enrol patients into the trial, the Chief Investigator/Principal Investigator or 
designee must apply for NHS permission from their Trust Research & Development (R&D) and be 
granted written permission.  It is the responsibility of the Chief Investigator/ Principal Investigator or 
designee at each site to ensure that all subsequent amendments gain the necessary approval from 
their Trust Research & Development (R&D). This does not affect the individual clinician’s 
responsibility to take immediate action if thought necessary to protect the health and interest of 
individual patients (see section 10.12 for reporting urgent safety measures). 
 
Within 90 days after the end of the trial, the CI/Sponsor will ensure that the main REC and the MHRA 
are notified that the trial has finished.  If the trial is terminated prematurely, those reports will be 
made within 15 days after the end of the trial. 
 
The CI will supply the Sponsor with a summary report of the clinical trial, which will then be 
submitted to the MHRA and main REC within 1 year after the end of the trial.  
16 
Monitoring requirement for the trial 
A trial-specific monitoring plan will be established for this study. The trial will be monitored with the 
agreed plan. 
17 
Finance 
Funds for this trial have been secured from the NIHR.  
18 
Insurance 
Imperial College London holds insurance against claims from participants for injury caused by their 
participation in the clinical trial. Participants may be able to claim compensation if they can prove 


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that Imperial College London has been negligent. However, as this clinical trial is being carried out in 
a hospital, the hospital continues to have a duty of care to the participant of the clinical trial.  
Imperial College London does not accept liability for any breach in the hospital’s duty of care, or any 
negligence on the part of hospital employees. This applies whether the hospital is an NHS Trust or 
otherwise.   
 
Participants may also be able to claim compensation for injury caused by participation in this clinical 
trial without the need to prove negligence on the part of Imperial College London or another party.  
Participants who sustain injury and wish to make a claim for compensation should do so in writing in 
the first instance to the Chief Investigator, who will pass the claim to the Sponsor’s Insurers, via the 
Sponsor’s office. 
 
19 
Publication policy 
All proposed publications will be discussed with the Sponsor prior to publishing other than those 
presented at scientific forums/meetings. Please refer to Imperial College London  publication policy. 
 
The Funder (NIHR) will review publications and poster presentations prior to presentation and, 
where possible, prior to submission. 
 
Published data will be fully anonymised and none of the patients involved in the trial will be 
identified in any report or publication.  
 
The study design and the results will be published on Clinicaltrials.Gov 
20 
Statement of compliance 
The trial will be conducted in compliance with the approved protocol, the UK Regulations, EU GCP 
and the applicable regulatory requirement(s). 
21 
References 
1.  Wilkinson TMA, Wilks M, Patel IS, Lloyd Owen, Donaldson GC, Wedzicha JA.  Airway bacterial 
colonisation and decline in lung function in COPD. Am J Resp Crit Care Med 2003 167: 1090-95. 
2.  Patel IS, Seemungal TAR, Wilks M, Lloyd Owen S, Donaldson GC, Wedzicha JA.  Relationship 
between bacterial colonisation and the frequency, character and severity of COPD exacerbations.  
Thorax 2002:57:759-64. 
3.   Seemungal TAR, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA Time course and recovery of 
exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med  
2000; 161: 1608-13 
4.   Davies L, Angus RM, Calverley PMA.  Oral corticosteroids in patients admitted to hospital with 
exacerbations of chronnic obstructive pulmonary disease: a prospective randomised controlled 
trial.  Lancet  1999; 354: 456-60 
5.   Niewoehner DE, Erbland ML, Deupree RH et al.  Effect of systemic glucocorticoids on 
exacerbations of chronic obstuctive pulmonary disease.  N Engl J Med  1999; 340: 1941-7 
6.   Anthonisen, NR., Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson NA.  Antibiotic 
therapy in exacerbations of chronic obstructive pulmonary disease. Ann. Intern. Med. 
1987;106:196-20 


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7.   Roede BM,  Bresser P, Bindels PJE,  Kok A,  Prins M, Rietter G, Geskus RB, Herings RMC, Prins JM.  
Antibiotic treatment is associated with reduced risk of a subsequent exacerbation in obstructive 
lung disease: an historical population based cohort study.  Thorax 2008; 63: 968-973. 
8.  Hurst JR, Donaldson GC, Quint JK, Goldring JJP, Baghai-Ravary B,  Wedzicha JA.  Temporal 
Clustering of Exacerbations in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care 
Med. 2009; 179: 369-374.  
9.   Roberts CM, Lowe D, Bucknall CE, Ryland I, Kelly Y, Pearson MG.  Clinical audit indicators of 
outcome following admission to hospital with acute exacerbation of chronic obstructive 
pulmonary disease.  Thorax 2002;57:137-41 
10.   Perera WR, Hurst JR, Wilkinson TMA, Sapsford RJ, Müllerova H, Donaldson GC, Wedzicha JA.  
Inflammatory changes and recurrence at COPD exacerbations.  Eur Resp J 2007; 29:527-34 
11.  Rabe K. F., et al. 2007. Global strategy for the diagnosis, management, and prevention of chronic 
obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med. 
176:532–555. 
12.  Woodhead M., et al. 2005. Guidelines for the management of adult lower respiratory tract 
infections. Eur. Respir. J. 26:1138–1180. 
13.  Balter M. S., et al. 2003. Canadian guidelines for the management of acute exacerbations of 
chronic bronchitis. Can. Respir. J. 10(Suppl.):3B–32B. 
14.  Kontou P, Chatzika K, Pitsiou G, Stanopoulos I, Argyropoulou-Pataka P, Kioumis I. 
Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically 
ventilated patients with chronic obstructive pulmonary disease. Antimicrob Agents Chemother. 
2011 Sep;55 (9):4149-53. Epub 2011 Jun 13. 
15.  GOLD Executive committee.  Global Strategy for Diagnosis, Management, and Prevention of 
COPD (Revised 2006).  http://www.goldcopd.com/Guidelineitem.asp 
 


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22 
 Schedule of Study Visits 
 
Pre-
Screening 
Screening 
visit 
First  follow 
up  
Second 
follow up 
Telephone 
call 
Exacerbation 
visit 
End of study 
visit 
Day: 
-14 
0 (±3) 
7 (+3) 
28 (±3) 
50-60 (±3) 
As needed Day 90 (±3) 
Visit name: 
 
V1 
V2 
V3 
Tel1 
EX 
V4 
Clinical events: 
 
 
 
 
 
 
Patient identified by treating clinician 
and referred to study team 
X 
 
 
 
 
 
 
Patient experiences COPD 
exacerbation 
X 
 
 
 
 
X 
 
Patient commences treatment for 
exacerbation (NIMP, as needed) 
X 
 
 
 
 
X 
 
Study procedures: 
 
 
 
 
 
 
 
Informed Consent Form 
 
X 
 
 
 
 
 
Inclusion/Exclusion criteria applied 
 
X 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
Vitals (Blood pressure, Pulse rate, 
respiratory rate, O2 sat) 
 
X 
 
 
 
X 
 
Spirometry (FEV1/FVC) 
 
X 
X 
X 
 
X 
X 
Full clinical examination (including 
Chest exam) 
 
X 
 
 
 
X 
 
IMP Issue  
 
X 
 
 
 
 
 
Pill Count  
 
 
X 
 
 
 
 
Diary Cards/reminder to fill in  
 
X 
X 
X 
X 
X 
X 
Concomitant medication assessment  
 
X 
X 
X 
 
X 
X 
Collect final data for study endpoints 
 
 
 
 
 
 
X 
Assess, record SAE/AE/exacerbations 
 
 
X 
X 
X 
X 
X 
Laboratory Investigations: 
 
 
 
 
 
 
 
Blood CRP level  
 
X 
X 
X 
 
X 
X 
Store serum inflammatory markers 
 
X 
X 
X 
 
X 
X 
Sputum (analysis/storage), if 
applicable 
 
X 
X 
X 
 
X 
X 
Pregnancy test if applicable 
 
X 
 
 
 
 
 
Questionnaires/healthcare indices: 
 
 
 
 
 
 
 
Screening trial-specific questionnaire 
to assess presence of symptoms 
 
X 
 
 
 
 
 
SGRQ 
 
X 
 
 
 
 
X 
CAT 
 
X 
X 
X 
 
X 
X 
EQ5D 
 
X 
 
 
 
 
X 
 

SAP_001.pdf: 
WP4 Statistical Analysis Plan 
15/1/2019 
The following provides the statistical analysis plan for Work Package 4 (WP4) trial.  
Its purpose is (i) to clarify the primary analyses, and (ii) to avoid misleading 
inferences that would arise from post-hoc analyses.  Thus the statistical analysis plan 
should be drawn up in advance of looking at the outcome data. 
Clinical trials.gov NCT 02300220 
EudraCT:-2012-002198 
 
Background to WP4 
The principal research question to be addressed by the trial is as follows: 
“Can patients with incompletely recovered COPD exacerbations experience 
significantly increased time until next exacerbation if treated with a 1-week course of 
ciprofloxacin?” 
The study is a multi-centre randomised controlled trial conducted in two hospitals, 
the Royal Brompton Hospital in London, University Hospital Aintree in Liverpool, St. 
Mary’s Hospital in London, St. George’s Hospital London. 
 
Inclusion/exclusion criteria 
Main Inclusion Criteria:  
- 
Diagnosis of COPD confirmed spirometrically at screening. 
- 
COPD exacerbation with treatment commenced 14 days prior to study 
enrolment and treated with 5-14 days of a non-quinolone antibiotic. Exacerbation 
here will be defined as an episode of symptomatic worsening of COPD that was 
treated by the patient’s attending clinician. Confirmation of the initial 
exacerbation diagnosis will be provided from the case notes, referral letter, or 
directly from the treating clinician, and will be documented in the CRF.  
- 
Age: ≥ 45 years of age at screening. 


- 
Persistent symptoms and/or a CRP≥8mg/dL when assessed 2 weeks after 
exacerbation onset. 
- 
Able to complete questionnaires for health status and symptoms and keep 
written diary cards. 
- 
Severity of disease: Patients with a measured FEV1<80% of predicted normal 
values at 2 weeks post exacerbation. 
- 
Able and willing to give signed and dated written informed consent to 
participate. 
 
 
Main Exclusion Criteria:  
• 
Other clinically predominant chronic respiratory disease.  
• 
Intubated and receiving mechanical ventilation. 
• 
Patients with known hypersensitivity to the antibiotic under 
evaluation, to other quinolones or any excipients of the IMP/placebo. 
• 
Patients with a prior history of tendonopathy or tendon rupture. 
• 
Elderly patients taking long term systemic corticosteroids. 
• 
Patients on long term antibiotics for other conditions. 
• 
Patient too unwell for randomisation, i.e. requiring retreatment in the 
judgment of the study doctor. 
• 
Female patients who are pregnant or planning on becoming pregnant 
during the study, or are breastfeeding.   
• 
Patient taking clinically significant contraindicated medication as per 
the SmPC, such as use of concomitant tizanidine or methotrexate. 
 
Consent 
The informed consent discussion will take place at the approved sites. The delegated 
individuals (as documented in the delegation log at sites) will be GCP trained, suitably 
qualified and experienced. 
 
When patients present with an exacerbation and are treated with standard antibiotics, 
the patient’s treating clinician will briefly discuss the study with the patient and 
obtain the patient’s permission for the study team to approach them. This will be 
documented in the patient’s medical records or source document. The study team 


will then contact the patient, discuss the study in more detail, give or send the patient 
a PIS and ensure they have a minimum of 24 hours to consider this information 
before agreeing to take part. Patients expressing an interest in participation will be 
offered a screening appointment at the hospital 2 weeks after the start of treatment 
for the initial exacerbation 
 
Prior to obtaining written consent at the screening visit, the delegated research staff 
will explain of the aims, methods, anticipated benefits and potential hazards of the 
study and give the patient opportunity to ask questions. It will also be explained to 
the patient that they are under no obligation to enter the trial and that they can 
withdraw at any time from the trial, without having to give a reason and without 
impact upon their usual clinical care. 
 
Written informed consent will include consent for all trial related procedures, access 
to all written and electronic medical records and databases, and contact with the 
patient’s usual medical team and general practitioner. A copy of the signed informed 
consent will be given to the participant.  The original signed form will be retained at 
the study sites and placed in the TMF/SMF; a third copy will be kept with the paper 
CRF.  
 
If new safety information results in significant changes in the risk/benefit 
assessment, the consent form will be reviewed and updated as necessary and subjects 
will be re-consented as appropriate. 
 
No clinical screening or trial procedures will be conducted prior to taking consent 
from the participant. Consent will not denote enrolment into trial.  All patients 
screened will be recorded on the screening log, along with a screening number. Those 
patients who are enrolled into the trial will be allocated a formal trial identifier at the 
point of randomisation, and this will be the study number used to identify them for 
all subsequent study procedures. 
 
Randomisation and Blinding 
- 
Randomisation will take place according to the trial specific randomisation SOP.  


- 
Sealed EnvelopeTM (www.sealedenvelope.com) will be responsible for the 
randomisation process including production of the randomisation list. The 
randomisation list will be held by Sealed EnvelopeTM until data lock.  
- 
Randomisation of patients will be conducted by delegated member of the 
research team at the sites using an internet randomisation service provided by 
Sealed Envelope, at visit 1 (screening visit) (if patient is eligible for the study 
following assessment of results), and after the patient has provided informed 
consent and baseline data (Class A method of randomisation).  
- 
Patients will be randomised equally into the treatment (ciprofloxacin) or control 
(placebo) group (1:1 randomisation) using a computer-generated permuted block 
system of variable sizes, stratified by site and presence or absence of symptoms 
(as defined by any one or more of persisting breathlessness, increased sputum 
volume, increased sputum colour. This will be assessed by the standardised 
symptom questionnaire detailed in section 8.4). 
- 
Upon randomisation, patients will be allocated a trial number and will be given a 
study specific patient card, which will have the study title, IMP details, patient 
trial number and the contact details of the PI/CI/research team and out of hours 
contact details in cases of emergency. 
- 
Randomisation details will also be entered on to the trial subject log held in the 
site file.  
- 
Following the randomisation process and the generation of a randomisation 
number, pharmacy at the research sites will be notified by an automatic email. 
The research fellow will give the study medication to the patient at the screening 
visit.  
 
Study variables and endpoints 
(i) Each centre provides information on patients not randomised into the trial (overall 
number, reasons for exclusion).  
(ii) For randomised patients, baseline data are collected for a variety of 
characteristics, including 
- 
Post-bronchodilator spirometry: Specifically the measurement of volume and 
flow of air inhaled and exhaled. The parameters measured will be the Forced vital 


capacity (FVC) and Forced expiratory volume (FEV) at 1 second. The FEV1/FVC 
ratio and FEV1 as a percentage of predicted normal value will be computed to 
assess FEV1 and FVC. A minimum of three spirometry readings will be taken to 
assess FEV1 and FVC. The highest individual FEV1 and FVC readings will be used 
to calculate the FEV1/FVC ratio and for comparison with the predicted normal 
value. This will be taken at screening visit (V1), first follow up (V2), second follow 
up (V3), end of study (V4) and if patient presents with exacerbation during study 
(EX).  
The spirometry will be considered post-bronchodilator if the patient has taken 
their usual long-acting bronchodilator medication OR if they have had a short-
acting bronchodilator administered in clinic 10-15 minutes prior to spirometry 
testing.  
- 
Diary Cards: These cards will be used to measure changes in symptoms/side 
effects, as well as in defining exacerbations for the primary endpoint, and 
therefore will be carefully explained to the patient at this time, and at every visit 
(as spirometry). 
- 
General baseline characteristics: Age, gender, smoking status, self-reported 
exacerbation frequency in the previous year, Smoking history (pack years) 
- 
Basic physiological measurements and clinical examination: These include blood 
pressure, oxygen saturations, pulse oximetry, respiratory rate, pulse rate, height, 
weight, BMI and a full clinical exam. These will all be performed in the usual 
manner, and measured at V1 and at exacerbation visit (EX). 
- 
Pill count: This will be taken at V2. 
- 
CRP Blood samples: Will be collected and analysed for CRP levels to measure 
presence of inflammation in the body. This is measured in milligrams per litre of 
blood (mg/L), and will be measured at every visit (as spirometry). 
- 
Serum samples: will be taken at every visit (as spirometry) and stored at -80C for 
future analysis of inflammatory markers.  
- 
Sputum samples: If spontaneously expectorated, the sputum samples will be 
collected and analysed to measure bacterial load in the lung. Concentrations will 
be log transformed and expressed as log10 CFU (colony forming units)/ml. 
Collection of sputum is not a requirement for study entry and this will therefore 
form a subgroup analysis. The sputum samples will be collected from patients at 


every visit (as spirometry) and processed as clinical samples in the hospital 
microbiology laboratories for:  
o Analysis for bacterial numbers by quantitative culture methods.  
o Evaluation of any bacterial resistance by susceptibility testing +/- gene 
sequencing.  
- 
Questionnaires (study specific symptom questionnaire, EQ5D, CAT, SGRQ) will be 
given to the patient to complete while in the clinic room. The study doctor will 
be on hand to answer any questions and give any necessary assistance.  
- 
     SGRQ: This is a standardized self-completed questionnaire for measuring 
impaired health and perceived well-being ('quality of life') in airways disease. It 
has been designed to allow comparative measurements of health between patient 
populations and quantify changes in health following therapy. It will be measured 
at V1 and V4. 
- 
     EQ5D: This is a standardised instrument for use as a measure of health 
outcome. It provides a simple descriptive profile and a single index value for 
health status.  Health outcome at treatment end will be compared to baseline 
data to assess change in health status. It will be measured at V1 and V4. 
- 
     CAT: This is a standardised self-completed symptom questionnaire, and will 
be measured at every visit (as spirometry). 
 
The flow of patients through the trial will be summarised in a CONSORT diagram, 
showing all exclusions including reasons for non-randomisation and drop-outs/lost 
to follow-up statistics. The CONSORT diagram will be stratified by randomised group. 
 
Discontinuation/withdrawal of participants and ‘stopping rules’  
Patients will be withdrawn from the study only when they drop out, with reasons 
recorded wherever possible. 
Patients will be discontinued from study medication but still followed-up in the case 
of:  
- 
AE/SAE of any type which prevents continued participation in the study, with 
reasons recorded. 


- 
Patient commences on medication that is contraindicated with the IMP (e.g. 
tizanidine). In this case the IMP will be discontinued and the patient will continue 
study procedures as per intention-to-treat protocol. 
- 
SUSAR. 
 
 
In all cases, when patients are discontinued from study medication, the following 
minimum information will be recorded in the CRF by the research fellow:  
- 
Date of discontinuation  
- 
Date last study medication taken  
- 
Pill count/drug count 
- 
A sputum sample taken if possible 
- 
Any SAE/AE 
 
Subjects who cease taking their randomised treatment (non-compliers) will continue 
to be followed up at the end of study visit (day 90), i.e. intention to treat analysis. 
They will not be “replaced” with a further randomised patient. 
 
It is unlikely that the trial will be stopped prematurely as the study IMP is routinely 
used for a similar duration to that here. However If a number of SAEs occur that in 
the opinion of the TSC are deemed unacceptable (if IMP behaving outside the normal 
safety profile) then the trial will be prematurely stopped. 
 
Compliance to the IMP 
- Patients will be asked to complete a daily diary card for the whole period of 
the trial (i.e. 90 days) to record daily symptoms, patient status, and the need for 
further therapy. This will also include documentation of IMP compliance, and any 
missed doses of study medication, during the week of IMP therapy. 
 
Sample size 
Over the two centres HES data suggest that it is possible to identify at least 350 
hospital admission or ambulatory exacerbations over the 18-month recruitment 


period (http://www.hscic.gov.uk/hes). Based on data from the London COPD Cohort, 
33% of exacerbating patients have a CRP of 8 or above at 2 weeks. We therefore expect 
that approximately 115 of the hospital admission or ambulatory exacerbations will 
be eligible for inclusion due to high CRP.  Furthermore, our pilot data suggest that of 
patients with a normal CRP (<8mg/L), at least 60% of patients report symptoms at 
day 14; thus of all sampled patients we expect approximately 115+0.6(350-115)=256 
to be eligible for inclusion into the trial.  Assuming that 90% of eligible patients will 
agree to take part we initially hoped to randomise 231 patients in total. 
 
Pilot data from our group suggests that at a level of CRP>10mg/l at 14 days, there 
will be 36% recurrent exacerbations within 50 days. Assuming a constant hazard of 
exacerbation this translates to around a 55% recurrent exacerbation rate at 90 days. 
A similar proportion of recurrent exacerbations are seen in the London COPD cohort 
(for both CRP>10 and CRP<10).  An observational database study by Roede et al. 
(2008) reported a hazard ratio of 0.62 when antibiotics were given in addition to 
usual treatment.  
 
Due to relocation from the Royal Free Hospital to the Royal Brompton Hospital, a 
more realistic sample size of 138 is now expected. We do not anticipate a change in 
the expected proportion of exacerbation-free survival at 90 days of 0.45, and we still 
allow for 5% dropout. This would result in:  
o 90% power to detect a HR of 0.39 – an increase in survival at 90 days 
from 0.45 to 0.73; 
o 80% power to detect a HR of 0.46 – an increase in survival at 90 days 
from 0.45 to 0.70. 
 
The recruitment period for this trial is estimated to be 18 months, requiring 
approximately 20 exacerbations per month to be identified across both sites. It is 
likely that 2/3 of these will come from RFH and 1/3 from UHA. 
 
Statistical Analysis Plan 
Timing of Analyses 
• 
Recruitment of the 138 patients began in the London site in July 2014, and 
should commence shortly at the Liverpool site. 


• 
Data for completed patients should begin to become available in October 
2014. 
 
Descriptive analyses 
(i) Should include CONSORT diagram describing patient flow with exclusions 
(including reasons for exclusions) and total numbers randomised to each treatment 
arm. This will include attendance at each visit and loss to follow-up (including 
follow-up time). 
 
(ii) Baseline comparability of randomised groups:  
• 
By December 2015 (approximately), recruitment should be completed, at 
which point tables of summary statistics will be produced. These tables will 
include (but are not limited to) the following baseline variables; age 
(continuous), sex, BMI, smoking status, smoking pack year history, centre, 
bacterial load, CRP (from blood sample), spirometry measurements, 
exacerbation history (number experienced in previous year) and 
questionnaire scores for each randomised group. 
• 
Continuous variables will be summarised using the following statistics; n (non-
missing sample size), mean, standard deviation, median, inter-quartile range, 
maximum and minimum. The number of missing observations will also be 
reported. 
• 
The frequency and percentages (based on the non-missing sample size) of 
observed levels will be reported for all categorical measures. The number of 
missing observations will also be reported. 
Primary outcome analysis 
 
The primary outcome is the time to the next exacerbation within the 90-day study 
period. This will analysed using Cox proportional hazards regression, stratified by 
centre. The estimated hazard ratio between the groups will be reported, along with 
its 95% CI. A Kaplan-Meier plot will be produced. Patients who do not suffer a 
recurrent exacerbation during follow-up will be treated as censored observations at 
their end of follow-up time. As analysis is intention to treat, non-compliers will be 


treated as belonging to the treatment group originally randomised to. Where patients 
withdraw from follow up, every effort will be made to ascertain their primary 
outcome (i.e. date of next exacerbation OR exacerbation-free survival to 90 days) by 
telephone. We will adjust only for number of exacerbations in previous year and 
centre in this primary analysis. 
 
Variables: 
o Time until event or censoring: excn.or.cens.d 
surv1 <- coxph(Surv(time, cens) ~ arm  
 
A supporting analysis will be undertaken that adjusts for site and patient self-
reported history of exacerbations in the previous year. 
 
o site: site 
o Excns in previous year: prev.excns 
o Arm: [not yet released] 
 
surv1 <- coxph(Surv(time, cens) ~ arm + strata(site) + prev.excns)  
 
An additional supporting analysis will be undertaken, additionally adjusting for 
baseline covariates age; sex; FEV1% predicted; SGRQ total score; number of 
exacerbations in previous year; whether hospitalised for index exacerbation; whether 
index exacerbation was treated with steroids in addition to antibiotics; whether 
included due to symptomatic or inflammatory criteria, and smoking status. This will 
be for hypothesis generation only. It will not be used to come to overall conclusions 
regarding treatment efficacy; this will be treated as a secondary analysis. 
 
o Age (continuous): age.cts 
o Sex: sex 
o FEV1% predicted at baseline: fev.pred 
o SGRQ total score at baseline: sgrq1.total 
o Hospitalised for index excn (y/n): hospital.yn 
o Index excn treated with steroids (y/n): steroids.given.yn 
o Included due to symptomatic criteria or inflammatory criteria [to be queried] 
o Smoking status: curr.smok 


 
surv2 <- coxph(Surv(time, cens) ~ arm + strata(site) + prev.excns + age.cts + sex + fev.pred + 
sgrq1.total + hospital.yn + steroids.given.yn + XXX[inclusion crit.] + curr.smok, data=wp4) 
 
The percentage of missing data will be summarised and spurious data double 
checked as far as possible. Primary analysis will be intention to treat, and so every 
effort will be made to collect all follow-up data from non-compliers and patients who 
discontinue treatment. All patients will be analysed from the date of randomisation 
until end of follow-up period or the date of drop-out. The primary analysis will 
therefore assume patients who drop-out of the trial do so ‘at random’. 
Secondary outcome analysis 
For each secondary outcome, two analyses will be undertaken – the first adjusting 
for centre and the baseline value of the endpoint being analysed (where available), 
and the second also taking into account the additional  baseline characteristics 
specified in the supporting analysis of the primary outcome above. 
When modelling continuous data, transformations will be undertaken as necessary 
to normalise the data. Where appropriate, analyses will take account of length of 
follow up as an offset, and also account for differences in at-risk periods. Summary 
measures of the secondary outcomes will be presented (mean, standard deviation, 
median, interquartile range for continuous variables, percentages for categorical 
variables) by treatment group and for both baseline and end of trial follow-up visits. 
The percentage of missing data will be summarised. 
 
Secondary outcomes 
- Time until resolution of first exacerbation will be compared between the active 
treatment and placebo groups, using Cox proportional hazards regression, 
stratified by centre. 
o Duration of first exacerbation: dur 
- The number of treatment-related adverse events will be analysed by using  
negative binomial regression. Negative binomial regression models collapse to 
Poisson regression if there is no overdispersion. 
o Number of treatment-related AEs: trt.rltd.aes 


- Exacerbation frequency: The rate of exacerbations experienced during the 
study period per person-year will be analysed by using negative binomial 
regression. 
o Number of exacerbations: excns 
- Frequency of antibiotic courses: The rate of antibiotic courses received for 
patients in the active treatment and placebo groups will be compared using 
negative binomial regression.  
- The rate of hospital attendances during the study period will be analysed by 
negative binomial regression. . 
- Changes in respiratory healthcare status, assessed using SGRQ. SGRQ (score 
between 0 and 100from baseline to day 90 will be modelled as a normally 
distributed random variable.  Linear regression will be used, 
- Changes in respiratory healthcare status, assessed using CAT. CAT (score 
between 0 and 40) from baseline to day 90 will be modelled as a normally 
distributed random variable. Repeated measures analysis will be used to assess 
treatment effects over time during the follow-up period. 
- Lung function: Changes in FEV1, FEV1 as % predicted, and FEV1/FVC ratio and 
FVC at day 90 from day 0 will be modelled separately as continuous outcomes 
and assumed to be normally distributed. Repeated measures analysis will be used 
to assess treatment effects over time during the follow-up period. 
- Change in CRP from study entry to 90 days will be modelled as a normally 
distributed random variable. Repeated measures analysis will be used to assess 
treatment effects over time during the follow-up period. 
- Resistance patterns (not resistant, resistant) will be analysed using logistic 
regression. 
- The change in (log10) bacterial load from trial beginning to end will be 
analysed using parametric survival regression(linear regression with censored 
outcome data). Values below limits of detection will be treated as left censored.  
- Adherence as assessed by pill counts. The number of pills taken over total 
number dispensed will be modelled using logistic. The difference in percent 
adherence will be assessed between treatment groups. 
- Cost-effectiveness will be assessed as part of a future study (WP5) 
 


This study is not powered to test these secondary outcomes – only the primary 
outcome. As such, analyses of the secondary outcomes will be hypothesis generating 
only.  
 
Subgroup analyses 
Relevant subgroups may be analysed (including patients who gave sputum samples), 
allowing the incorporation of any important new information and methodological 
concerns identified between now and the time of writing the analysis plan. However, 
such analyses should be undertaken before unblinding, and keeping in mind that any 
analyses will be hypothesis generating only. 
Sensitivity analysis 
In the primary analysis, sensitivity analyses will be undertaken: The efficacy of the 
IMP will be investigated using a per-protocol analysis. Such an analysis includes only 
patients who comply fully.. This is in contrast to the main intention to treat analysis, 
which includes as much patient data as possible, regardless of loss to follow up or 
ending treatment. If there is great discrepancy between both sets of results, then 
further investigation will be undertaken using inverse probability-of-censoring 
weights (IPCW). 
 
Interim analysis 
An interim analysis will not be required on the primary end point. The IMP has a well-
established safety record and is being administered for a short course only; all 
treatment-related adverse events will be reviewed with the PI and trial steering 
committee during the trial. If there is suspicion that the IMP is acting outside its 
normal safety profile then further analysis will be undertaken.  
 
Both the sponsor and the investigator reserve the right to terminate the study at any 
time. Should this be necessary, the procedure for an early termination or temporary 
halt will be arranged after consultation by all involved parties. This will be recorded 
in the CRF and documented in the final report. Unblinding at this point is unlikely to 
be necessary. 


 
The sponsor will submit a written notification to the Regulatory Authority concerned 
and Ethics Committee/Institutional Review Board providing the justification of 
premature ending or of the temporary halt.   
 
Other statistical considerations 
Any deviations from the statistical plan will be discouraged. However, any unforeseen 
changes will be described and justified in the final report, as appropriate.  The 
sponsor, CI, TMG and or DMC will be notified of these deviations. Where required the 
sponsor and Chief Investigator will notify REC, Regulatory Authorities and the 
funder. 
References 
1.  Wilkinson TMA, Wilks M, Patel IS, Lloyd Owen, Donaldson GC, Wedzicha JA.  
Airway bacterial colonisation and decline in lung function in COPD. Am J Resp 
Crit Care Med 2003 167: 1090-95. 
2.  Patel IS, Seemungal TAR, Wilks M, Lloyd Owen S, Donaldson GC, Wedzicha JA.  
Relationship between bacterial colonisation and the frequency, character and 
severity of COPD exacerbations.  Thorax 2002:57:759-64. 
3.   Seemungal TAR, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA Time course 
and recovery of exacerbations in patients with chronic obstructive pulmonary 
disease. Am J Respir Crit Care Med  2000; 161: 1608-13 
4.   Davies L, Angus RM, Calverley PMA.  Oral corticosteroids in patients admitted to 
hospital with exacerbations of chronnic obstructive pulmonary disease: a 
prospective randomised controlled trial.  Lancet  1999; 354: 456-60 
5.   Niewoehner DE, Erbland ML, Deupree RH et al.  Effect of systemic glucocorticoids 
on exacerbations of chronic obstuctive pulmonary disease.  N Engl J Med  1999; 
340: 1941-7 
6.   Anthonisen, NR., Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson 
NA.  Antibiotic therapy in exacerbations of chronic obstructive pulmonary 
disease. Ann. Intern. Med. 1987;106:196-20 
7.   Roede BM,  Bresser P, Bindels PJE,  Kok A,  Prins M, Rietter G, Geskus RB, Herings 
RMC, Prins JM.  Antibiotic treatment is associated with reduced risk of a 
subsequent exacerbation in obstructive lung disease: an historical population 
based cohort study.  Thorax 2008; 63: 968-973. 
8.  Hurst JR, Donaldson GC, Quint JK, Goldring JJP, Baghai-Ravary B,  Wedzicha JA.  
Temporal Clustering of Exacerbations in Chronic Obstructive Pulmonary Disease 
Am. J. Respir. Crit. Care Med. 2009; 179: 369-374.  
9.   Roberts CM, Lowe D, Bucknall CE, Ryland I, Kelly Y, Pearson MG.  Clinical audit 
indicators of outcome following admission to hospital with acute exacerbation of 
chronic obstructive pulmonary disease.  Thorax 2002;57:137-41 


10.   
Perera WR, Hurst JR, Wilkinson TMA, Sapsford RJ, Müllerova H, Donaldson GC, 
Wedzicha JA.  Inflammatory changes and recurrence at COPD exacerbations.  Eur 
Resp J 2007; 29:527-34 
11.  Rabe K. F., et al. 2007. Global strategy for the diagnosis, management, and 
prevention of chronic obstructive pulmonary disease: GOLD executive summary. 
Am. J. Respir. Crit. Care Med. 176:532–555. 
12.  Woodhead M., et al. 2005. Guidelines for the management of adult lower 
respiratory tract infections. Eur. Respir. J. 26:1138–1180. 
13.  Balter M. S., et al. 2003. Canadian guidelines for the management of acute 
exacerbations of chronic bronchitis. Can. Respir. J. 10(Suppl.):3B–32B. 
14.  Kontou P, Chatzika K, Pitsiou G, Stanopoulos I, Argyropoulou-Pataka P, Kioumis 
I. Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions 
of mechanically ventilated patients with chronic obstructive pulmonary disease. 
Antimicrob Agents Chemother. 2011 Sep;55 (9):4149-53. Epub 2011 Jun 13. 
15.  GOLD Executive committee.  Global Strategy for Diagnosis, Management, and 
Prevention 
of 
COPD 
(Revised 
2006).  
http://www.goldcopd.com/Guidelineitem.asp 
 
 
Signed 
 
……………………………………………………………………………..    
………………….. 
 
Professor J.A. Wedzicha  
 
 
 
Date 
 
……………………………………………………………………………..    
………………….. 
Professor Gavin Donaldson 
 
 
 
Date