Metformin to Reduce Airway Glucose in COPD Patients
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Imperial College London

 
A pilot, randomised, double-blind, placebo-controlled, cross-over study of 
metformin to reduce airway glucose in chronic obstructive pulmonary 
disease (COPD) 
 
 
 
 
 
SHORT TRIAL TITLE 
A pilot study of metformin to reduce airway glucose in COPD 
 
FULL/LONG TITLE OF THE TRIAL 
A pilot, randomised, double-blind, placebo-controlled, cross-over study of metformin to reduce airway 
glucose in chronic obstructive pulmonary disease (COPD) 
 
ACRONYM 
Metformin and Airway Glucose In COPD (MAGIC) 
 
 
PROTOCOL VERSION NUMBER AND DATE 
Version 4. 03/08/2022 
 
RESEARCH REFERENCE NUMBERS 
IRAS Number: 
247421 
EudraCT Number: 
2018-001755-12 
ISRCTN Number / Clinical 
trials.gov Number: 
TBC 
SPONSORS Number: 
FUNDERS Number: 
P74536 

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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
GCP guidelines, the Sponsor’s (and any other relevant) SOPs, and other regulatory requirements as 
amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor 
I also confirm that I will make the findings of the trial publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the trial will be given; and that any discrepancies and serious breaches of GCP from the 
trial as planned in this protocol will be explained. 
 
 
For and on behalf of the Trial Sponsor: 
Signature: 
...................................................................................................... 
Name (please print): 
...................................................................................................... 
Position: 
...................................................................................................... 
 
Chief Investigator: 
Signature: 
...................................................................................................... 
Name: (please print): 
 
Sebastian Johnston  
 
(Optional) Statistician: 
Signature: 
...................................................................................................... 
Name: (please print): 
...................................................................................................... 
 
 
Date: 
....../....../...... 
 
 
 
 
 
 
 
Date: 
....../....../...... 

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Position: 
...................................................................................................... 
 
KEY TRIAL CONTACTS 
 
 
Chief Investigator 
Professor Sebastian Johnston 
+44 20 7594 3764 
s.johnston@imperial.ac.uk 
Trial Co-ordinator 
Professor Sebastian Johnston 
+44 20 7594 3764, 
s.johnston@imperial.ac.uk 
Sponsor 
Nilabhra Dutta 
Clinical Trials Manager 
Room 221 
Level 2, Medical School Building 
Norfolk Place 
London W2 1PG 
020759 41862 
ilyas.ali@imperial.ac.uk 
Joint-sponsor(s)/co-sponsor(s) 
Funder(s) 
Paul Craven 
NIHR Imperial BRC 
Norfolk Place, St Mary's Campus 
South Wharf Road 
London W2 1NY 
p.craven@imperial.ac.uk 
Clinical Trials Unit 
Amanda Bravery 
Development Team Leader 
Imperial Clinical Trials Unit 
School of Public Health 
Imperial College London 
Stadium House, 68 Wood Lane 
London,W12 7RH 
Mobile: 07872850162 (or College extension 50162) 
a.bravery@imperial.ac.uk 
Key Protocol Contributors 
Dr J Tregoning 
Statistician 
Dr Les Huson 
Honorary Lecturer in Medical Statistics 
Centre for Pharmacology and Therapeutics 
Division of Experimental Medicine 
l.huson@imperial.ac.uk 
Trials Pharmacist 
Committees 
N/A 

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i. LIST of CONTENTS 
 
GENERAL INFORMATION 
Page No. 
TITLE PAGE 
1 
RESEARCH REFERENCE NUMBERS 
1 
SIGNATURE PAGE 
2 
KEY TRIAL CONTACTS 
3 
i. LIST of CONTENTS 
4 
ii. LIST OF ABBREVIATIONS 
5 
iii. TRIAL SUMMARY 
7 
iv. FUNDING 
8 
v. ROLE OF SPONSOR AND FUNDER 
8 
vi. ROLES & RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES, GROUPS 
AND INDIVIDUALS 
8 
vii, PROTOCOL CONTRIBUTERS 
8 
viii. KEYWORDS 
8 
ix. TRIAL FLOW CHART 
9 
SECTION 
1. BACKGROUND 
10 
2. RATIONALE 
10 
3. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
12 
4. TRIAL DESIGN 
14 
5. TRIAL SETTING 
15 
6. PARTICIPANT ELIGIBILITY CRITERIA 
15 
7. TRIAL PROCEDURES 
15 
8. TRIAL TREATMENTS 
18 
9. PHARMACOVIGILANCE 
20 
10. STATISTICS AND DATA ANALYSIS 
24 
11. DATA MANAGEMENT 
25 
12. MONITORING, AUDIT & INSPECTION 
26 
13 ETHICAL AND REGULATORY CONSIDERATIONS 
26 
14. DISSEMINATION POLICY 
28 
15. REFERENCES 
29 
16. APPENDICIES 
39 

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ii. LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CI 
Chief Investigator 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
CTU 
Clinical Trials Unit 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
European Commission 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical 
requirements for registration of pharmaceuticals for human 
use 
ICTU 
Imperial Clinical Trials Unit 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File (This forms part of the TMF) 
ISRCTN 
International Standard Randomised Controlled Trials 
Number 
MA 
Marketing Authorisation 

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MHRA 
Medicines and Healthcare products Regulatory Agency 
MS 
Member State 
NHS R&D 
National Health Service Research & Development 
NIMP 
Non-Investigational Medicinal Product 
PI 
Principal Investigator 
PIC 
Participant Identification Centre 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAM 
Synthetic Absorption Matrix 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
SmPC 
Summary of Product Characteristics 
SSI 
Site Specific Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 

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iii. TRIAL SUMMARY 
 
Trial Title 
A pilot, randomised, double-blind, placebo-controlled, cross- 
over study of metformin to reduce airway glucose in chronic 
obstructive pulmonary disease (COPD) 
Internal ref. no. (or short title) 
A pilot study of metformin to reduce airway glucose in COPD 
Clinical Phase 
Exploratory Phase II pilot study 
Trial Design 
Randomised, double-blind, placebo-controlled, cross-over 
Trial Participants 
Chronic obstructive pulmonary disease (COPD) patients 
Planned Sample Size 
40 subjects 
Treatment duration 
3 months one study arm, 2 weeks wash out, 3 months in 
other study arm 
Follow up duration 
6.5 months 
Planned Trial Period 
24 months 
Objectives 
Outcome Measures 
Primary 
Effect of metformin on airway 
glucose 
Sputum glucose after 3 
months treatment with 
metformin 
Secondary 
Effects of metformin on: 
1. Glucose levels in the nose 
2. Bacterial infection 
3. Inflammation in the lung 
4. COPD exacerbations 
5. Quality of life and 
symptoms 
6. Lung function 
1. Glucose levels in nasal 
SAM strips 
2. Bacterial load in sputum 
3. Inflammatory markers in 
sputum 
4. Number of COPD 
exacerbations 
5. Quality of life and symptom 
scores 
6. Spirometry 
Investigational Medicinal Product(s) 
Metformin 
Formulation, Dose, Route of 
Administration 
1000mg bd, po 

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iv. FUNDING AND SUPPORT IN KIND 
 
FUNDER(S) 
(Names and contact details of ALL organisations 
providing funding and/or support in kind for this 
trial) 
FINANCIAL AND NON FINANCIALSUPPORT 
GIVEN 
NIHR Imperial Biomedical Research Centre 
(BRC) 
£ 173,511 
 
 
 
v. ROLE OF TRIAL SPONSOR AND FUNDER 
Imperial College is the Trial Sponsor responsible for the initiation and management of the trial. The 
funder had no input into the trial design, conduct, data analysis and interpretation, manuscript writing, 
and dissemination of results 
 
vi. ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITEES/GROUPS & 
INDIVIDUALS 
 
vii. Protocol contributors 
The protocol was written by Dr Patrick Mallia, Dr J Tregoning and Professor Sebastian Johnston. 
 
 
 
viii. KEY WORDS: 
COPD, lung glucose, metformin, pilot study, cross-over trial 

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Placebo 
Washout 
period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ix. TRIAL FLOW CHART 
Subjects screened 
Ineligible 
subjects 
Suitable subjects 
IMP 
Placebo 
Monthly 
Washout 
period 
Monthly 
 
 
 
Crossover 
to other 
arm 
IMP 
Monthly 
Monthly 
Monthly 
Monthly 
Monthly 
Monthly 
Monthly 
Monthly 
Monthly 
Monthly 
Completion of study 

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1 
BACKGROUND 
Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death worldwide and 
continues to increase in prevalence (1). Lung infection plays a major role in disease progression and 
acute exacerbations. Bacterial infection is detected in 30-40% of stable COPD patients and is associated 
with disease progression, airway inflammation, impaired quality of life, more symptoms and frequent 
exacerbations (2). COPD patients frequently experience acute exacerbations that are associated with 
enormous morbidity, mortality and frequent hospitalisation, and bacteria are detected in 50-60% of 
exacerbations (2). Use of antibiotics to treat COPD exacerbations contributes to the development of 
antibiotic resistance. Therefore there is a clear unmet medical need to develop antibiotic-independent 
approaches to reduce bacterial infection in COPD. This has the potential to improve outcomes in COPD 
and reduce exacerbations. Glucose concentrations in the lungs are increased in COPD patients and 
linked to bacterial infection (3). This suggests that reducing airway glucose may be a promising potential 
therapeutic strategy 
 
 
2 
RATIONALE 
COPD affects 1.2 million people in the UK, costing the NHS >£800 million annually. COPD patients are 
more susceptible to both chronic and acute bacterial infections. Patients with chronic lung bacterial 
infection have worse quality of life, faster disease progression, more symptoms and frequent 
exacerbations. Acute respiratory infections are the main cause of acute COPD exacerbations which 
cause COPD patients to become acutely unwell and often result in hospitalisation, especially in the 
winter. Bacteria are detected in 50-60% of COPD exacerbations. Antibiotics are frequently used to treat 
COPD exacerbations and this contributes to the development of antibiotic resistance. Therefore any 
intervention that prevents or reduces bacterial infection in COPD, especially if it is not an antibiotic, will 
have major benefits for COPD patients, the NHS and for society as a whole. 
It is likely that there are many reasons why COPD patients are more susceptible to bacterial infections. 
From experimental work we have carried out we believe that one of the reasons is high glucose 
concentrations in the lung (3). In healthy lungs glucose levels are kept low and this is probably to inhibit 
bacterial growth by depriving them of an essential nutrient. In animal studies if levels of glucose in the 
lung are high, bacterial lung infection is more common (4). We measured lung glucose concentrations 
in COPD patients and found that they are higher compared with people without COPD. 
COPD patients with higher levels of glucose also had more bacteria in their lungs and sputum samples 
from COPD patients with higher glucose concentrations supported greater bacterial growth (3). 

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Therefore this study was the first to link elevated glucose in the lung to bacterial infection in COPD. 
Therefore reducing airway glucose has the potential to inhibit bacterial growth in COPD patients. One 
potential approach is to use the anti-diabetic drug metformin. In animal studies we have demonstrated 
that metformin decreases airway glucose and bacterial colonisation (4). The aim of the proposed study 
is to investigate whether metformin can achieve the same effects in COPD patients. Metformin is safe, 
cheap, does not cause hypoglycaemia and has been extensively used in COPD patients with diabetes 
with an excellent safety record (5). The primary aim of this study will be to evaluate the effects of 
metformin on lung glucose in COPD patients. If the study successfully demonstrates that metformin 
reduces airway glucose it will provide the data needed to justify a clinical trial of metformin with 
exacerbations as the primary outcome. 
 
2.1 
Assessment and management of risk 
Risks related to metformin 
The side effects of metformin are mainly gastrointestinal. The relevant summary of product 
characteristics (SmPC) lists gastrointestinal disorders, such as nausea, vomiting, diarrhoea, abdominal 
pain and loss of appetite, as very common (frequency >1/10). It states that these side effects ‘occur 
most frequently during initiation of therapy and resolve spontaneously in most cases.’ Taste disturbance 
is listed as a common side effect (frequency >1/100). All other side effects are described as very rare 
(<1/10,000) or not known (cannot be estimated from available data). In accordance with the SmPC, to 
minimise gastrointestinal effects as far as possible, the study tablets will be administered after meals, 
and the dose will be escalated gradually to the target dose. 
 
Hypoglycaemia: 
Metformin does not induce low blood sugar levels (hypoglycaemia) when used as the sole glucose- 
lowering therapy in diabetic patients. It does not exert a hypoglycaemic action in non-diabetic patients 
unless taken in overdose. Even in the setting of overdose, hypoglycaemia has not been seen with 
metformin doses up to 85g. As diabetes is an exclusion criterion, the use of other oral glucose-lowering 
agents will not be permitted in this study. 
Although not listed in the SmPC, it is suggested that there may be a risk of hypoglycaemia if metformin 
is administered in the setting of malnutrition, inadequate caloric intake, or excessive alcohol 
consumption. Therefore these will be exclusion criteria in this study. 

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Lactic acidosis: 
A predecessor of metformin - phenformin - has been associated with lactic acidosis. However a 
systematic review published in 2010 evaluated the risk for lactic acidosis in type 2 diabetic patients 
taking metformin and showed no cases of fatal or nonfatal lactic acidosis in 347 prospective trials and 
cohort studies with more than 70,490 patient-years of metformin use. The authors concluded that there 
is no evidence that metformin is associated with an increased risk of lactic acidosis (6). 
 
Metformin and COPD 
Metformin is routinely used in COPD patients who also have diabetes. There are 3 studies of metformin 
use in COPD patients and serious adverse effects were not reported. In fact these studies found that 
COPD patients taking metformin had less breathlessness, less exacerbations, less hospitalisations and 
longer survival (5, 7, 8). A systematic review and meta-analysis of the adverse effects of metformin in 
polycystic ovarian disease (PCOS) also found that metformin was safe and well-tolerated (9). Therefore 
from the available studies metformin has been reported safe in COPD (and may actually have beneficial 
effects) and in non-diabetic patients with PCOS. 
 
Risks related to study procedures 
Sputum induction carries a small risk of bronchoconstriction. We have performed sputum inductions in 
COPD patients for >15 years and we have a well-established protocol to minimise the risk of 
bronchoconstriction and detect immediately if it occurs. Using this protocol we have carried out >350 
inductions with no adverse events, including in patients with severe COPD and in COPD patients during 
acute exacerbations 
 
This trial is categorised as: 
• Type B (somewhat higher than the risk of standard medical care). As the study participants will 
be taking and additional medication to their usual medical care there is an increased risk of adverse 
effects. However as the medication is licensed and has been extensively used in this population group 
with minimal adverse effects (and possibly beneficial effects – see references 5, 7 and 8) this study is 
not Type C (Markedly higher the risk of standard medical care). 

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3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
3.1 
Primary objective 
To determine the effect of metformin on the glucose in sputum in COPD patients after 3 months 
treatment with metformin. 
 
3.2 
Secondary objectives 
Secondary objectives will be to determine the effect of metformin on: 
1) Nasal glucose 
2) Bacterial infection 
3) Inflammatory markers in sputum 
4) COPD exacerbations 
5) Quality of life and symptoms 
6) Lung function 
 
 
3.3 
Outcome measures/endpoints 
3.4 
Primary endpoint/outcome 
The median concentration of glucose in sputum in COPD patients after 3 months treatment with 
metformin compared with 3 months of placebo. 
 
3.5 
Secondary endpoints/outcomes 
These will also be assessed in COPD patients after 3 months treatment with metformin compared with 
placebo. 
1) Median glucose concentration measured in nasal SAM strips 
2) Bacterial infection (sputum semi-quantitative culture) 
3) Inflammatory markers measured in sputum 
4) Number of COPD exacerbations 
5) Quality of life/symptom scores 
6) Lung function measured using spirometry 
 
 
3.6 
Exploratory endpoints/outcomes 
Nil 

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3.7 
Table of endpoints/outcomes 
 
Objectives 
Outcome Measures 
Timepoint(s) of evaluation 
of this outcome measure (if 
applicable) 
Primary Objective 
To determine the effect of 
metformin on sputum glucose in 
COPD patients 
The 
median 
concentration 
of 
glucose in sputum in COPD patients 
after 3 months treatment with 
metformin compared with placebo. 
3 months 
Secondary Objectives 
To determine the effect of 
metformin on: 
1) Nasal glucose 
2) Bacterial infection 
3) Inflammatory markers in 
sputum 
4) COPD exacerbations 
5) Quality 
of 
life 
and 
symptoms 
6) Lung function 
1) Median 
glucose 
concentration measured in 
nasal SAM strips 
2) Bacterial infection (sputum 
semi-quantitative culture) 
3) Inflammatory 
markers 
measured in sputum 
4) Number 
of 
COPD 
exacerbations 
5) Quality 
of 
life/symptom 
scores 
6) Lung 
function 
measured 
using spirometry 
3 months 
 
 
4 
TRIAL DESIGN 
The proposed study will be a randomised, double-blinded, placebo-controlled, cross-over study of 
metformin in patients between the ages of 40 and 75 with a confirmed diagnosis of COPD. It will be an 
exploratory pilot trial, to gather preliminary information on the effects of metformin on sputum glucose 
and the feasibility of conducting a full-scale trial. 
All subjects will have clinical assessments and blood, airway samples (nasal SAM and sputum) collected 
at baseline prior to the treatment phase. Clinical assessments will include lung function (FEV1 and FVC), 
quality of life and symptom questionnaires (St George’s Respiratory Questionnaire, COPD assessment 
test). Subjects will then either be commenced on metformin or placebo for a period of 3 months and 
blood, sputum and nasal samples collected at monthly intervals. Following a 2 week washout period the 
subjects will crossover to the other study arm for another 3 months and repeat samples collected. 
 
Primary Outcome 
The primary outcome will be sputum glucose measured using an enzymatic assay (AmplexRed® – 
ThermoFisher) after 3 months treatment with metformin. There is currently no data on which to base a 
power calculation and therefore this pilot study will assess what the size of any effect of metformin is in 
COPD subjects and thereby provide data that can be used to power any future, larger clinical trials. 

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5 
TRIAL SETTING 
Imperial College Healthcare NHS Trust, St Mary’s Hospital, London and Imperial College London 
 
 
 
6 
PARTICIPANT ELIGIBILITY CRITERIA 
 
The trial population will be patients with a diagnosis of COPD who fulfil the inclusion/exclusion criteria 
outlined below 
6.1 
Inclusion criteria 
Age 40-85 years 
A clinical diagnosis of COPD confirmed with spirometry (Post-bronchodilator FEV1/FVC <70%) 
A smoking history of at least 15 pack years 
Absence of infection for at least 8 weeks prior to study entry 
No use of antibiotics and oral corticosteroids at least 8 weeks prior to study entry 
Able to understand and consent to the study procedures 
 
6.2 
Exclusion criteria 
Diagnosis of diabetes irrespective of treatment 
Diabetes diagnosed on screening bloods 
History of hepatic/renal impairment or hepatic/renal impairment diagnosed on screening bloods 
Excessive alcohol intake (>21 units/week in males and >14 units in females) 
BMI < 18.5kg/m2 
Taking metformin irrespective of indication 
History of allergy or hypersensitivity to metformin or hypersensitivity or intolerance to any of the placebo 
compounds 
Pregnancy or breastfeeding 
Unable to provide informed consent 
Any contraindication for Metformin treatment as detailed in Metformin SmPC including: 
Acute conditions with the potential to alter renal function such as dehydration, severe infection, shock 
Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent 
myocardial infarction, shock 
Any type of acute metabolic acidosis 

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7 
TRIAL PROCEDURES 
All subjects will have clinical assessments and blood, airway samples (nasal SAM and sputum) collected 
at baseline prior to the treatment phase. Clinical assessments will include lung function (FEV1 and FVC), 
quality of life and symptom questionnaires (St George’s Respiratory Questionnaire, COPD assessment 
test). Women of childbearing potential will only be included after a confirmed menstrual period and a 
negative highly sensitive urine pregnancy test. Subjects will then either be commenced on metformin or 
placebo for a period of 3 months and blood, sputum and nasal samples collected at monthly intervals. 
Following a 2 week washout period the subjects will crossover to the other study arm for another 3 
months and repeat samples collected. 
7.1 
Recruitment 
The study will be carried out in conjunction with the clinical team at Imperial College Healthcare NHS 
Trust. The PI is part of this team. Potential participants will be identified from COPD patients attending 
the clinical service. The applicant will identify potential participants. 
 
7.1.1 Participant identification 
Potential participants will be identified from COPD patients attending the clinical service. The PI who is 
part of the normal clinical team will identify potential participants and confirm eligibility. 
 
7.1.2 
Screening 
A clinical diagnosis of COPD 
 
7.1.3 
Payment 
A payment of £50 plus travel expense will be offered as compensation for the participants’ time. 
 
 
7.2 Consent 
The PI will obtain informed consent from all participants. Potential participants will be provided with 
written information if they express an interest in participating in the study and given time to read this 
and discuss any questions that arise from this prior to providing informed consent. We will not recruit 
participants who have difficulties in adequately understanding written or verbal information in English. 
 
7.2.1 Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary studies, if applicable 

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Samples collected during the course of the study will be used for pre-specified analyses and any unused 
samples will be stored in an ethically approved research tissue bank for future specified or unspecified 
research. Participants will be asked for consent for use in future research related to the clinical condition 
under trial and may opt out but still participate in the main trial. 
 
7.3 
The randomisation scheme 
Simple randomisation 
 
7.3.1 Method of implementing the randomisation/allocation sequence 
The randomisation will be carried out using INFORM. 
 
7.4 
Blinding 
The trial participants, care providers and outcome assessors will all be blinded. Randomisation will be the 
responsibility of the trial statistician and the medication will be dispensed in a blinded fashion from the 
hospital pharmacy. The trial medication will be over encapsulated. The final unblinding of all trial participants 
will occur at the end of the study after a close out visit and the creation of a locked analysis data set. 
 
7.5 
Emergency Unblinding 
The trial code will only be broken for valid medical or safety reasons e.g. in the case of a serious adverse 
event where it is necessary for the investigator or treating health care professional to know which treatment 
the patient is receiving before the participant can be treated. This will be will be carried out using INFORM. 
 
7.6 
Baseline data 
Baseline data collected will include: 
1) Demographic data 
2) Blood tests (full blood count, blood glucose, renal function, liver function tests) 
3) Lung function 
4) Sputum samples (either spontaneous or induced) 
5) Nasal SAM strips 
6) Quality of life/symptom scores 
 
7.7 
Trial assessments 

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After baseline assessment, participants will either be commenced on metformin or placebo for 3 months 
during which time the participants will have monthly visits. At these visits the following assessments will 
be carried out: 
1) Collection of data regarding exacerbations and adverse events 
2) Physical examination 
3) Blood tests (renal function, liver function tests) 
4) Lung function 
5) Sputum samples collected (either spontaneous or induced) 
6) Nasal SAM strips 
7) Quality of life/symptom scores 
Following a 2 week washout period the subjects will crossover to the other study arm for another 3 
months and follow the same study protocol. 
 
7.8 
Long term follow-up assessments 
N/A 
 
7.9 
Qualitative assessments 
N/A 
 
7.10 
Withdrawal criteria 
Participants will be withdrawn from the trial if: 
1) They no longer wish to continue in the study and withdraw consent 
2) They experience a serious adverse event 
3) They experience an adverse event not related to the study medication that requires them to be 
withdrawn (e.g. they develop renal or hepatic impairment). 
 
7.11 
Storage and analysis of clinical samples 
The samples will all be processed and stored in the laboratories in the Department of Respiratory Medicine 
at Imperial College, St Mary’s campus according to previously established laboratory protocols. 
 
7.12 
End of trial 
The end of the trial will be the date of the last visit of the last patient undergoing the trial. 
 
 
8 
TRIAL TREATMENTS 

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8.1 
Name and description of investigational medicinal product(s) 
The IMP is metformin. The IMP and placebo will be provided by Sharp Clinical Services Ltd (MHRA 
authorisation number 10284). Metformin and placebo will be packaged in an identical manner. A unique 
pack ID will be used to identify each pack and its content. 
 
8.2 
Regulatory status of the drug 
The IMP has a MA in the UK. Repackaging and trial labelling for the trial will be carried out by Sharp 
Clinical Services Ltd (MHRA authorisation number 10284). 
 
8.3 
Product Characteristics 
The SmPC for metformin will be provided. 
 
8.4 
Drug storage and supply 
The IMP will be provided by the supplier (Sharp Clinical Services Ltd) and will be stored at and dispensed 
from the inpatient pharmacy at St Mary’s Hospital. Each subject will be dispensed 1 month’s supply when 
they attend for their baseline visit according to their randomisation code on INFORM. They will then be 
dispensed 1 month’s supply at each of their follow-up monthly visits. Any remaining medication at the 
end of the study will be collected and counted at the pharmacy who will also be responsible for its 
destruction. 
 
8.5 
Preparation and labelling of Investigational Medicinal Product 
The IMP will be prepared and labelled by the supplier. It will be packaged in containers each with 1 
month’s supply of medication. 
 
8.6 
Dosage schedules 
The IMP will be commenced at a dose of 500mg twice daily. After 1 week it will be increased to 1000mg 
twice daily. 
 
8.7 
Dosage modifications 
N/A 
 
8.8 
Known drug reactions and interaction with other therapies 
Concomitant use not recommended: 

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Alcohol. Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases 
of fasting, malnutrition or hepatic impairment. Therefore any potential participants with excessive alcohol 
intake (>21 units/week in males and >14 units in females) will not be recruited. 
Iodinated contrast agents. Metformin should be discontinued prior to or at the time of the imaging 
procedure and not restarted until at least 48 hours, provided that renal function has been re-evaluated 
and found to be stable. 
 
8.9 
Concomitant 
medication 
Combinations requiring precautions for use: 
Some medicinal products can adversely affect renal function which may increase the risk of lactic 
acidosis, e.g. NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, 
angiotension II receptor antagonists and diuretics, especially loop diuretics. 
Organic cation transporters (OCTs) are active transporters of metformin into the hepatocyte. Drugs that 
inhibit or induce OCTs have the potential to interfere with the transport of metformin and affect both 
plasma and intracellular concentrations of metformin. However only a small number of clinically relevant 
DDIs with metformin have been reported including cimetidine, dolutegravir, pyrimethamine, rifampicin, 
trimethoprim and verapamil. 
If any such products are started during the study, close monitoring of renal function will be carried out. 
 
 
8.10 
Trial restrictions 
Women of childbearing potential (WOCBP) are defined according to the Clinical Trial Facilitation Group 
document (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/ Working_Groups 
/CTFG/2014_09_HMA_CTFG_Contraception.pdf). 
A woman is considered of childbearing potential following menarche and until becoming post- 
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 
months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient. 
 
WOCPB are required to use adequate contraception for the duration of the trial. This includes: 
1) Intrauterine Device (IUD) 
2) Hormonal based contraception (pill, contraceptive injection etc.) 

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3) Double Barrier contraception (condom and occlusive cap e.g. diaphragm or cervical cap with 
spermicide) 
4) True abstinence. Sexual abstinence is defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject 
 
8.11 
Assessment of compliance with treatment 
Subjects will complete a diary card recording medication usage and return any unused medication that 
will be counted at the monthly visits. Percentage of noncompliance acceptable for a subject to 
continue in the trial is <80%. 
 
8.12 
Name and description of each Non-Investigational Medicinal Product (NIMP) 
N/A 
 
 
 
9 
PHARMACOVIGILANCE 
9.1 
Definitions 
 
Term 
Definition 
Adverse Event 
(AE) 
Any untoward medical occurrence in a participant to whom a medicinal product has 
been administered, including occurrences which are not necessarily caused by or 
related to that product. 
Adverse Reaction 
(AR) 
An untoward and unintended response in a participant to an IMP which is related to 
any dose administered to that participant. The phrase "response to an IMP" means 
that a causal relationship between a trial medication and an AE is at least a 
reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the 
Sponsor as having a reasonable suspected causal relationship to the trial medication 
qualify as adverse reactions. It is important to note that this is entirely separate to the 
known side effects listed in the SmPC. It is specifically a temporal relationship 
between taking the drug, the half-life, and the time of the event or any valid alternative 
etiology that would explain the event. 
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
 
results in death 
 
is life-threatening 
 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity 
 
consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they jeopardise 
the participant or require an intervention to prevent one of the above consequences. 

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NOTE: The term "life-threatening" in the definition of "serious" refers to an event in 
which the participant was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the reporting Investigator, 
believed with reasonable probability to be due to one of the trial treatments, based 
on the information provided. 
Suspected 
Unexpected 
Serious Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent with 
the information about the medicinal product in question set out in the reference safety 
information: 
 
9.2 
Operational definitions for (S)AEs 
As the IMP has a well-known and well established safety profile, new or unreported AEs and ARs are 
not expected in such a small trial. All AEs and ARs will be recorded. Acute exacerbations are expected 
to occur in COPD patients and therefore will not be recorded as (S)AEs or ((S)ARs). Breaking the blind 
will only take place where information about the participant’s trial treatment is clearly necessary for the 
appropriate medical management of the participant 
 
9.3 
Recording and reporting of SAEs, SARs AND SUSARs 
All SAEs / SAEs occurring from the time of written informed consent until 30 days post cessation 
of trial treatment must be recorded on the AE Form and emailed to the Sponsor 
(JRCO.CTIMP.TEAM@imperial.ac.uk) within 24 hours of the research staff becoming aware of 
the event. 
For each SAEs the following information will be collected: 
 
Full details in medical terms and case description 
 
Event duration (start and end dates, if applicable) 
 
Action taken 
 
Outcome 
 
Seriousness criteria 
 
Causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
 
Whether the event would be considered anticipated. 
Any change of condition or other follow-up information should be emailed to the Sponsor as soon 
as it is available or at least within 24 hours of the information becoming available. Events will be 
followed up until the event has resolved or a final outcome has been reached. 

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All ARs/SARs/SUSARs occurring from the time of start of trial treatment until 30 days post cessation of 
trial treatment must be recorded on the AE Form and emailed to the Sponsor within 24 hours of the 
research staff becoming aware of the event. 
For each AR/SAR/SUSAR the following information will be collected: 
 
Full details in medical terms and case description 
 
Event duration (start and end dates, if applicable) 
 
Action taken 
 
Outcome 
 
Seriousness criteria 
 
Causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
 
Whether the event would be considered anticipated. 
Any change of condition or other follow-up information will be emailed to the Sponsor as soon as 
it is available or at least within 24 hours of the information becoming available. Events will be 
followed up until the event has resolved or a final outcome has been reached. 
All SAEs assigned by the PI or delegate (or following central review) as both suspected to be related to 
IMP treatment and unexpected will be classified as SUSARs and will be subject to expedited reporting 
to the Medicines and Healthcare Products Regulatory Agency (MHRA). The CI/delegated team will 
inform the Sponsor, MHRA, the REC and Marketing Authorisation Holder (if not the sponsor) of SUSARs 
within the required expedited reporting timescales: fatal and life-threatening within 7 days of notification 
and non-life threatening within 15 days. 
 
9.4 
Responsibilities 
Chief Investigator (CI): 
1. 
Checking for AEs and ARs when participants attend for treatment / follow-up. 
2. 
Clinical oversight of the safety of patients participating in the trial, including an ongoing review 
of the risk / benefit. 
3. 
Using medical judgement in assigning the SAEs seriousness, causality and whether the event 
was anticipated (in line with the Reference Safety Information) where it has not been possible to 
obtain local medical assessment. 
4. 
Using medical judgement in assigning whether and event/reaction was anticipated or 
expectedness in line with the Reference Safety Information. 
5. 
Immediate review of all SUSARs. 
6. 
Review of specific SAEs and SARs in accordance with the trial risk assessment and protocol 
as detailed in the Trial Monitoring Plan. 

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7. 
Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System coding to all 
SAEs and SARs. 
8. 
Ensuring that all SAEs are recorded and reported to the sponsor within 24 hours of becoming 
aware of the event and provide further follow-up information as soon as available. 
9. 
Ensuring that AEs and ARs are recorded and reported to the sponsor in line with the 
requirements of the protocol. 
10. 
Expedited reporting of SUSARs to the MHRA and REC within required timelines. 
11. 
Notifying Investigators of SUSARs that occur within the trial. 
12. 
Checking for and notifying PIs of updates to the Reference Safety Information for the trial. 
Sponsor: 
1. 
Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs according to 
the trial protocol onto a database. 
2. 
The unblinding of a participant for the purpose of expedited SUSAR reporting. 
 
 
9.5 
Notification of deaths 
All deaths, including deaths deemed unrelated to the IMP, if they occur earlier than expected will be 
reported to the sponsor”. 
 
9.6 
Pregnancy reporting 
All pregnancies within the trial (either the trial participant or the participant’s partner, with participants 
consent) should be reported to the Chief Investigator and the Sponsor using the relevant Pregnancy 
Reporting Form within 24 hours of notification 
Pregnancy is not considered an AE unless a negative or consequential outcome is recorded for the 
mother or child/foetus. If the outcome meets the serious criteria, this would be considered an SAE 
 
9.7 
Overdose 
An overdose will be defined as taking more than the study dose of medication as reported by the patient 
or from pill counts. It will be recorded as an AE or SAE. The CI will decide whether the patient will be 
withdrawn from the trial 
 
9.8 
Reporting urgent safety measures 
If any urgent safety measures are taken the CI/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. 

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9.9 
The type and duration of the follow-up of participants after adverse reactions. 
Any SUSAR will be reported to the Sponsor irrespective of how long after IMP administration the reaction 
has occurred until resolved. 
 
9.10 
Development safety update reports 
‘Reference Safety Information’ in this study is section 4.8 of Metformin SmPC. The CI will provide (in 
addition to the expedited reporting above) DSURs once a year throughout the clinical trial, or as 
necessary, to the Competent Authority (MHRA in the UK), where relevant the Research Ethics 
Committee and the sponsor. The report will be submitted within 60 days of the Developmental 
International Birth Date (DIBD) of the trial each year until the trial is declared ended 
 
 
10 
STATISTICS AND DATA ANALYSIS 
10.1 
Sample size calculation 
The primary outcome will be change in sputum glucose from baseline after treatment with metformin, 
measured using an enzymatic assay (AmplexRed®). The median glucose concentration in COPD subjects 
measured in our previous study was 1,007 μM (SD 733μM). Metformin reduced airway glucose by c.30% 
in studies carried out in mice. Therefore to detect a similar effect in humans would require 30 subjects with 
90% power at 5% significance. We aim to recruit 40 subjects to account for possible withdrawals. 
 
10.2 
Planned recruitment rate 
The target number of participants will be 40 that will be recruited over 12 months, therefore our target 
recruitment rate will be 3 – 4 participants per month. 
 
10.3 
Statistical analysis plan 
10.3.1 Summary of baseline data and flow of patients 
The variables to be used to assess baseline comparability of the randomised groups will include: 
1) Age 
2) Sex 
3) Lung function 
4) Number of exacerbations in the previous year 
5) GOLD COPD category 
A consort flow diagram will be produced 

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10.3.2 Primary outcome analysis 
The primary endpoint (median sputum glucose in treated versus non-treated participants) will be 
analysed using a Mann-Whitney test. The post-treatment sputum glucose will also be compared with 
baseline glucose using Wilcoxon matched-pairs test. Similar methods will be used to analyse the 
secondary endpoints. 
 
10.3.3 Secondary outcome analysis 
Same as for primary outcome 
 
 
10.7 
Participant population 
The participant populations whose data will be subjected to the trial analysis will be the protocol- 
compliant population: Any participant who was randomised and received the protocol required trial drug 
exposure and required protocol processing 
 
10.8 Procedure(s) to account for missing or spurious data 
As the study is a small single-centre pilot study with a single primary outcome measure we do not 
expect missing or spurious data. 
 
 
 
11 
DATA MANAGEMENT 
11.1 
Data collection tools and source document identification 
All patient data will be kept on a paper CRF and electronic CRF. 
 
 
11.2 
Data handling and record keeping 
CRFs will be kept in a dedicated facility in ICCRU. Each participant will be assigned a unique participant 
identification code that allows identification of all the data reported for each participant. 
 
11.3 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections in line with participant 
consent. 

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11.4 
Archiving 
Archiving will be authorised by the Sponsor following submission of the end of trial report. All essential 
documents will be archived for a minimum of 10 years after completion of trial and destruction of 
essential documents will require authorisation from the Sponsor. 
 
 
12 
MONITORING, AUDIT & INSPECTION 
The JRCO via an assigned monitor will establish a monitoring plan which will take in consideration a 
risk-based approach to determine the monitoring schedule required. 
 
 
13 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 
Research Ethics Committee (REC) review & reports 
Before the start of the trial, approval will be sought from a REC for the trial protocol, informed consent 
forms and other relevant documents. Substantial amendments that require review by REC will not be 
implemented until the REC grants a favourable opinion for the trial. All correspondence with the REC 
will be retained in the Trial Master File/Investigator Site File. 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 CI will notify the REC of the end of the trial and if the 
trial is ended prematurely, the CI will notify the REC, including the reasons for the premature termination. 
Within one year after the end of the trial, the Chief Investigator will submit a final report with the results, 
including any publications/abstracts, to the REC and the EU trials register. 
 
13.2 
Peer review 
The trial was peer reviewed by the funder (Imperial BRC) 
 
 
13.4 
Regulatory Compliance 
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from the MHRA and 
Favourable REC opinion. The protocol and trial conduct will comply with the Medicines for Human Use 
(Clinical Trials) Regulations 2004 and any relevant amendments. The CI will ensure that appropriate 
approvals from participating organisations are in place. 

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13.5 
Protocol compliance 
Prospective, planned deviations or waivers to the protocol will not be allowed. Accidental protocol 
deviations will be adequately documented on the relevant forms and reported to the CI and Sponsor 
immediately. 
 
13.6 
Notification of Serious Breaches to GCP and/or the protocol 
The sponsor will be notified immediately of any case where a serious breach occurs during the trial 
conduct phase. The sponsor will notify the licensing authority in writing of any serious breach of: 
The conditions and principles of GCP in connection with the trial; or 
The protocol relating to that trial, as amended from time to time, within 7 days of becoming aware of that 
breach. 
 
13.7 
Data protection and patient confidentiality 
All investigators and trial site staff will comply with the requirements of the UK Data Protection Act 2018 
with regards to the collection, storage, processing and disclosure of personal information and will uphold 
the Act’s core principles. 
Personal information collected will be kept in a secure location in a dedicated facility in ICCRU as stated 
previously. 
Each participant will have a unique, coded, depersonalised identification number. 
All clinical samples will be identified with this number. 
 
13.8 
Financial and other competing interests for the chief investigator, PIs at each site and 
committee members for the overall trial management 
The investigators have no competing interests that might influence trial design, conduct or reporting. 
 
 
13.9 
Indemnity 
Imperial College London holds negligent harm and non-negligent harm insurance policies which apply to 
this study. 

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13.10 Amendments 
If we wish to make a substantial amendment to the CTA or the documents that supported the original 
application for the CTA, we will submit a valid notice of amendment to the licencing authority (MHRA) for 
consideration. If we wish to make a substantial amendment to the REC application or the supporting 
documents, we will submit a valid notice of amendment to the REC for consideration. Amendments also 
need to be notified to the R&D office 
 
13.11 Post trial care 
On completion of the trial participants will revert to their usual standard of care that currently does not 
include metformin. 
 
13.12 Access to the final trial dataset 
The CI will have access to the final dataset. 
14 
DISSEMINIATION POLICY 
14.1 
Dissemination policy 
On completion of the trial, the data will be analysed and tabulated and a Final Trial Report prepared. 
The participating investigators will have rights to publish the trial data and the funding body will be 
acknowledged within the publications. Participants will be notified of the outcome of the trial, if they have 
requested this. 
 
14.2 
Authorship eligibility guidelines and any intended use of professional writers 
The investigators will be named as authors. No professional medical writers will be used. 

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15 
REFERENCES 
(1) Ferkol T, Schraufnagel D. The global burden of respiratory disease. Ann Am Thorac Soc. 2014 
Mar;11(3):404-6 
(2) Beasley V et al. Lung microbiology and exacerbations in COPD. International Journal of COPD 2012; 
7: 555-569 
(3) Mallia P et al. 2017. Role of airway glucose in bacterial infections in Chronic Obstructive Pulmonary 
Disease. Journal of Allergy and Clinical Immunology 2018 Sep;142(3):815-823.e6 
(4) Garnett JP, Baker EH, Naik S, Lindsay JA, Knight GM, Gill S, Tregoning JS, Baines DL. 2013. 
Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus 
load independently of effects on blood glucose. Thorax 68:835-845. 
(5) Hitchings AW et al. Safety of metformin in patients with COPD and type 2 diabetes mellitus. COPD. 
2015;12(2):126-31 
(6) Salpeter SR et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes 
mellitus. Cochrane Database Systematic Rev. 2010:CD002967. 
(7) Bishwakarma R et al. Metformin use and health care utilization in patients with coexisting COPD and 
diabetes mellitus. Int J COPD. 2018;13:793-800. 
(8) Sexton P et al. Respiratory effects of insulin sensitisation with metformin: a prospective observational 
study. COPD. 2014;11(2):133–142 
(9) Domecq JP et al. Adverse effects of the common treatments for polycystic ovary syndrome: a 
systematic review and meta-analysis. J Clin Endocrinol Metab. 2013 Dec;98(12):4646-54. 

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Risks associated with trial interventions 
A ≡ Comparable to the risk of standard medical care 
  B ≡ Somewhat higher than the risk of standard medical care 
C ≡ Markedly higher than the risk of standard medical care 
 
 
16. 
APPENDICIES 
16.1 
Appendix 1- Risk 
Metformin is a licensed medication that has been used extensively for many decades with a well 
described side effect and safety profile. Therefore in this study that is small, short-term and in which 
people at a higher risk of adverse effects will be excluded, no new, unexpected adverse effects are 
expected. Therefore category B is justified. 

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16.4 
Appendix 2 – Schedule of Procedures 
 
Procedures 
Visits 
Screening 
Baseline 
Treatment Phase 
 
Arm 1 
Arm 2 
 
1 
month 
2 
months 
3 
months 
Baseline 
1 
month 
2 
months 
3 
months 
Informed 
consent 
x 
Demographics 
x 
Medical history 
x 
Physical 
examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
Laboratory 
tests 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Eligibility 
assessment 
x 
Randomisation 
x 
Dispensing of 
trial drugs 
x 
x 
x 
x 
x 
x 
Compliance 
x 
x 
x 
x 
x 
x 
x 
x 
Blood test 
x 
x 
x 
x 
x 
x 
x 
x 
Sputum 
sample 
x 
x 
x 
x 
x 
x 
x 
x 
Nasal SAM 
x 
x 
x 
x 
x 
x 
x 
x 
Lung function 
x 
x 
x 
x 
x 
x 
x 
x 
SGRQ 
x 
x 
x 
x 
x 
x 
x 
x 
CAT 
x 
x 
x 
x 
x 
x 
Adverse event 
assessments 
x 
x 
x 
x 
x 

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16.6 
Appendix 3 – Amendment History 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
 
List details of all protocol amendments here whenever a new version of the protocol is produced. 
Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC 
committee or MHRA.