Clinical trial NCT02257177
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Galecto Biotech AB
Start date: 2014-09-01; Completion date: 2016-12-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be divided into 2 parts. Part 1 is a randomized, double-blind, single centre, placebo-controlled, single ascending dose (SAD) phase I study designed to assess the safety, tolerability, PK and PD (Pharmacodynamic) of TD139 in up to 36 healthy male subjects. Part 2 will be a randomized, double-blind, multi-centre, placebo-controlled, multiple dose expansion cohort, designed to assess the safety, tolerability, PK and PD of TD139 in up to 24 male subjects and female subjects of non child-bearing potential with IPF.

Detailed description:
Up to 6 cohorts of 6 subjects will be randomly assigned in a blinded fashion to receive either a single dose of TD139 or matching placebo via DPI (dry powder inhaler) in an ascending dose fashion.

A single cohort of up to 24 patients will be randomly assigned in a blinded fashion to receive a single dose of TD139 or placebo via DPI once daily for 14 days in a 2:1 TD139 to placebo ratio. The dose of TD139 selected will be based on data from Part 1 and on pre-clinical efficacy and safety data.

Arms: arm 1: 4 Healthy Subjects are administered a single dose of 0.15mg TD139 inhaled as a dry powder in a fasted state. Each cohort will include a dose leader volunteer to be dosed a day before the rest of the cohort, followed by the remaining 3 subjects who will be dosed approximately 24 hours later. arm 2: 4 Healthy Subjects are administered a single dose of 1.5mg TD139 inhaled as a dry powder in a fasted state. Each cohort will include a dose leader volunteer to be dosed a day before the rest of the cohort, followed by the remaining 3 subjects who will be dosed approximately 24 hours later. arm 3: 4 Healthy Subjects are administered a single dose of 3mg TD139 inhaled as a dry powder in a fasted state. Each cohort will include a dose leader volunteer to be dosed a day before the rest of the cohort, followed by the remaining 3 subjects who will be dosed approximately 24 hours later. arm 4: 4 Healthy Subjects are administered a single dose of 10mg TD139 inhaled as a dry powder in a fasted state. Each cohort will include a dose leader volunteer to be dosed a day before the rest of the cohort, followed by the remaining 3 subjects who will be dosed approximately 24 hours later. arm 5: 4 Healthy Subjects are administered a single dose of 20mg TD139 inhaled as a dry powder in a fasted state. Each cohort will include a dose leader volunteer to be dosed a day before the rest of the cohort, followed by the remaining 3 subjects who will be dosed approximately 24 hours later. arm 6: 4 Healthy Subjects are administered a single dose of 50mg TD139 inhaled as a dry powder in a fasted state. Each cohort will include a dose leader volunteer to be dosed a day before the rest of the cohort, followed by the remaining 3 subjects who will be dosed approximately 24 hours later. arm 7: 12 Healthy Subjects are administered placebo inhaled as a dry powder in a fasted state. Each cohort will include a dose leader volunteer to be dosed a day before the rest of the cohort, followed by the remaining 3 subjects who will be dosed approximately 24 hours later. arm 8: 5 Patients with IPF are administered a single dose of 0.3mg TD139 once daily for 14 days inhaled as a dry powder. arm 9: 5 Patients with IPF are administered a single dose of 3mg TD139 once daily for 14 days inhaled as a dry powder. arm 10: 5 Patients with IPF are administered a single dose of 10mg TD139 once daily for 14 days inhaled as a dry powder. arm 11: 9 Patients with IPF are administered placebo inhaled as a dry powder.
Interventions: intervention 1: Inhaled TD139 intervention 2: Placebo
Intervention descriptions: intervention 1: DPI Galectin-3 inhibitor intervention 2: DPI placebo

Protocol documents:
Prot_000.pdf: 
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STUDY PROTOCOL 
STUDY TITLE: 
A randomised, double-blind, multi centre, placebo-
controlled dose escalation study in healthy subjects 
investigating the safety, tolerability and pharmacokinetic 
properties of TD139, a galectin-3 inhibitor, followed by 
an expansion cohort treating subjects with idiopathic 
pulmonary fibrosis (IPF) 
STUDY NUMBER:
RD 676/25641 
SPONSOR NUMBER:
GB-HV-01 
EudraCT NUMBER: 
2014-001187-35 
INVESTIGATIONAL 
TD139 and matching placebo administered via dry
MEDICINAL PRODUCT: 
powder inhaler 
PLANNED STUDY DOSES: 
Part 1 (Single dose): 0.15mg, 1.5mg, 3mg, 10mg, 20mg and 
50mg
CHIEF INVESTIGATOR:
STUDY SPONSOR: 
Part 2 (Multiple doses): starting dose = 3mg 
Galecto Biotech AB  
Cobis Science Park 
Ole Maaloes Vej 3 
DK-2200 Copenhagen 
Denmark 
PROTOCOL FINALIZATION STATEMENT 
This protocol is not considered final unless accompanied by an approval letter from the Research 
Ethics Committees and Notice of Acceptance from the relevant Competent Authority. 
Protocol Prepared by: DF/OK 


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SIGNATURE PAGES 
1.1 
Sponsor Signature Page 
I declare that I have read and understood this Study Protocol.  I agree to abide by this 
protocol (subject to any amendments agreed in writing between the Sponsor and Chief 
Investigator).  Any changes in procedure will only be made if necessary to protect the safety, 
rights or welfare of the subjects. 
STUDY SPONSOR: 
Galecto Biotech AB  
Cobis Science Park, Ole Maaloes Vej 
3 DK-2200, Copenhagen 
Denmark 
 
Signature: 
Date: 
1.2 
Investigator Signature Page 
I declare that I have read and understood this Study Protocol.  I agree to abide by this 
protocol (subject to any amendments agreed in writing between the Sponsor and Chief 
Investigator).  Any changes in procedure will only be made if necessary to protect the safety, 
rights or welfare of the subjects. 
CHIEF INVESTIGATOR 
Royal Brompton 
Hospital Sydney Street 
London, SW3 6NP 
UK 
 
Signature: 
Date: 


SIMBEC 
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PRINCIPAL INVESTIGATOR: 
Edinburgh University Hospital 
47 Little France Crescent 
Edinburgh, EH16 4TJ 
UK 
ii' 
PRINCIPAL INVESTIGATOR: 
Royal Victoria Infirmary 
Queen Victoria Road 
Newcastle upon Tyne 
NE! 4LP 
UK 
ii' 
PRINCIPAL INVESTIGATOR: 
Royal Devon & Exeter Hospital 
Barrack Road, Exeter, Devon 
EX2 SOW, 
UK 
ii' 
Protocol Template: Version 15 (4 February 2014) 
Date: 
Signature: 
Date: 
Signature: 
Date: 
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Signature: 


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PRINCIPAL INVESTIGATOR: 
Simbec Research Limited 
Merthyr Tydfil 
CF48 4DR 
UK  
 
Signature:* 
Date:* 
* Part 1 of the study (healthy volunteers) has finished and a CSR has been finalised, so the PI at Simbec is no
longer required to have any involvement in the study.  The PI at Simbec has no responsibilities in terms of Part
2 of the study and will therefore not be required to sign off any protocol amendments that relate to this part of
the study.


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SYNOPSIS 
NAME OF COMPANY: Galecto Biotech AB 
NAME OF INVESTIGATIONAL MEDICINAL PRODUCT: 
TD139 and matching placebo via dry powder inhaler (DPI)
NAME OF ACTIVE INGREDIENT: 
TD139 (galectin-3 inhibitor) 
TITLE OF STUDY: 
A randomised, double-blind, multi centre, placebo-controlled dose escalation study in healthy subjects 
investigating the safety, tolerability and pharmacokinetic properties of TD139, a galectin-3 inhibitor, followed 
by an expansion cohort treating subjects with idiopathic pulmonary fibrosis (IPF).  
CHIEF INVESTIGATOR:  
PART 1 STUDY CENTRE: 
Simbec Research Ltd (Simbec) 
      Merthyr Tydfil, UK 
PART 2 STUDY CENTRES: 
Royal Brompton Hospital, London, UK  
Edinburgh University Hospital, Edinburgh, UK 
       Royal Victoria Infirmary, Newcastle, UK 
       Royal Devon and Exeter Hospital, UK 
CLINICAL PHASE: I/IIa 
OBJECTIVES: 
Primary objective 
To evaluate the safety and tolerability of single ascending doses of TD139 in healthy male subjects. 
To evaluate the safety and tolerability of multiple doses of TD139 in male and female subjects of non 
child-bearing potential with IPF. 
Secondary objective 
To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of TD139 when administered as a 
single dose to healthy male subjects.  
To evaluate the PK and PD of TD139 when administered in multiple doses to male and female subjects 
of non child-bearing potential with IPF.  
METHODOLOGY: 
This study will be divided into 2 parts. Part 1 is a randomised, double-blind, single centre, placebo-controlled, 
single ascending dose (SAD) phase I study designed to assess the safety, tolerability, PK and PD of TD139 in up 
to 36 healthy male subjects. Part 2 will be a randomised, double-blind, multi-centre, placebo-controlled, 
multiple dose expansion cohort, designed to assess the safety, tolerability, PK and PD of TD139 in up to 24 
male subjects and female subjects of non child-bearing potential with IPF. 
Part 1 of the study will take place in healthy male volunteers and will consist of up to 6 cohorts of 6 subjects. 
Within each cohort, 4 subjects will receive a single dose of TD139 and 2 subjects will receive a single dose of 
placebo. Each cohort will include a dose leader group of 2 volunteers (1 TD139 and 1 placebo) to be dosed a 
day before the rest of the cohort, followed by the remaining 4 subjects who will be dosed approximately 24 
hours later.  The remaining 4 subjects will be randomised such that one further volunteer receives placebo. 
The lowest dose of TD139 will be evaluated first (0.15 mg). Dose administration in the subsequent cohorts will 
only proceed after blinded safety and PK data for 3 days (48 hours post-dose) after dose administration from a 
minimum of 5 subjects in the preceding cohort have been reviewed by the Sponsor and Chief Investigator and 
are found to be satisfactory.  The study will be discontinued at any time if any unacceptable safety findings are 
identified. The maximum dose of TD139 will be 50 mg.  
Part 2 of the study will take place in male subjects and female subjects of non child-bearing potential with IPF. 


 
 
 
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This part of the study will include up to 24 IPF subjects, who will receive a single dose of TD139 or placebo via 
DPI once daily for 14 days (subjects will receive TD139 and placebo as per Table S1, page 12). Subjects will be 
studied in up to 3 multiple ascending dose cohorts.  Based on the safety and PK data from single doses up to 
10mg in Part 1, a starting dose of 3 mg has been selected for the first Cohort  in Part 2 (8 subjects, 5 TD139 and 
3 placebo). The dose escalation design of Part 2 is presented in Table S1. At each interim safety review 
meeting, the available blinded safety, BAL and PK data would be reviewed by the Sponsor and the 
Chief/Principal Investigator.  
There will be an interim review after Cohort 1 has been dosed to review the available data. Following a review 
of this data, if it is decided that it meets the dose escalation requirements then Cohort 2 (8 subjects, 5 TD139 and 
3 placebo) will receive the next dose level. An interim review would then take place after Cohort 2 has been 
dose to review the available data. Following a review of this data, if it is decided that it meets the dose 
escalation requirements then Cohort 3 (8 subjects, 5 TD139 and 3 placebo) will receive a third dose level 
(Outcome 1). If it is decided that the data in Cohort 2 does not meet the dose escalation requirements, a 4 further 
subjects would be dosed in Cohort 2 with the same dose level (3 TD139 and 1 placebo) (Outcome 2). 
After the interim review of Cohort 1 data, if it is decided that the dose escalation requirements have not been 
met, 4 further subjects would be dosed in Cohort 1 with 3mg (3 TD139 and 1 placebo). After the extra subjects 
have been dosed an interim review would then take place to review the data, before moving on to the next dose 
level in Cohort 2 (8 subjects, 5 TD139 and 3 placebo). An interim review would then take place after Cohort 2 
has been completed to review the available data. Following a review of this data, if it is decided that it meets the 
dose escalation requirements then no further subjects would be dosed (Outcome 3). If it is decided that the data 
in Cohort 2 does not meet the dose escalation requirements, a 4 further subjects would be dosed in Cohort 2 with 
the same dose level (3 TD139 and 1 placebo) (Outcome 4). 
The highest acceptable dose level in Part 1 of the study will not be exceeded in Part 2. Part 2 will be 
discontinued at any time if any unacceptable safety findings are identified (see Study Stopping Criteria). At the 
interim review meetings it may be decided it is not appropriate to escalate the dose. In this event the same dose, 
an intermediate dose or a lower dose may be given following discussion between the Sponsor and the 
Chief/Principal Investigator. The dose and PK sampling times may also be modified following a review of the 
data.   
Part 1 
Pre-study assessments 
Pre-study assessments will be carried out in the 28 day period before dosing in order to assess the volunteer for 
suitability to take part in the study.  Potential volunteers will be required to provide written Informed Consent 
prior to undertaking any screening procedures.  Pre-study assessments will include medical history, vital signs 
(blood pressure, pulse, O2 saturation, oral temperature, and respiratory rate), physical examination (including 
body weight, height and BMI), 12-lead ECG, lung function testing, (FEV1 & FVC) and laboratory safety screen 
(haematology, biochemistry, urinalysis, urine drugs of abuse screen). 
Volunteers who fulfil all screening requirements will be invited to return for the Study Period. 
Study Period 
Each cohort of subjects will undergo 1 Study Period and each cohort will be separated by a data review period.  
Each Study Period will be approximately 15 days in duration and subjects will be dosed and monitored on a 
combined inpatient and outpatient basis.   
Volunteers will be admitted to the Clinical Centre in the morning of Day -1 where final confirmation of 
eligibility will be made after baseline assessments have been performed. 
Two subjects (dose leaders) will receive either a single dose of TD139 or placebo via DPI (1 
treatment/volunteer) following an overnight fast a day before the remaining subjects in the cohort.  The 
remaining 4 subjects of each cohort will be dosed approximately 24 hours later providing there are no safety 
concerns for either of the dose leaders. These 4 subjects will be randomised such that one further volunteer 
receives placebo. The randomisation code will be generated using the PROC PLAN procedure of SAS®. 
Each subject will stay at the Clinical Centre until 24 h post-dose (morning of Day 2) where they will be 
discharged providing the scheduled assessments have been completed and there are no ongoing safety concerns. 


 
 
 
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Subjects will return to the Clinical Centre on an outpatient basis on Day 3 for PK/safety and then Days 8 and 14 
for safety assessments. 
During the Study Period, assessments will include: 
 
Vital signs (supine blood pressure, pulse, O2 saturation, oral temperature and respiratory rate) 
 
12-lead ECG 
 
Physical examination 
 
Laboratory safety screen (haematology, biochemistry, urinalysis and urine drugs of abuse screen) 
 
Blood samples for PK, PG and PD measurements 
 
Exhaled breath condensate (EBC) collection for PD measurements 
All Adverse Events (AE) and concomitant medications will be recorded from the time of the screening visit 
until the post-study follow-up visit. 
Post-study assessments will be carried out 12 - 16 days after the last day of the Study Period. 
Part 2 
Part 2 of the study will include up to 24 male and female subjects of non child-bearing potential with IPF.  Four 
NHS centres (Royal Brompton Hospital, Edinburgh University Hospital, Royal Victoria Infirmary and Royal 
Devon and Exeter Hospital) will serve as Clinical Centres for Part 2 of the study and will identify eligible 
patients who present with IPF.  Patients who agree to take part in the study will be selected based upon the study 
inclusion and exclusion criteria. 
During Part 2, patients will receive a single dose of TD139 or placebo once daily for 14 days (dosing with 
TD139 or placebo as per Table S1). Patients will undergo study specific assessments throughout and post-study 
assessments will be carried out (26-30) days after the last day of the Study Period. 
Pre-study assessments 
Pre-study assessments will be carried out in the 28 day period before dosing in order to assess the volunteer for 
suitability to take part in the study.  Potential volunteers will be required to provide written Informed Consent 
prior to undertaking any screening procedures.  Pre-study assessments will include medical history, vital signs 
(blood pressure, pulse, O2 saturation, oral temperature, and respiratory rate), physical examination (including 
body weight, height and BMI), 12-lead ECG, detailed lung function testing including Carbon Monoxide 
Diffusing Capacity (DLCO), and laboratory safety screen (haematology, biochemistry, urinalysis, urine drugs of 
abuse screen). 
Volunteers who fulfil all screening requirements will be invited to return for the Study Period. 
Study Period 
The Study Period will be approximately 43 days in duration and subjects will be dosed and monitored on an 
outpatient basis.   
Volunteers will attend the Clinical Centre in the morning of Day -1 where final confirmation of eligibility will 
be made after baseline assessments have been performed. Volunteers will then be allowed to leave the unit and 
return in time for pre-dose procedures on the morning of Day 1. 
Each subject will receive either a single dose of TD139 or placebo via DPI once daily for 14 days, following an 
overnight fast on day -1.  The randomisation code will be generated using the PROC PLAN procedure of SAS®. 
Subjects will remain in the unit until 12 hrs post-dose on Day 1, providing the scheduled assessments have been 
completed and there are no ongoing safety concerns. Subjects will then return to the Clinical Centre on Days 2, 
3, 7, 14 and 15 for scheduled assessments and to receive the IMP. On Days when subjects are not required to 
attend the Clinical Centre, they will self administer the IMP at home. 
During the Study Period, assessments will include: 
 
Vital signs (supine blood pressure, pulse, O2 saturation, oral temperature and respiratory rate) 


 
 
 
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Lung function testing 
 
12-lead ECG 
 
Physical examination 
 
Laboratory safety screen (haematology, biochemistry, urinalysis and urine drugs of abuse screen) 
 
Blood samples for PK and PD measurements 
 
BAL fluid sampling for PK, PG and PD measurements. 
 
Exhaled breath condensate (EBC) collection for PD measurements 
All Adverse Events (AE) and concomitant medications will be recorded from the time of the screening visit 
until the post-study follow-up visit. 
Post-study assessments will be carried out 26 - 30 days after the last day of the Study Period. 
NUMBER OF SUBJECTS: 
Part 1  
Up to 36 healthy male subjects (studied as up to 6 groups of 6 subjects).  
Part 2  
Up to 24 male and female subjects of non child-bearing potential with IPF. 
 
INCLUSION CRITERIA: 
Part 1  
 
Healthy male subjects aged between 18 and 55 years of age. 
 
Male subject willing to use a condom, if applicable (unless anatomically sterile or where abstaining 
from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from Day 1 until 
3 months afterwards. 
 
Subject with a body weight of at least 50 kg and a Body Mass Index (BMI) within the range of 18-35 
kg/m2. BMI = Body weight (kg) / [Height (m)]2. 
 
Subject with no clinically significant abnormal serum biochemistry, haematology and urine 
examination values within 28 days of the first dose.   
 
Subject with a negative urinary drugs of abuse screen, determined within 28 days of the first dose (N.B. 
a positive alcohol result may be repeated at the discretion of the Investigator). 
 
Subject with negative human immunodeficiency virus (HIV) and hepatitis B surface antigen (Hep B) 
and hepatitis C virus antibody (Hep C) results. 
 
Subject with no clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined 
within 28 days of the first dose. 
 
Subjects must be a non-smoker or a former smoker (having ceased smoking for at least 6 months). 
 
Subjects with no clinically significant impairment in oxygen saturation. 
 
Subject must satisfy a medical examiner about their fitness to participate in the study. 
 
Subject must provide written informed consent to participate in the study. 
 
Subject must be available to complete the study (including all follow up visits). 
Part 2 
 
Male subject or female subject of non child-bearing potential with IPF. 


 
 
 
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For the purposes of this study, a female subject of non child-bearing potential is defined as the subject 
being amenorrheic for at least 12 consecutive months or at least 4 months post-surgical sterilisation 
(including bilateral fallopian tube ligation or bilateral oophorectomy with or without hysterectomy).   
 
Male subject willing to use a condom, if applicable (unless anatomically sterile or where abstaining 
from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from Day 1 until 
3 months afterwards. 
 
Subject aged between 45 and 85 years of age. 
 
Subjects with an FVC ≥ 45% predicted and an FEV1/FVC ratio ≥ 0.7. 
 
Subjects with oxygen saturation >90% by pulse oximetry while breathing ambient air at rest. 
 
Subjects with a diffusing capacity (DLCO) >25%. 
 
Subjects must have adequate organ function and a clinical diagnosis consistent with IPF prior to 
screening (based on the American Thoracic Society, the European Respiratory Society, the Japanese 
Respiratory Society and the Latin American Thoracic Association (ATS/ERS/JRS/ALAT) consensus 
criteria. The diagnosis would ordinarily have been confirmed at a multidisciplinary team meeting 
where the HRCT findings in particular will have been discussed with a radiologist with Respiratory 
expertise. 
 
Subjects who are able to undergo bronchoalveolar lavage (BAL). 
 
Subject must provide written informed consent to participate in the study. 
 
Subject must be available to complete the study (including all follow up visits). 
 
Subject with negative human immunodeficiency virus (HIV) and hepatitis B surface antigen (Hep B) 
and hepatitis C virus antibody (Hep C) results. 
 
Subject with no clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined 
within 28 days of the first dose. 
 
Subject with a negative urinary drugs of abuse screen, determined within 28 days of the first dose (N.B. 
a positive alcohol result may be repeated at the discretion of the Investigator). 
EXCLUSION CRITERIA: 
Part 1 
 
A clinically significant illness or surgery within 8 weeks prior to first administration of the study 
medication. 
 
Significant medical history that, in the Investigator’s opinion, may adversely affect participation. 
 
History of allergy or significant adverse reaction to drugs similar to the investigational drug, to 
nicotine, or to cholinergic drugs or to any drugs with a similar chemical structure. 
 
History of hypersensitivity (anaphylaxis, angioedema) to any drug. 
 
Use of any drug known to induce or inhibit hepatic drug metabolism, within 30 days prior to first 
administration of the study medication. 
 
Use of medications known to prolong QT/QTc interval within 14 days prior to the first administration 
of the study medication. 
 
Any clinically significant findings of physical examination or laboratory findings at Screening Visit. 
 
A clinically significant history of drug or alcohol abuse. 
 
Receipt of regular/over the counter medication within 14 days of the first dose that may have an impact 
on the safety and objectives of the study (at the Investigator’s discretion). 
 
Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular or metabolic 


 
 
 
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dysfunction. 
 
Inability to communicate well with the Investigator (i.e., language problem, poor mental development 
or impaired cerebral function). 
 
Participation in a New Chemical Entity clinical study within the previous 4 months or a marketed drug 
clinical study within the previous 3 months.  (N.B.  washout period between studies is defined as the 
period of time elapsed between the last dose of the previous study and the first dose of the next study). 
 
Donation of 450 mL or more blood within the previous 3 months. 
Part 2 
 
Any condition that makes the patient at unacceptable risk for bronchoscopy. 
 
Active cigarette smoking (defined as smoking more than 3 cigarettes daily within the last 6 months). 
 
Presence of a significant co-morbidity felt to limit life expectancy to less than 12 months. 
 
HRCT pattern showing emphysema more than the extent of fibrosis of the lung area conducted within 
12 months of Day 1. 
 
Evidence of renal, hepatic, central nervous system, or metabolic dysfunction 
 
Evidence of poorly controlled diabetes mellitus (defined as a HbA1c of > 59 mmol/mol [7.5%]). 
 
Use of systemic immunosuppressants within 30 days of dosing. 
 
Subjects currently receiving oral corticosteroids, cytotoxic drugs (e.g. chlorambucil, azathioprine, 
cyclophosphamide, methotrexate), antifibrotic drugs (e.g. pirfenidone), vasodilator therapies for 
pulmonary hypertension (e.g bosentan), unapproved (e.g. INF-γ, penicillamine, cyclosporine, 
mycophenolate) and/or investigational therapies for IPF or administration of such therapies within 4 
weeks of initial screening.  A current inhaled steroid dose of ≤1000 micrograms beclomethasone 
dipropionate (BDP) equivalent per day is acceptable if the dose is anticipated to remain stable during 
the study. 
 
History of malignancy, including carcinoma during the preceding five years. 
 
History of, or current asthma. 
 
Participation in a clinical study of an unlicensed drug in the previous 4 months, or a marketed drug 
study within the previous 3 months. (N.B. washout period between trials defined as the period of time 
elapsed between the last dose of the previous study and the first dose of the next study).  
 
Females of child-bearing potential and/or with a positive pregnancy test at Screening Visit. 
STUDY DRUG ADMINISTRATION: 
All doses will be administered using the Plastiape DPI. 
Part 1 
Up to 6 cohorts of 6 subjects will be randomly assigned in a blinded fashion to receive either a single dose of 
TD139 or matching placebo via DPI in an ascending dose fashion. Dose levels may be changed at the discretion 
of the safety committee based on PK and safety findings. The 6 currently planned ascending doses will be: 
Cohort 1: 0.15mg TD139 or matching placebo 
Cohort 2: 1.5mg TD139 or matching placebo 
Cohort 3: 3mg TD139 or matching placebo 
Cohort 4: 10mg TD139 or matching placebo 
Cohort 5: 20mg TD139 or matching placebo 
Cohort 6: 50mg TD139 or matching placebo 
Within each cohort, 4 subjects will receive TD139 and 2 subjects will receive placebo. One subject of the dose 


 
 
 
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leader group (total of 2 subjects) will receive TD139 and 1 subject will receive placebo.  The remaining 4 
subjects will be randomised such that one further volunteer receives placebo. 
TD139 capsules will be available in 0.15mg, 1.5mg, 5mg and 50mg strengths. 
 
Part 2 
Up to 24 patients will be randomly assigned in a blinded fashion to receive a single dose of TD139 or placebo 
via DPI once daily for 14 days as per Table S1. Based on the safety and PK data from single doses up to 10mg 
in Part 1 and on pre-clinical efficacy and safety data, a starting dose of 3 mg has been selected for the first 
Cohort in Part 2 (8 subjects, 5 TD139 and 3 placebo). 
Subsequent patients will be dosed according to the dose escalation design presented in Table S1. 
CRITERIA FOR EVALUATION: 
Part 1 
Safety Assessments:  
 
Adverse events and concomitant medication, 12-lead ECG, vital signs (blood pressure, pulse, O2 
saturation, oral temperature, respiratory rate), routine laboratory assessments (haematology, 
biochemistry and urinalysis) and urine drugs of abuse test. 
Pharmacokinetic Assessments:  
 
Plasma concentrations of TD139.  
Pharmacodynamic Assessments:  
 
Exhaled breath condensate analysis.  
 
Peripheral blood flow cytometry.  
 
Galectin-3 plasma levels. 
Pharmacogenetic Assessments:  
 
mRNA expression levels from blood leucocytes. 
Part 2 
Safety Assessments:  
 
Adverse events and concomitant medication, 12-lead ECG, vital signs (blood pressure, pulse, O2 
saturation, oral temperature, respiratory rate), routine laboratory assessments (haematology, 
biochemistry and urinalysis) and urine drugs of abuse test. 
Pharmacokinetic Assessments:  
 
Plasma, alveolar macrophage and BAL fluid (saline) concentrations of TD139.  
Pharmacodynamic Assessments:  
 
Macrophage morphology, ex-vivo macrophage function and analysis of soluble markers from BAL. 
 
Exhaled breath condensate analysis. 
 
Peripheral blood flow cytometry. 
 
Galectin-3 plasma levels. 
Pharmacogenetic Assessments:  
 
Macrophage phenotypic and mRNA pattern expression analysis from BAL. 
 
mRNA expression levels from blood leucocytes and analysis of peripheral blood mononuclear cells for 


 
 
 
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IPF gene signatures. 
STATISTICAL METHODS: 
Part 1 
Pharmacokinetics: Non-compartmental analysis: Cmax is calculated as the experimental value with the highest 
plasma concentration.   The time of tmax is the experimental data point when Cmax is measured.   The t1/2 is the 
time over which plasma concentration falls by one half.  The AUC0-t and AUC0-∞ will be calculated using the 
trapezoidal rule.   
Pharmacokinetic parameters of the studied population will be derived using standard non-compartmental 
methods with Phoenix WinNonlin®.   
Safety analysis: Descriptive statistics including number of observations, mean, SD and associated CV, 
minimum and maximum for numerical data, and counts and frequency for categorical data, will be tabulated for 
safety parameters by treatment group.  
Part 2 
Pharmacokinetics: Non-compartmental analysis: Cmax is calculated as the experimental value with the highest 
plasma concentration.   The time of tmax is the experimental data point when Cmax is measured.   The t1/2 is the 
time over which plasma concentration falls by one half.  The AUC0-t and AUC0-∞ will be calculated using the 
trapezoidal rule.   
Pharmacokinetic parameters of the studied population will be derived using standard non-compartmental 
methods with Phoenix WinNonlin®.   
Drug compartment measurements in BAL and AM as per the method set out in the study by Naderer et al[1]  
(e.g. TD139AM = TD139pellet/VAC [where the volume of alveolar cells - VAC, is estimated at 2.42μl/106 cells])[1]. 
Safety analysis: Descriptive statistics including number of observations, mean, SD and associated CV, 
minimum and maximum for numerical data, and counts and frequency for categorical data, will be tabulated for 
safety parameters by treatment group.  
 
DURATION OF STUDY: 
Part 1: Approximately 8 weeks for each individual (from the Screening 
Visit to Post-Study Visit) 
Part 2: Approximately 11 weeks for each individual (from the Screening 
Visit to Post-Study Visit) 
 


 
 
 
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Table S1: Part 2 Dose Escalation Flow Chart


 
 
 
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TABLE OF CONTENTS 
1 
SIGNATURE PAGES ..................................................................................................2 
1.1 
Sponsor Signature Page ................................................................................................2 
1.2 
Investigator Signature Page ..........................................................................................2 
2 
SYNOPSIS ...................................................................................................................5 
3 
TABLE OF CONTENTS ...........................................................................................14 
4 
ABBREVIATIONS USED IN THE TEXT ...............................................................17 
5 
ETHICS ......................................................................................................................19 
5.1 
Research Ethics Committee or Institutional Review Board .......................................19 
5.2 
Ethical Conduct of the Study ......................................................................................19 
5.3 
Subject Information and Consent ...............................................................................20 
6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................21 
6.1 
Study Personnel ..........................................................................................................21 
6.2 
Indemnity Arrangements ............................................................................................22 
7 
INTRODUCTION ......................................................................................................23 
8 
STUDY OBJECTIVES ..............................................................................................25 
8.1 
Primary Study Objective .............................................................................................25 
8.2 
Secondary Study Objective .........................................................................................25 
9 
INVESTIGATIONAL PLAN .....................................................................................26 
9.1 
Overall Study Design and Plan ...................................................................................26 
9.2 
Dose Escalation Procedures and Stopping Criteria ....................................................29 
9.2.1 
Dose Escalation Procedures (Part 1) ...........................................................................29 
9.2.2 
Dose Decision and Review Procedures (Part 2) .........................................................30 
9.2.3 
Study Stopping Criteria ..............................................................................................31 
9.3 
Discussion of Study Design, including the choice of Control Groups and 
Dose Leaders ..............................................................................................................32 
9.4 
Selection of Study Population ....................................................................................33 
9.4.1 
Inclusion Criteria ........................................................................................................34 
9.4.2 
Exclusion Criteria .......................................................................................................36 
9.4.3 
Removal of Subjects from Therapy or Assessment ....................................................37 
9.5 
Additional Advice for Study Population ....................................................................38 
9.5.1 
Contraception ..............................................................................................................38 


 
 
 
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9.5.2 
Sperm Donation ..........................................................................................................38 
9.5.3 
Diet and Fluid Restrictions .........................................................................................39 
9.5.3.1 
Meal Times/Fasts ........................................................................................................39 
9.5.3.2 
Fluid Intake .................................................................................................................39 
9.5.3.3 
Alcohol Intake ............................................................................................................39 
9.5.3.4 
Caffeine .......................................................................................................................39 
9.5.3.5 
Poppy Seeds ................................................................................................................39 
9.5.3.6 
Grapefruit Juice and Other Restrictions .....................................................................39 
9.5.4 
Other Life-Style Restrictions ......................................................................................40 
9.5.4.1 
Strenuous Exercise ......................................................................................................40 
9.5.4.2 
Blood Donation ...........................................................................................................40 
9.6 
Investigational Medicinal Product ..............................................................................40 
9.6.1 
Identity ........................................................................................................................40 
9.6.2 
Receipt and Storage ....................................................................................................40 
9.6.3 
Assembly and Release ................................................................................................40 
9.6.4 
Administration ............................................................................................................41 
9.6.5 
Return/Destruction ......................................................................................................42 
9.6.6 
Method of Assigning Subjects to Treatment Groups .................................................43 
9.6.7 
Selection of Doses in the Study ..................................................................................43 
9.6.8 
Timing of Dose for Each Subject ...............................................................................44 
9.6.9 
Blinding ......................................................................................................................44 
9.6.10 
Prior and Concomitant Therapy ..................................................................................45 
9.6.11 
Treatment Compliance ................................................................................................46 
9.7 
Efficacy and Safety Variables ....................................................................................46 
9.7.1 
Efficacy and Safety Measurements Assessed and Flow Chart ...................................46 
9.7.1.1 
Demographic and Background Assessments ..............................................................51 
9.7.1.1.1 
Demographics .............................................................................................................51 
9.7.1.1.2 
Medical History and Concurrent Conditions ..............................................................51 
9.7.1.1.3 
Physical Examination .................................................................................................51 
9.7.1.1.4 
Virology ......................................................................................................................51 
9.7.1.1.5 
Drugs of Abuse and Alcohol ......................................................................................51 
9.7.1.1.6 
Pregnancy Test, Menstrual and Obstetric History ......................................................51 
9.7.1.2 
Compliance with Inclusion/Exclusion Criteria ...........................................................51 


 
 
 
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9.7.1.3 
Efficacy Assessments .................................................................................................51 
9.7.1.4 
Safety Assessments .....................................................................................................52 
9.7.1.4.1 
Adverse Events ...........................................................................................................52 
9.7.1.4.2 
Laboratory Safety Assessments ..................................................................................55 
9.7.1.4.3 
Vital signs ...................................................................................................................55 
9.7.1.4.4 
12-lead ECG ...............................................................................................................55 
9.7.1.4.5 
Concomitant Medication ............................................................................................56 
9.7.1.4.6 
Spirometry ..................................................................................................................56 
9.7.2 
Appropriateness of Measurements .............................................................................56 
9.7.3 
Primary Efficacy Variable(s) ......................................................................................56 
9.7.4 
Drug Concentration Measurements ............................................................................56 
9.7.4.1 
Pharmacokinetic Blood Sampling ..............................................................................56 
9.7.4.2 
Drug concentration measurements in BAL ................................................................57 
9.7.5 
Pharmacodynamics .....................................................................................................57 
9.7.5.1 
Exhaled Breath Condensate Sampling ........................................................................57 
9.7.5.2 
Galectin-3 Blood Sampling ........................................................................................57 
9.7.5.3 
Peripheral Blood Flow Cytometry Blood Sampling ...................................................57 
9.7.5.4 
Bronchoalveolar Lavage (BAL) .................................................................................57 
9.7.6 
Pharmacogenetics .......................................................................................................58 
9.8 
Data Quality Assurance ..............................................................................................58 
9.9 
Statistical Methods and Determination of Sample Size .............................................60 
9.9.1 
Statistical and Analytical Plan ....................................................................................60 
9.9.1.1 
Primary and Secondary Variables for Assessment .....................................................60 
9.9.1.2 
Definition of Evaluability ...........................................................................................60 
9.9.1.3 
Description of Statistical Methods ..............................................................................61 
9.9.2 
Sample Size Calculation .............................................................................................64 
10 
PRACTICAL CONSIDERATIONS ..........................................................................65 
10.1 
Storage of Data ...........................................................................................................65 
10.2 
Protocol Amendments ................................................................................................65 
10.3 
Confidentiality ............................................................................................................65 
10.4 
Study Report and Publication Policy ..........................................................................65 
11 
REFERENCES ...........................................................................................................67 
APPENDIX 1: DECLARATION OF HELSINKI (BRAZIL, 2013) .............................................69 


 
 
 
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4 
ABBREVIATIONS USED IN THE TEXT 
 λz 
elimination rate constant 
 ABPI 
Association of the British 
 
Pharmaceutical Industry 
 AE(s) 
adverse event(s) 
 ALB 
albumin 
 ALT 
alanine transaminase 
 AST 
aspartate transaminase 
 AUC 
area under the plasma 
 
concentration versus time 
 
curve  
 AUC0-t 
AUC from the time of dosing 
 
to the time of the last 
 
observed concentration 
 AUC0-inf 
AUC extrapolated to infinity 
 
from dosing time, based on 
 
the last observed 
 
concentration 
 BAL 
bronchoalveolar lavage 
 BASO 
basophils 
 BIA  
BioIndustry Association 
 BIL-T 
total bilirubin 
 BMI 
body mass index  
 CCRA  
Clinical Contract Research 
 
Association 
 Cmax 
maximum plasma 
 
concentration 
 CL/F 
clearance 
 CREA 
creatinine 
 CRF 
case report form 
 CTA 
Clinical Trial Authorisation 
 CV% 
coefficient of variation 
 DLCO 
Carbon Monoxide Diffusing  
 
Capacity 
 DPI 
Dry Powder Inhaler 
 EBC 
Exhaled breath condensate 
 EC 
European Commission 
 ECG 
electrocardiogram  
 EOS 
eosinophils 
 FEV1 
Forced Expired Volume in 1 
 
second  
 FVC 
Forced Vital Capacity 
 g 
gram 
 GCP 
Good Clinical Practice 
 GGT 
gamma glutamyl transferase 
 GLP 
Good Laboratory Practice 
 GLU 
glucose  
 GMP 
Good Manufacturing Practice 
 hr(s) 
hour(s) 
 Hep B 
hepatitis B surface antigen 
 Hep C 
hepatitis C virus antibody 
 HCO3 
bicarbonate 
 HCT 
haematocrit 
 HGB 
haemoglobin 
 HIV 
human immunodeficiency 
 
virus 
 ICH 
International Conference on 
 
Harmonisation 
 IMP 
investigational medicinal 
 
product 
 ISF 
Investigator Site File 
 K 
potassium 
 Ltd 
Limited 
 LYMP 
lymphocytes 
 MCV 
mean cell volume 
 MCH 
mean cell haemoglobin 
 MCHC 
mean cell haemoglobin 
 
concentration 
 MedDRA 
Medical Dictionary for 
Regulatory Activities 
 MHRA 
Medicines and Healthcare 
products Regulatory Agency 
 min(s) 
minute(s) 
 MoA 
mechanism of action 
 MONO 
monocytes 
 N 
number dosed 
 n 
number of observations 
 NA 
sodium 
 NEUT 
neutrophils 
 PD 
pharmacodynamic 
 PK 
pharmacokinetic 
 PLT 
platelets 
 


 
 
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 PR interval 
time the electrical impulse 
 
takes to travel from the sinus 
 
node through the AV node 
 
and entering the ventricles; 
 
measured from the beginning 
 
of the P wave to the beginning 
 
of the QRS complex 
 QP 
qualified person 
 QRS 
QRS complex represents 
 
ventricular depolarization 
 QT interval 
the time for both ventricular 
 
depolarization and 
 
repolarization to occur, and 
 
therefore roughly estimates 
 
the duration of an average 
 
ventricular action potential. 
 QTc 
corrected QT interval 
 QTcB 
corrected QT interval using 
 
Bazett’s formula 
 RBC 
red blood cells 
 REC 
Research Ethics Committee 
 SAE 
serious adverse event 
 SAP 
statistical analysis plan 
 SAS 
statistical analysis software by 
 
SAS Institute Inc., USA 
 SD 
standard deviation 
 SOC 
system organ class 
 SOP 
standard operating procedure 
 SUSAR 
suspected unexpected serious 
 
adverse reaction 
 tds 
ter die sumendum, three 
 
times a day 
 t½ 
terminal half-life 
 tmax 
the time to Cmax during a 
 
dosing interval 
 TP 
total protein 
 UK 
United Kingdom 
 WBC 
white blood cells 


 
 
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5 
ETHICS 
5.1 
Research Ethics Committee or Institutional Review Board  
This Study Protocol will be submitted to the Research Ethics Committee (REC) for review 
and approval.  The approval of the REC must be obtained before commencement of any 
study procedures. 
All substantial protocol amendments must be approved by the REC responsible for the study.  
Non-substantial amendments will not require prior approval by the REC. 
If the study is stopped due to adverse events (AEs) it will not be recommenced without 
reference to the REC responsible for the study. 
The outcome of the study (e.g. completed) will be reported to the REC responsible for the 
study within 90 days of completion of the last subject’s final study procedures.  In the event 
of the study being prematurely terminated a report will be submitted to the REC responsible 
for the study within 15 days. 
A summary of the Clinical Study Report will be submitted to the REC responsible for the 
study within 1 year of completion of the last subject’s final study procedures. 
The REC will be informed that Simbec is a commercial organisation and that the study is 
funded by Galecto Biotech AB. The subjects who take part in the clinical study will be paid 
for their inconvenience and have been informed that there will be no benefits gained by their 
participation. All potential conflicts of interest will be declared by the Investigators.  
5.2 
Ethical Conduct of the Study 
The Chief Investigator shall be responsible for ensuring that the clinical study is performed in 
accordance with the following: 
 Declaration of Helsinki (Brazil 2013)[2]. 
 Association of the British Pharmaceutical Industry (ABPI) Guidelines for Phase 1 
Trials (2012)[3]. 
 International Conference on Harmonisation (ICH) Harmonised Tripartite 
Guideline for Good Clinical Practice (GCP)[4]. 
 The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory 
Instrument 2004 No. 1031) and subsequent amendments[5]. 
This clinical study has been registered in the EudraCT database and a Clinical Trials 
Authorisation (CTA) will be obtained from the Medicines and Healthcare products 
Regulatory Agency (MHRA) prior to the start of the study in accordance with Part 3, 
Regulation 12 of the United Kingdom (UK) Statutory Instrument. 
 


 
 
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5.3 
Subject Information and Consent 
Prior to undergoing any study-specific procedure, each potential study subject will be asked 
to provide signed acknowledgement of their freely given informed consent. Either the Chief 
Investigator or a designated person, qualified to meet any applicable local regulations, who is 
equally knowledgeable about the study will explain the aims, methods, anticipated benefits 
and potential hazards of the study and any discomfort it may entail. A corresponding written 
explanation (Subject Information Sheet) will also be provided and the subject will be allowed 
sufficient time to consider the study information. 
Prior to signing the Informed Consent Form, the subject will be given an opportunity to 
discuss any issues concerning the study with a physician who has suitable knowledge of the 
study and will have all questions answered openly and honestly. 
If the subject is willing to participate in the study, the Informed Consent Form will be signed 
and personally dated by the subject, the physician taking the consent and, if applicable, the 
designated person who explained the nature of the study. The subject will receive a copy of 
the Informed Consent Form together with the Subject Information Sheet, and the original 
signed Informed Consent Form will be retained with the study records at the Investigator site.  
 


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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Part 1 of the study will be performed at a single site, Simbec Research Limited (Ltd.) and 
Part 2 of the study will be performed at 4 NHS Centres (Royal Brompton Hospital, 
Edinburgh University Hospital, Royal Victoria Infirmary and Royal Devon and Exeter 
Hospital).  The trial manager will act on behalf of the Chief Investigator to ensure the smooth 
and efficient running of all aspects of the study. 
6.1 
Study Personnel 
Galecto Biotech AB (Sponsor) 
Project Manager (Main Contact):  
Sponsor’s Responsible Physician: 
Monitor:  
  
 
Simbec Research Ltd (Contract Research Organisation) 
Principal Investigator: 
Trial Manager:  
Co-Investigators:  
Pharmacokinetics (PK): 
Statistics:  
 
 
Principal Scientist, Bioanalytical Unit: 
The Principal Scientist will be assigned prior to 
study start and documented in the Bioanalytical 
Phase Plan. 
Manager, Simbec Central Laboratories:  
Edinburgh University Hospital 
Principal Investigator: 
Royal Brompton Hospital 
Chief Investigator: 
Royal Victoria Infirmary 
Principal Investigator: 
Royal Devon and Exeter Hospital 
Principal Investigator: 
Pharmacovigilance (PV): 
 
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The Chief Investigator will delegate study related activities according to staff responsibilities 
and job descriptions. This will be documented in a study specific Delegation of 
Responsibilities form. 
6.2 
Indemnity Arrangements 
Each study site carries insurance to pay compensation for injury, accident, ill health or death 
caused by participation in this study without regard to proof of negligence and without delay.  
Provision for arbitration in the case of disagreement must be agreed with the insured.  It is 
suggested that a Barrister of at least 10 years standing appointed by the Royal College of 
Physicians be arbiter. 
Where there is any doubt about causation, the benefit of the doubt must be given to the 
subject. 
Where ill health, injury or death is due to negligence by the Sponsor party, the study site 
should promptly compensate the subject but reserve the right to take action against the 
Sponsor in order to recoup such compensation. 
It is hoped that insurance companies will honour life and sickness policies of subjects 
participating in research that has been approved by an appropriately constituted REC and 
involves no more than minimal risk. 
The above section accords with Insurance and compensation in the event of injury in phase I 
clinical trials 2012[6], guidance developed by the ABPI, the BioIndustry Association (BIA) 
and the Clinical Contract Research Association (CCRA) in consultation with the Department 
of Health and the National Research Ethics Service. 


 
 
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7 
INTRODUCTION 
Idiopathic pulmonary fibrosis (IPF) is a progressive and invariably fatal disease characterized 
by progressive scarring of the lung.  IPF is thought to occur after recurrent injury to the 
alveolar epithelium followed by abnormal repair; this abnormal repair is characterized by the 
formation of fibroblast and myofibroblast foci and excessive deposition of extracellular 
matrix[7][8]. 
IPF occurs more commonly in men than women and typically presents in individuals of 
between 40 and 70 years of age.  Recently published estimates from the USA suggest the 
prevalence of IPF is between 14 and 42.7 per 100 000 with an annual incidence of 6.8–16.3 
per 100 000.  In the UK the incidence of IPF has been estimated at 4.6 per 100 000 and 
accounts for 5000 deaths per year, a figure greater than many malignancies, including 
myeloma, lymphoma, and stomach cancer[7][8].   
Individuals with IPF typically present with breathlessness and cough, which becomes 
progressively debilitating over time. The overwhelming majority of patients with IPF 
eventually die from respiratory failure, with a median survival from diagnosis of 2.9–5.0 
years[7][8].  More effective treatments for IPF represent a very important unmet clinical need. 
It is a debilitating disease, which results in progressive lung scarring with a rapid decline in 
lung function and a high mortality rate. There are approximately 5,000 cases of IPF 
diagnosed in the UK each year[9] and the incidence is rising. In the US and Canada the overall 
prevalence is estimated at 150,000[10]. The outlook for patients with IPF is poor - 50% of 
patients with IPF in the UK die within 3 years of diagnosis. Though Esbriet (pirfenidone), a 
drug with anti-inflammatory and anti-fibrotic effects has recently been approved by the FDA 
for the treatment of IPF, the lack of a clearly defined mechanism of action (MoA), high price, 
frequent incidence of upper gastrointestinal side effects and moderate therapeutic effect 
impede its clinical use whilst drug developmental issues surrounding its MoA make drug 
class specific improvements extremely difficult. Ofev (Nintedanib) has also been approved 
but is similarly priced and whilst its MOA is established (tyrosine kinase inhibitor) the 
incidence of side effects with this drug is even higher than that of Esbriet. Therefore a novel, 
targeted therapy with a clear MoA and limited side effect profile that could halt and 
potentially reverse disease progression is urgently required. In addition, the inhaled delivery 
route could offer further benefits in targeting the site of disease whilst limiting systemic 
toxicity. 
Galecto Biotech has developed a novel IPF treatment (TD139) that acts as a Galectin-3 (Gal-
3) inhibitor.  TD139 has been inhibitor developed as a dry powder for inhalation (DPI) for the 
indication “Treatment of adults with Idiopathic Pulmonary Fibrosis” (IPF). The chemical 
name is Bis-(3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-ß-D-galactopyranosyl) 
sulfane.  Galectin-3 is a member of the lectin family of carbohydrate-binding proteins and it 
is implicated in a number of cellular processes, including cell adhesion, cell activation, 
chemo-attraction, cell growth, differentiation and apoptosis. Galectin-3 binds to itself and to 
TGFβ receptors, forming lattices that hold the receptors at the cell surface thus altering TGFβ 
signal transduction. TGFβ signalling is thought to drive many of the processes associated 
with fibrosis and inhibiting this pathway should reduce IPF disease progression. 


 
 
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In this trial, TD139 will be studied to explore its safety and tolerability in healthy volunteers 
and subsequently safety and tolerability in patients with IPF whilst pharmacodynamic 
measurements from samples taken from the lung in these patients before and after 14 days of 
treatment with TD139 may help to establish a proof of mechanism for TD139.    
Further details regarding the mechanism of action of TD139, including safety data and a 
summary of the known and potential risks and benefits can be found in the IB[11] . A separate 
interim report (Interim Report Part 1, v1.0 28 Nov 2014), summarising safety and PK up to 
the 10mg doses of TD139 in healthy volunteers has been written. All adverse events were 
mild and self-limiting and there were no significant changes from baseline in any of the 
following parameters; ECG, vital signs, biochemistry, haematology and urinalysis. 


 
 
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8 
STUDY OBJECTIVES 
8.1 
Primary Study Objective 
 
To evaluate the safety and tolerability of single ascending doses of TD139 in 
healthy male subjects.  
 
To evaluate the safety and tolerability of multiple doses of TD139 in male and 
female subjects of non child-bearing potential with IPF. 
8.2 
Secondary Study Objective 
 
To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of TD139 
when administered as a single dose to healthy male subjects.  
 
To evaluate the PK and PD of TD139 when administered in multiple doses to 
male and female subjects of non child-bearing potential with IPF. 
 
 
 


 
 
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INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study will be divided into 2 parts. Part 1 is a randomised, double-blind, single centre, 
placebo-controlled, single ascending dose (SAD), phase I study designed to assess the safety, 
tolerability, PK and PD of TD139 in up to 36 healthy male subjects. Part 2 will be a 
randomised, double-blind, multi-centre, placebo-controlled, multiple dose expansion cohort, 
designed to assess the safety, tolerability, PK and PD of TD139 in up to 24 male subjects and 
female subjects of non child-bearing potential with IPF. 
Part 1 of the study will take place in healthy male volunteers and will consist of up to 6 
cohorts of 6 subjects.  Within each cohort, 4 subjects will receive a single dose of TD139 and 
2 subjects will receive a single dose of placebo. Each cohort will include a dose leader group 
of 2 volunteers (1 TD139 and 1 placebo) to be dosed a day before the rest of the cohort, 
followed by the remaining 4 subjects who will be dosed approximately 24 hours later.  The 
remaining 4 subjects will be randomised such that one further volunteer receives placebo. 
The lowest dose (0.15 mg) of TD139 will be evaluated first. Dose administration in the 
subsequent cohorts will only proceed after blinded safety and PK data for 3 days after dose 
administration from a minimum of 5 subjects in the preceding cohort have been reviewed by 
the Sponsor and Chief Investigator and are found to be satisfactory.  The study will be 
discontinued at any time if any unacceptable safety findings are identified. The maximum 
dose of TD139 will be 50 mg.  
Part 2 of the study will take place in male subjects and female subjects of non child-bearing 
potential with IPF.  This part of the study will include up to 24 IPF subjects, who will receive 
a single dose of TD139 or placebo via DPI once daily for 14 days (subjects will receive 
TD139 and placebo as per Table S1). Subjects will be studied in up to 3 multiple ascending 
dose cohorts.  Based on the safety and PK data from single doses up to 10mg in Part 1, a 
starting dose of 3 mg has been selected for the first Cohort in Part 2 (8 subjects, 5 TD139 and 
3 placebo). The dose escalation design of Part 2 is presented in Table S1. At each interim 
safety review meeting, the available blinded safety, BAL and PK data would be reviewed by 
the Sponsor and the Chief/Principal Investigator.  
There will be an interim review after Cohort 1 has been dosed to review the available data. 
Following a review of this data, if it is decided that it meets the dose escalation requirements 
then Cohort 2 (8 subjects, 5 TD139 and 3 placebo) will receive the next dose level. An 
interim review would then take place after Cohort 2 has been dose to review the available 
data. Following a review of this data, if it is decided that it meets the dose escalation 
requirements then Cohort 3 (8 subjects, 5 TD139 and 3 placebo) will receive a third dose 
level (Outcome 1). If it is decided that the data in Cohort 2 does not meet the dose escalation 
requirements, a 4 further subjects would be dosed in Cohort 2 with the same dose level (3 
TD139 and 1 placebo) (Outcome 2). 
After the interim review of Cohort 1 data, if it is decided that the dose escalation 
requirements have not been met, 4 further subjects would be dosed in Cohort 1 with 3mg (3 
TD139 and 1 placebo). After the extra subjects have been dosed an interim review would 
then take place to review the data, before moving on to the next dose level in Cohort 2 (8 


 
 
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subjects, 5 TD139 and 3 placebo). An interim review would then take place after Cohort 2 
has been completed to review the available data. Following a review of this data, if it is 
decided that it meets the dose escalation requirements then no further subjects would be 
dosed (Outcome 3). If it is decided that the data in Cohort 2 does not meet the dose escalation 
requirements, a 4 further subjects would be dosed in Cohort 2 with the same dose level (3 
TD139 and 1 placebo) (Outcome 4). 
The highest acceptable dose level in Part 1 of the study will not be exceeded in Part 2. Part 2 
will be discontinued at any time if any unacceptable safety findings are identified (see Study 
Stopping Criteria). At the interim review meetings it may be decided it is not appropriate to 
escalate the dose. In this event the same dose, an intermediate dose or a lower dose may be 
given following discussion between the Sponsor and the Chief/Principal Investigators. The 
dose and PK sampling times may also be modified following a review of the data. 
Part 1 
Pre-study assessments 
Pre-study assessments will be carried out in the 28 day period before dosing in order to assess 
the volunteer for suitability to take part in the study.  Potential volunteers will be required to 
provide written Informed Consent prior to undertaking any screening procedures.  Pre-study 
assessments will include medical history, vital signs (blood pressure, pulse, O2 saturation, 
oral temperature, and respiratory rate), physical examination (including body weight, height 
and BMI), 12-lead ECG, lung function testing, (FEV1 & FVC) and laboratory safety screen 
(haematology, biochemistry, urinalysis, urine drugs of abuse screen). 
Volunteers who fulfil all screening requirements will be invited to return for the Study 
Period. 
Study Period 
Each cohort of subjects will undergo 1 Study Period and each cohort will be separated by a 
data review period.  Each Study Period will be approximately 15 days in duration and 
subjects will be dosed and monitored on a combined inpatient and outpatient basis.   
Volunteers will be admitted to the Clinical Centre in the morning of Day -1 where final 
confirmation of eligibility will be made after baseline assessments have been performed. 
Two subjects (dose leaders) will receive either a single dose of TD139 or placebo via DPI (1 
treatment/volunteer) following an overnight fast a day before the remaining subjects in the 
cohort.  The remaining 4 subjects of each cohort will be dosed approximately 24 hours later 
providing there are no safety concerns for either of the dose leaders. These 4 subjects will be 
randomised such that one further volunteer receives placebo. The randomisation code will be 
generated using the PROC PLAN procedure of SAS®. 
Each subject will stay at the Clinical Centre until 24 h post-dose (morning of Day 2) where 
they will be discharged providing the scheduled assessments have been completed and there 
are no ongoing safety concerns. Subjects will return to the Clinical Centre on an outpatient 
basis on Days 3 for PK/safety and then Day 8 and 14 for assessments. 
During the Study Period, assessments will include: 


 
 
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 Vital signs (supine blood pressure, pulse, O2 saturation, oral temperature and 
respiratory rate) 
 12-lead ECG 
 Physical examination 
 Laboratory safety screen (haematology, biochemistry, urinalysis and urine drugs of 
abuse screen) 
 Blood samples for PK, PG and PD measurements 
 Exhaled breath condensate (EBC) collection for PD measurements 
All Adverse Events (AE) and concomitant medications will be recorded from the time of the 
screening visit until the post-study follow-up visit. 
Post-study assessments will be carried out 12 - 16 days after the last day of the Study Period 
(See Table 9.7.1). 
Part 2 
Part 2 of the study will include up to 24 male subjects and female subjects of non child-
bearing potential with IPF.  Four NHS centres (Royal Brompton Hospital, Edinburgh 
University Hospital, Royal Victoria Infirmary and Royal Devon and Exeter Hospital) will 
serve as Clinical Centres for Part 2 of the study and will identify eligible patients who 
present with IPF.  Patients who agree to take part in the study will be selected based upon the 
study inclusion and exclusion criteria. 
During Part 2, patients will receive a single dose of TD139 or placebo once daily for 14 days 
(TD139 and placebo dosed according to Table S1).  Patients will undergo study specific 
assessments throughout and post-study assessments will be carried out (26-30) days after the 
last day of the Study Period (See Table 9.7.12). 
Pre-study assessments 
Pre-study assessments will be carried out in the 28 day period before dosing in order to assess 
the volunteer for suitability to take part in the study.  Potential volunteers will be required to 
provide written Informed Consent prior to undertaking any screening procedures.  Pre-study 
assessments will include medical history, vital signs (blood pressure, pulse, O2 saturation, 
oral temperature, and respiratory rate), physical examination (including body weight, height 
and BMI), 12-lead ECG, detailed lung function testing including Carbon Monoxide Diffusing 
Capacity (DLCO), and laboratory safety screen (haematology, biochemistry, urinalysis, urine 
drugs of abuse screen). 
Volunteers who fulfil all screening requirements will be invited to return for the Study 
Period. 
Study Period 
The Study Period will be approximately 43 days in duration and subjects will be dosed and 
monitored on an outpatient basis.   
Volunteers will attend the Clinical Centre in the morning of Day -1 where final confirmation 
of eligibility will be made after baseline assessments have been performed. Volunteers will 


 
 
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then be allowed to leave the unit and return in time for pre-dose procedures on the morning of 
Day 1. 
Each subject will receive either a single dose of TD139 or placebo via DPI once daily for 14 
days, following an overnight fast on day-1.  The randomisation code will be generated using 
the PROC PLAN procedure of SAS®. Subjects will remain in the unit until 12 hrs post-dose 
on Day 1, providing the scheduled assessments have been completed and there are no 
ongoing safety concerns. Subjects will then return to the Clinical Centre on Days 2, 3, 7, 14 
and 15 for scheduled assessments and to receive the IMP. On Days when subjects are not 
required to attend the Clinical Centre, they will self administer the IMP at home. 
During the Study Period, assessments will include: 
 Vital signs (supine blood pressure, pulse, O2 saturation, oral temperature and 
respiratory rate) 
 Lung function testing 
 12-lead ECG 
 Physical examination 
 Laboratory safety screen (haematology, biochemistry, urinalysis and urine drugs of 
abuse screen) 
 Blood samples for PK, PG and PD measurements 
 BAL fluid sampling for PK, PG and PD measurements. 
 Exhaled breath condensate (EBC) collection for PD measurements 
All Adverse Events (AE) and concomitant medications will be recorded from the time of the 
screening visit until the post-study follow-up visit. 
Post-study assessments will be carried out 26 - 30 days after the last day of the Study Period 
(See Table 9.7.1). 
The conclusion of the study is defined as the last visit of the last subject. 
9.2 
Dose Escalation Procedures and Stopping Criteria 
9.2.1 
Dose Escalation Procedures (Part 1) 
Following completion of each cohort, a summary of all relevant safety data (AEs, vital signs, 
12-Lead ECG and laboratory safety tests) and PK data (Cmax, Tmax, AUC0-24, AUC0-t, 
AUC0-∞ and t½) up to Day 3 (48 hours post dose) will be produced on behalf of the Chief 
Investigator. Planned doses may be modified following a review of emerging data. 
Progression to the next dose level and dose selection will be based on the available safety and 
PK data from at least 5 subjects from the preceding dose level. If fewer than 5 evaluable 
subjects are obtained then additional subjects must be dosed for that cohort prior to 
considering dose escalation. If it is not appropriate to escalate the dose according to the 
proposed dose escalation schedule, then the same dose, an intermediate dose or a lower dose 
may be given following discussion between the Sponsor and the Investigator. If the dose 
escalation stopping criteria in section 9.2.3 are met, then the dose level that was tested will 


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not be repeated or exceeded, however a lower dose may be given following discussion 
between the Sponsor and the Investigator.  
The members of the dose escalation review committee will consist of XXXXXXXXXXX 
(chair and voting member), XXXXXXX (voting member) and XXXXXX (PK, non voting 
member).  Both voting safety committee members must participate in all meetings or provide 
an acceptable designee if unavailable.   
There will be a Telephone Conference at a pre-appointed time to involve the Simbec Trial 
manager and Investigator (or their deputies) and the Sponsor’s representative(s). After 
discussion of all the data, the decision will be made to dose escalate and a written document 
signed by the Investigator (or deputy) and Sponsor will be produced ratifying that decision. 
Recommendations to continue the study will require unanimous consent from the 2 voting 
members. In the event that unexpected safety issues are observed that are beyond the 
expertise of committee members, additional committee members or ad hoc committee 
members may be added to the safety committee. In the event that there is not a unanimous 
decision among the 2 voting members, an independent arbiter will be appointed to resolve the 
disagreement.  Full minutes, to be agreed by all parties, will be produced for each discussion 
regarding dose escalation and filed in the Investigator Site File (ISF).  A copy will be 
provided to the Simbec Pharmacist and this will allow the Investigational Medicinal Product 
(IMP) to be assembled for the next dose level prior to the performance of the next stage of the 
protocol.  
The continuation of the study will be dependent upon the accrual of acceptable safety data 
following each cohort as indicated by the signature of each safety summary by the Chief 
Investigator or delegate and by the Sponsor. 
Please see Section 9.2.3 for dose escalation stopping criteria. 
9.2.2 
Dose Decision and Review Procedures (Part 2) 
Dose Selection for Part 2: 
The dose of TD139 to be administered in Part 2 will be 3mg, based on data from Part 1 
(single doses up to 10mg) and on pre-clinical efficacy and safety data. The highest acceptable 
dose level in Part 1 of the study will not be exceeded in Part 2. 
Ongoing Safety Review: 
Part 2 will be discontinued at any time if any unacceptable safety findings are identified (see 
Study Stopping Criteria in section 9.2.3). 
Formal Interim Review: 
During Part 2 there will be an interim review by a safety committee after 8 subjects have 
been dosed to review the available blinded safety and PK data. The initial 8 subjects will be 
randomised in such a way that 5 will receive TD139 and 3 will receive placebo. Following a 
review of this data a decision will made as to whether to randomise up to 4 further subjects 
(where 3 subjects will receive TD139 and 1 will receive placebo). The dose and PK sampling 
times may also be modified following a review of the data.  
The following will be reviewed at the interim review meeting: 


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A summary of all relevant safety data from at least 7 out of 8 subjects (AEs, vital 
signs, 12-Lead ECG, spirometry and laboratory safety tests),  
PK data from at least 7 out of 8 subjects (Cmax, Tmax, AUC0- τ, 
AUC0-t, AUC0-∞ 
and t½)  
BAL data: At least 7 out of 8 subjects will have completed both of the following: 
o
paired BAL samples
o
adequate BAL macrophage cell yields (absolute minimum macrophage
numbers = 4 million)
The data will be compiled by Simbec on behalf of the Chief Investigator once the first 8 
subjects have been dosed. Subsequent interim review meetings will take place as detailed in 
Table S1. Each site will be required to scan the applicable CRF pages and transfer the 
required safety data needed to Simbec data management in order for the data to be 
consolidated from each site. PK samples will be shipped to Simbec for assaying and 
subsequent PK analysis. A summary of all of the available data will be provided to all the 
safety committee for review. 
The members of the safety committee will consist of XXXXXX (joint chair and voting 
member), XXXXXXX (joint chair and voting member), XXXXXXXXXXXXX (joint chair 
and voting member), XXXXXXXX (joint chair and voting member) and XXXXXXXXX 
(voting member).  All 5 voting safety committee members must participate in all meetings or 
provide an acceptable designee if unavailable.   
There will be a Telephone Conference at a pre-appointed time to involve all of the safety 
committee members. After discussion of all the data, the decision will be made as to whether 
to randomise up to 4 further subjects in Cohort 1 or move on to a second dose level in Cohort 
2 (see Table S1). It will also be decided whether the dose and PK sampling times will also be 
modified. Recommendations to continue/discontinue/amend the study will require unanimous 
consent from the 5 voting members. In the event that unexpected safety issues are observed 
that are beyond the expertise of committee members, additional committee members or ad 
hoc committee members may be added to the safety committee. In the event that there is not a 
unanimous decision among the 5 voting members, an independent arbiter will be appointed to 
resolve the disagreement.  
A written document signed by each site Investigator (or deputy) and Sponsor will be 
produced ratifying that decision.  Full minutes, to be agreed by all parties, will be produced 
for each discussion regarding dose escalation and filed in the Investigator Site File (ISF).  A 
copy will be provided to the Simbec Pharmacist and this will allow the Investigational 
Medicinal Product (IMP) to be assembled accordingly for each site. The procedure for the 
ongoing and interim data review in Part 2 will be fully documented to a dose review manual.  
The manual will be approved by the sponsor and all clinical site Investigators prior to the 
start of the trial.  
Please see Section 9.2.3 for study stopping criteria. 
9.2.3 
Study Stopping Criteria 
Part 1:  


 
 
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 Dose Escalation will stop if 3 or more subjects in a cohort experience the same 
moderate adverse event that is deemed possibly, probably or definitely related to IMP 
treatment. 
 Dose Escalation will stop if 1 or more subjects in a cohort experience severe adverse 
event that is deemed possibly, probably or definitely related to IMP treatment. 
 Dose escalation would stop if 1 or more than 1 subject in the cohort experience a drug 
related SAE or a clinically significant drug-related non-SAE. 
 Dose escalation will stop if the Cmax and/or AUC values in each cohort reach or 
exceed those observed in the dog following 9.1 mg/kg/day 14 day repeat dosing, 
equating to a gender-averaged AUC(0-t) of 2450 ng*hr/mL and Cmax of 558 ng/mL 
on Day 14. 
Part 2:  
 The study will be stopped if 3 or more subjects experience the same moderate adverse 
event. 
 The study will be stopped if 2 or more subjects experience a severe adverse event. 
 The study will be stopped if 1 subject experiences a drug related SAE or a clinically 
significant drug-related non-SAE. 
 The study will be stopped if the Cmax and/or AUC values reach or exceed those 
observed in the dog following 9.1 mg/kg/day 14 day dosing, equating to gender-
averaged AUC(0-t) of 2450 ng*hr/mL and Cmax of 558 ng/mL on Day 14. 
 
During the clinical conduct of the study, all Investigators will be required to immediately 
inform the Chief Investigator, the sponsor and Simbec of any moderate, severe, SAE or 
clinically significant non-SAE.   This notification is required in order to allow coordination of 
information and assessment on whether the stopping criteria has been met.  
 
The procedure for the ongoing and interim data review in Part 2 will be fully documented to a 
dose review manual, approved by all parties. 
The study will be discontinued if any unacceptable safety findings are identified. The Chief 
Investigator, Principal Investigators and the Sponsor will make this decision jointly.  A 
written document signed by the Investigator (or deputy) and Sponsor will be produced 
ratifying the decision. 
Please see Section 9.4.3 for possible reasons for discontinuation of an individual subject. 
9.3 
Discussion of Study Design, including the choice of Control Groups 
and Dose Leaders 
This study will be divided into 2 parts. Part 1 is a randomised, double-blind, single centre, 
placebo-controlled, SAD, phase I study designed to assess the safety, tolerability, PK and PD 
of TD139 in up to 36 healthy male subjects.  
Part 1 of this study employs a single ascending dose design; corresponding placebo control 
will be administered in order to evaluate treatment-related effects.   
The design of Part 1 of this study is typical of that used for FIM studies with a “dose leader” 
design for built-in safety.  A dose leader design will be implemented in which 2 subjects (1 


 
 
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TD139 and 1 placebo) in each cohort will be dosed approximately 24 hours before the rest of 
the Cohort. Providing there have been no safety concerns in the dose leader group up to the 
24 hour time point, the remainder of the cohort (4 subjects) will be dosed a day later and will 
be randomised in such a way that one further subject receives placebo.  This design allows 
maintenance of the “blind”. 
Safety and PK data from a minimum of 5 subjects of each cohort will be required for data 
review prior to dose escalation.   
Part 2 will be a randomised, double-blind, multi-centre, placebo-controlled, multiple dose 
expansion cohort study designed to assess the safety, tolerability, PK and PD of TD139 in up 
to 24 male and female subjects of non child-bearing potential with IPF. 
This part of the study will consist of 1 cohort of up to 24 IPF subjects, who will receive a 
single dose of TD139 or placebo via DPI once daily for 14 days (TD139 and placebo dosed 
according to Table S1).  The initial dose level used will be 3mg based on PK and safety data 
from Part 1 and on pre-clinical efficacy and safety data.  
During Part 2 there will be an interim review by the safety committee after 8 subjects have 
been dosed to review the available blinded safety and PK data. The initial 8 subjects will be 
randomised in such a way that 5 will receive TD139 and 3 will receive placebo. Following a 
review of this data a decision will made as to whether to randomise up to 4 further subjects 
(where 3 subjects will receive TD139 and 1 will receive placebo) in Cohort 1 or move on to a 
second dose level in Cohort 2 (see Table S1). The dose and PK sampling times may also be 
modified following a review of the data. 
9.4 
Selection of Study Population 
Up to 36 healthy male subjects will be required to complete Part 1 of the study.  The subjects 
will be selected from a large panel who have offered their services as volunteers to Simbec 
for the purpose of undertaking REC and Regulatory Authority-approved studies on drug 
safety, absorption and disposition. 
Part 1 of the study is to be conducted in healthy subjects and therefore participants are not 
expected to derive any therapeutic benefit from taking part.  TD139 has not been previously 
administered to humans; therefore its effects in humans are as yet unknown.  A healthy 
subject population with carefully considered inclusion/exclusion criteria will avoid the 
potential for interaction of TD139 with any underlying disease state or concomitant 
medication that it may be necessary for patients to take, while ensuring that subjects are fit 
and well enough for participation in the study.   
Up to 24 male and female subjects of non child-bearing potential with a confirmed diagnosis 
of IPF will participate in Part 2 of this study.  Eligible subjects will be identified at 4 NHS 
centres (Royal Brompton Hospital, Edinburgh University Hospital, Royal Victoria Infirmary 
and Royal Devon and Exeter Hospital). 
This clinical study can fulfil its objectives only if appropriate subjects are enrolled.  The 
following eligibility criteria are designed to select subjects for whom protocol treatment and 
procedures are considered appropriate.  All relevant medical and non-medical conditions 
should be taken into consideration when deciding whether this protocol is suitable for a 
particular subject. 


 
 
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9.4.1 
Inclusion Criteria 
Part 1 
To be confirmed at Screening Visit: 
 Healthy male subjects aged between 18 and 55 years of age. 
 Male subject willing to use a condom, if applicable (unless anatomically sterile or 
where abstaining from sexual intercourse is in line with the preferred and usual 
lifestyle of the subject) from Day 1 until 3 months afterwards. 
 Subject with a body weight of at least 50 kg and a Body Mass Index (BMI) within 
the range of 18-35 kg/m2. BMI = Body weight (kg) / [Height (m)]2. 
 Subject with no clinically significant abnormal serum biochemistry, haematology 
and urine examination values within 28 days of the first dose.   
 Subject with a negative urinary drugs of abuse screen, determined within 28 days 
of the first dose (N.B. a positive alcohol result may be repeated at the discretion of 
the Investigator). 
 Subject with negative human immunodeficiency virus (HIV) and hepatitis B 
surface antigen (Hep B) and hepatitis C virus antibody (Hep C) results. 
 Subject with no clinically significant abnormalities in 12-lead electrocardiogram 
(ECG) determined within 28 days of the first dose. 
 Subjects must be a non-smoker or a former smoker (having ceased smoking for at 
least 6 months). 
 Subjects with no clinically significant impairment in oxygen saturation. 
 Subject must satisfy a medical examiner about their fitness to participate in the 
study. 
 Subject must provide written informed consent to participate in the study. 
 Subject must be available to complete the study (including all follow up visits). 
To be confirmed at Baseline / Prior to First Dose: 
 Subject continues to meet all screening inclusion criteria. 
 Subject with a negative urinary drugs of abuse screen (including alcohol) prior to 
dosing. 
 
 


 
 
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Part 2 
To be confirmed at Screening Visit: 
 Male subject or female subject of non child-bearing potential with IPF. 
 For the purposes of this study, a female subject of non child-bearing potential is 
defined as the subject being amenorrheic for at least 12 consecutive months or at 
least 4 months post-surgical sterilisation (including bilateral fallopian tube 
ligation or bilateral oophorectomy with or without hysterectomy).   
 Male subject willing to use a condom, if applicable (unless anatomically sterile or 
where abstaining from sexual intercourse is in line with the preferred and usual 
lifestyle of the subject) from the first IMP administration until at least 3 months 
after receiving the last dose of the IMP. 
 Subject aged between 45 and 85 years of age. 
 Subjects with an FVC ≥ 45% predicted and an FEV1/FVC ratio ≥ 0.7. 
 Subjects with oxygen saturation >90% by pulse oximetry while breathing ambient 
air at rest. 
 Subjects with a diffusing capacity (DLCO) >25%. 
 
Subjects must have adequate organ function and a clinical diagnosis consistent 
with IPF prior to screening (based on the American Thoracic Society, the 
European Respiratory Society, the Japanese Respiratory Society and the Latin 
American Thoracic Association (ATS/ERS/JRS/ALAT) consensus criteria. The 
diagnosis would ordinarily have been confirmed at a multidisciplinary team 
meeting where the HRCT findings in particular will have been discussed with a 
radiologist with Respiratory expertise. 
 Subjects who are able to undergo bronchoalveolar lavage (BAL). 
 Subject must provide written informed consent to participate in the study. 
 Subject must be available to complete the study (including all follow up visits). 
 Subject with a negative urinary drugs of abuse screen, determined within 28 days 
of the first dose (N.B. a positive alcohol result may be repeated at the discretion of 
the Investigator). 
 Subject with negative human immunodeficiency virus (HIV) and hepatitis B 
surface antigen (Hep B) and hepatitis C virus antibody (Hep C) results. 
 Subject with no clinically significant abnormalities in 12-lead electrocardiogram 
(ECG) determined within 28 days of the first dose. 
To be confirmed at Baseline / Prior to First Dose: 
 Subject continues to meet all screening inclusion criteria. 
 
 


 
 
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9.4.2 
Exclusion Criteria 
Part 1 
To be confirmed at Screening Visit: 
 A clinically significant illness or surgery within 8 weeks prior to first 
administration of the study medication. 
 Significant medical history that, in the Investigator’s opinion, may adversely 
affect participation. 
 History of allergy or significant adverse reaction to drugs similar to the 
investigational drug, to nicotine, or to cholinergic drugs or to any drugs with a 
similar chemical structure. 
 History of hypersensitivity (anaphylaxis, angioedema) to any drug. 
 Use of any drug known to induce or inhibit hepatic drug metabolism, within 30 
days prior to first administration of the study medication. 
 Use of medications known to prolong QT/QTc interval within 14 days prior to the 
first administration of the study medication. 
 Any clinically significant findings of physical examination or laboratory findings 
at Screening Visit. 
 A clinically significant history of drug or alcohol abuse. 
 Receipt of regular/OTC medication within 14 days of the first dose that may have 
an impact on the safety and objectives of the study (at the Investigator’s 
discretion). 
 Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular or 
metabolic dysfunction. 
 Inability to communicate well with the Investigator (i.e., language problem, poor 
mental development or impaired cerebral function). 
 Participation in a New Chemical Entity clinical study within the previous 4 
months or a marketed drug clinical study within the previous 3 months.  (N.B.  
washout period between studies is defined as the period of time elapsed between 
the last dose of the previous study and the first dose of the next study). 
 Donation of 450 mL or more blood within the previous 3 months. 
To be confirmed at Baseline / Prior to First Dose: 
 Development of any exclusion criteria since the Screening Visit 
 Receipt of any medication since the Screening Visit that may have an impact on 
the safety and objectives of the study (at the Investigator’s discretion). 
Part 2 
 Any condition that makes the patient at unacceptable risk for bronchoscopy. 


 
 
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 Active cigarette smoking (defined as smoking more than 3 cigarettes daily within 
the last 6 months). 
 Presence of a significant co-morbidity felt to limit life expectancy to less than 12 
months. 
 HRCT pattern showing emphysema more than the extent of fibrosis of the lung 
area conducted within 12 months of Day 1. 
 Evidence of renal, hepatic, central nervous system, or metabolic dysfunction 
 Evidence of poorly controlled diabetes mellitus (defined as a HbA1c of > 59 
mmol/mol (7.5%). 
 Use of systemic immunosuppressants within 30 days of dosing. 
 Subjects currently receiving oral steroids, cytotoxic drugs (e.g. chlorambucil, 
azathioprine, cyclophosphamide, methotrexate), antifibrotic drugs (e.g. 
pirfenidone), vasodilator therapies for pulmonary hypertension (e.g bosentan), 
unapproved (e.g. INF-γ, penicillamine, cyclosporine, mycophenolate) and/or 
investigational therapies for IPF or administration of such therapies within 4 
weeks of initial screening.  A current inhaled steroid dose of ≤1000 micrograms 
Beclomethasone dipropionate (BDP) equivalent per day   is acceptable if the dose 
is anticipated to remain stable during the study.  
 History of malignancy, including carcinoma during the preceding five years. 
 History of, or current asthma. 
 Participation in a clinical study of an unlicensed drug in the previous 4 months, or 
a marketed drug study within the previous 3 months. (N.B. washout period 
between trials defined as the period of time elapsed between the last dose of the 
previous study and the first dose of the next study).  
 Females of child-bearing potential and/or with a positive pregnancy test at 
Screening Visit. 
To be confirmed at Screening Visit: 
 Development of any exclusion criteria since the Screening Visit 
9.4.3 
Removal of Subjects from Therapy or Assessment 
Each subject will be informed of their right to withdraw from the study at any time and for 
any reason. 
The Investigator may withdraw a subject from the study at any time for any of the following 
reasons: 
 If a subject experiences a serious or intolerable AE, that prevents them from 
continuing. As there have been no significant clinical or pre-clinical toxicology 
flags in studies with TD139 there are no drug specific side effects anticipated. 
 If a subject incurs a significant protocol violation. 


 
 
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 At the request of the Sponsor. 
 If the Investigator considers that remaining in the study compromises the subject’s 
health or the subject is not sufficiently cooperative. 
 If a subject is lost to follow-up. 
The reasons for any subject withdrawal will be recorded on the study completion form of the 
Case Report Form (CRF). 
If a subject is withdrawn, chooses to withdraw from the study for any reason or prematurely 
discontinues the IMP, the Chief Investigator will make every possible effort to perform the 
evaluations described for the Post Study Visit.  At the discretion of the Chief Investigator, the 
subject could continue with study assessments after discontinuation of IMP until the Post-
Study Visit is performed.  Once a subject prematurely discontinues the IMP or is withdrawn 
the subject cannot re-enter the study.  The data collected from withdrawn subjects will be 
included in the study report. 
In the event of any abnormalities considered to be clinically significant by the investigating 
physician, subjects will be followed up with appropriate medical management until values are 
considered to be clinically acceptable.  Referral or collaborative care will be organized if 
considered necessary. 
In Part 1 up to 36 subjects and in Part 2 up to 24 subjects are required to complete the study.  
Subjects who withdraw from the study before receiving any study medication will be 
replaced.  Subjects who are withdrawn from the study due to significant drug-related AEs 
will not be replaced.  Replacement of all other subjects withdrawn from the study after 
receiving study medication will be decided on a case by case basis by the Chief Investigator 
and Sponsor. 
9.5 
Additional Advice for Study Population 
9.5.1 
Contraception  
To prevent pregnancy male subjects (Part 1 and Part 2) with female partners of child 
bearing potential must take adequate contraceptive precautions for the entire duration of 
study participation. Adequate contraceptive precautions for male subjects include: 
 Condom  
 Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
The chosen contraception method(s) must be followed from the first IMP administration until 
at least 3 months after receiving the last dose of the IMP. 
9.5.2 
Sperm Donation 
Subjects must not donate sperm throughout the study and for a safety period of at least 
3 months after the final dose of IMP. 


 
 
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9.5.3 
Diet and Fluid Restrictions 
9.5.3.1 
Meal Times/Fasts 
Part 1 
Subjects will fast overnight for at least 10 hours (hrs) then - 
Lunch will be served: 4 hrs post-dose 
Dinner will be served: 8 hrs post-dose 
Snack will be served: 12 hrs post-dose 
On all non-dosing study days, whilst resident at the Clinical Unit, meals will be served at 
standard times. 
Part 2 
In Part 2 there will be no restrictions on volunteer meal times. 
9.5.3.2 
Fluid Intake 
Water is allowed ad libitum during the study.   
In Part 1, decaffeinated tea and coffee as well as squash/cordial are allowed from 4 hrs post-
dose. 
9.5.3.3 
Alcohol Intake 
The consumption of alcohol will be limited to a maximum of 2 units per day from 7 days 
prior to the administration of the first dose.  Alcohol will be avoided completely for a period 
of not less than 48 hrs prior to the first dose and throughout the study period. 
N.B.  Any deviation outside this alcohol intake restriction will be assessed on a case by case 
basis at the Investigator’s discretion (provided the subject’s alcohol intake will not impact in 
the safety aspects and objectives of the study and the subject has a negative alcohol screen 
prior to dosing). 
9.5.3.4 
Caffeine 
Food or drink containing caffeine, including coffee, tea, cola, energy drinks or chocolates 
will be avoided completely whilst the subjects are resident in the Clinical Unit (during the 
dosing period). 
9.5.3.5 
Poppy Seeds 
Subjects will be advised that they must not eat food containing poppy seeds for 3 days before 
each visit to the Clinical Unit as consumption of poppy seeds can lead to a positive opiate 
result in the drugs of abuse test. 
9.5.3.6 
Grapefruit Juice and Other Restrictions  
No food or drink containing grapefruit, cranberry, or Seville oranges (including marmalade 
and fruit juices), and/or food or drink, sweets, candies or other confectionary containing 
liquorice will be allowed from 7 days before dosing until the end of the study. 


 
 
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9.5.4 
Other Life-Style Restrictions 
9.5.4.1 
Strenuous Exercise 
Subjects should not engage in any strenuous exercise from 3 days before the first dose until 
the end of the study (i.e. completion of follow up visit). 
9.5.4.2 
Blood Donation 
Subjects will be advised that they should not donate blood for at least 3 months after the final 
study visit. 
9.6 
Investigational Medicinal Product  
9.6.1 
Identity 
The identity of each treatment is detailed in Table 9.6.1. 
Table 9.6.1 
Identity of Investigational Medicinal Products  
IMP Name 
Strength 
Presentation/Form 
Route 
TD139 
0.15mg  
Capsule 
Inhalation via DPI 
TD139 
1.5mg 
Capsule 
Inhalation via DPI 
TD139 
5mg 
Capsule 
Inhalation via DPI 
TD139 
50mg 
Capsule 
Inhalation via DPI 
Placebo for TD-139 
N/A 
Capsule 
Inhalation via DPI 
The documentation supplied with the bulk IMP will make it possible to retrace the 
composition and pharmaceutical quality of the product. 
9.6.2 
Receipt and Storage 
The IMPs will be prepared by the sponsor and supplied to the Investigator as open labeled 
bulk medication. The Sponsor must notify the Investigator prior to dispatch of IMP supplies, 
and of the anticipated date of their arrival. The IMP should arrive at each study site at least 7 
days before the first dosing day.  
The IMPs must be received at each Investigational site by a designated person, handled and 
stored safely and properly, and kept in a secured location to which only the Investigator and 
designated staff have access. After a review of the temperature monitors included with 
shipments the Sponsor will confirm that the transportation conditions were acceptable. 
The IMPs will be stored under quarantine in a segregated, study-specific area, at room 
temperature in a secure, temperature-controlled pharmacy.  
9.6.3 
Assembly and Release 
The IMP will be assembled by suitably trained staff according to local pharmacy SOPs at 
each Investigational site.  


 
 
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The IMP will be labelled as specified in Annex 13 (manufacture of investigational medicinal 
products) of the European Commission (EC) guide to Good Manufacturing Practice (GMP) 
[10]. 
In Part 1 the finished IMP will be certified by Simbec’s QP according to the Simbec SOP 
BD/324/13/29. 
The Investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Drug accountability will be noted by the Monitor during 
site visits and/or at the completion of the trial. 
9.6.4 
Administration 
All doses will be administered using the Plastiape DPI (a CE marked device). Study centre 
personnel will dispense the IMPs, and site personnel will facilitate administration when the 
subject is in the clinic, however subjects themselves will hold the DPI device during 
inhalation. 
Capsules will be loaded into the DPI as per the instructions provided with the device. A 
single device will be used per capsule actuation throughout Part 1 of the study (to avoid any 
potential carry over). This means that in Part 1, each time a subject/patient is dosed with a 
capsule they will use a new device (e.g. if the dose requires 2 capsules, then 2 devices are 
used). For Part 2, subjects will use a new device per week (7 days) for the 14 day dosing 
period.  
Two inhalations will be performed on each capsule. Any problems with drug administration 
will be noted in the CRF. All empty capsules should be retained for accountability purposes. 
In Part 2 where some of the doses will be administered at home, site staff will instruct the 
patient on how to take the drug, including the number of capsules to be inhaled each day and 
the timing of dose administration. For daily doses taken at home, patients should be advised 
to administer the study drug at approximately the same time of day. Subjects will be given a 
DPI device and enough supplies to cover the number of home doses required. Subjects will 
be asked to make a note in their diary if they have an issue whilst using the inhaler. The 
subjects will also be instructed to bring back used and unused medication at selected time-
points for drug accountability checking. 
All subjects must be trained in the use of the inhaler device on Day -1, according to the 
instructions provided with the device. Placebo capsules and inhaler devices will be provided 
for training and demonstration purposes. The same DPI devices can be used for training 
throughout the study but must not be used for dosing. 
Part 1 
A dose leader design will be implemented in which 2 subjects in each cohort will be dosed 
approximately 24 hours before the rest of the Cohort. Of these 2 subjects, 1 will receive 
TD139 and 1 will receive placebo. Providing there have been no safety concerns in the dose 
leader group up to the 24 hour time point, the remainder of the cohort (4 subjects) will be 
dosed. Of these 4 subjects, 3 will receive TD139 and 1 will receive placebo.   


 
 
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Dose escalation will only proceed in the subsequent cohorts if blinded safety and PK data (up 
to Day 3) from the subjects in the preceding cohort have been reviewed by the Sponsor and 
Chief Investigator and have been found to be satisfactory.  
Planned dose levels are as follows: 
 
Up to 6 cohorts (Cohorts 1-6) of 6 subjects will be randomly assigned to receive either a 
single oral dose of TD139 in an ascending dose fashion or a single dose of placebo. Within 
each cohort, 4 subjects will receive TD139 and 2 subjects will receive placebo.  
The 6 planned ascending doses to be studied are:  
 Cohort 1: 0.15mg TD139 or matching placebo 
 Cohort 2: 1.5mg TD139 or matching placebo 
 Cohort 3: 3mg TD139 or matching placebo 
 Cohort 4: 10mg TD139 or matching placebo 
 Cohort 5: 20mg TD139 or matching placebo 
 Cohort 6: 50mg TD139 or matching placebo 
Dose escalation will stop at any time or dose levels may be modified downwards if 
unacceptable safety findings are identified.  If there is any indication that it is not possible to 
maintain an ample safety margin with higher doses in subsequent cohorts, the dose escalation 
will be stopped or modified accordingly. Subsequent doses may vary from those planned 
depending on safety and pharmacokinetic results. The maximum dose of TD139 (50 mg) will 
not be exceeded. 
IMP administration will be documented in the Case Report Forms (CRFs). 
There will be at least 14 days between cohorts. 
Part 2 
Part 2 will include up to 24 subjects with IPF.  Randomisation of the 24 subjects will take 
place according to the schedule outlined in Table S1 with TD139 and placebo via DPI once 
daily for 14 days. The randomisation code will be designed so that the first 8 subjects will be 
randomised in a 5:3 TD139 to placebo ratio.. 
The starting dose of TD139 to be administered in Part 2 is 3mg based on interim data from 
Part 1 and on pre-clinical efficacy and safety data. The highest acceptable dose level in Part 1 
of the study will not be exceeded in Part 2. Dose escalation will not take place or dose levels 
may be modified downwards if unacceptable safety findings are identified.   
IMP administration will be documented in the Case Report Forms (CRFs) whilst the subject 
is in house or in a subject diary whilst they are at home. 
9.6.5 
Return/Destruction 
Following the Sponsor’s approval, all remaining IMP will either be returned to the Sponsor 
or sent for destruction within 8 weeks of completion of the study-dosing period.   


 
 
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All used IMP containers and unused IMP will be held under quarantine in the investigator 
site pharmacy pending return/destruction.  
9.6.6 
Method of Assigning Subjects to Treatment Groups 
Part 1 
Subjects will be allocated to treatment cohorts according to a randomisation code produced 
by Simbec Research using the PROC PLAN procedure of SAS® version 9.1.3. 
A dose leader design will be implemented for each Cohort, with 2 subjects being dosed on 
the first dosing day (of these, 1 will receive TD139 and 1 will receive placebo) and the 
remainder of the cohort dosed 24 hours later (4, including 1 further subject receiving 
placebo).  Thus the remainder of the volunteers should be randomly allocated 3:1 to receive 
TD139 or placebo. 
Up to 36 subjects will be randomised (6 cohorts of 6 subjects). 
Subjects will be numbered sequentially from 001 (i.e. 001, 002 etc).  Replacement subjects 
will be assigned the same number and randomisation as the subject they are replacing, 
however, the number will be prefixed with 100 (i.e. 101 would replace 001 etc). 
Part 2 
Subjects will be allocated to treatment according to a randomisation code produced by 
Simbec Research using the PROC PLAN procedure of SAS® version 9.1.3. Up to 24 
subjects will be randomised. The randomisation code will be designed so that the first 8 
subjects will be randomised in a 5:3 TD139 to placebo ratio and thereafter according to the 
schedule in Table S1.Following each interim review meeting in Part 2, a new randomisation 
code will be produced based on the decision of the safety committee. 
The randomisation process and subject numbering format will be documented in a Part 2 
pharmacy manual. 
9.6.7 
Selection of Doses in the Study 
For Part 1, the planned doses of TD139 to be studied are: 0.15mg, 1.5mg, 3mg, 10mg, 20mg 
and 50mg.  The maximum dose of TD139 (50 mg) will not be exceeded. 
The planned dose levels have been selected following review of non-clinical 
pharmacokinetic, safety pharmacology and toxicology data.  
Pharmacokinetic, toxicokinetic and toxicology studies in mice, rats and dogs indicate the 
drug is readily bioavailable via the inhaled route with little or no accumulation after 14-day 
dosing and is excreted in the faeces with a t1/2 of approximately 6 h. The human starting dose 
is 0.15mg. Given the NOAEL’s in mouse and dog studies, this FIM dose is over 100-fold 
below the industry accepted safe starting dose. Given the lack of adverse effects seen in the 
two species, no direct anticipated adverse drug specific side effects are expected in man nor 
are any drug interactions anticipated given the clear cytochrome profiling.  Further details 
regarding non-clinical pharmacokinetic, safety pharmacology and toxicology data can be 
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If unacceptable safety findings are identified or if there is any indication that it is not possible 
to maintain an ample safety margin with higher doses in subsequent cohorts the dose 
escalation will be stopped or modified accordingly.  Subsequent doses therefore may vary 
from those planned depending on safety and pharmacokinetic results.  If the dose escalation 
stopping criteria for Part 1 in section 9.2.3 are met, then the dose level that was tested will not 
be repeated or exceeded, however a lower dose may be given following discussion between 
the Sponsor and the Investigator. 
The selection of the 3mg starting dose for Part 2 was determined based upon interim safety 
and PK data from Part 1 (in single doses up to 10mg) and on pre-clinical efficacy and safety 
data.  The highest acceptable dose level in Part 1 of the study will not be exceeded in Part 2. 
9.6.8 
Timing of Dose for Each Subject 
In Part 1 doses will be administered on day 1 at approximately 9.00 a.m.   
In Part 2 doses will be administered on Day 1 at approximately 9.00 am. For doses taken at 
home, patients should be advised to administer the study drug at approximately the same time 
as the first dose, each day it is taken. 
9.6.9 
Blinding 
A designated individual from the Pharmacy Department at Simbec will generate the 
randomisation code under the guidance of a statistician.  All site and Sponsor personnel 
involved in the study will be blinded with regard to the IMP being administered with the 
exception of the pharmacist or designee at each site responsible for the preparation of subject 
doses who will not be blinded. A copy of the original randomisation code will be issued to 
the pharmacist or designee for this purpose. 
The Bioanalytical Scientist (at Simbec) will be provided with a copy of the randomisation 
code for the purposes of analysing the samples.  The Bioanalytical Scientist will provide the 
drug concentration data in a re-coded subject number format, in order to maintain the blind of 
study personnel.  Re-coded PK data will also be included in an interim data report following 
completion of the single-dosing periods for each cohort.  Analysis of the safety data will also 
be performed on blinded data.   
Subject doses: Once the randomisation code has been authorised as per Simbec SOPs, each 
subject dose will be packaged and labelled for individual subjects by designated individuals 
from the Pharmacy Department at each clinical site on behalf of the Sponsor.   
Code break envelopes: Once the randomisation code has been authorised as per applicable 
Simbec SOPs, the pharmacist or designee will produce individual sealed code-break 
envelopes that contain the treatment allocation(s) for each subject.  The pharmacist or 
designee will provide the Principal Investigator with the applicable set of sealed envelopes.  
Each site will store the sealed envelopes in the restricted access pharmacy. A set of code 
break envelopes will also be provided to the person responsible for pharmacovigilance. 
If the Investigator believes that knowledge of the IMPs received by a subject is essential for 
appropriate treatment of an AE, the Investigator should ideally consult the Sponsor before 
breaking the code.  In any event, the Investigator should inform the Sponsor as soon as 
practical whenever the code has been broken for a subject.  In the event that the site requires 


 
 
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emergency access to an individual subject code and personnel from the Sponsor are not 
available each site may break the blind without prior consultation with the Sponsor.  In such 
an event, the Chief Investigator, Principal Investigator or delegate would notify the Sponsor 
as soon as possible via email or fax. If the Investigator needs to break the blind for an 
individual subject, the date and reason will be recorded in the subject’s CRF. The Investigator 
will not reveal the unblinded treatment code to any other member of the clinical team 
involved in the study or to the Study Monitor. If the code is broken for any individual subject, 
the subject will be withdrawn from the study and the procedures accompanying withdrawal 
performed. If the code is broken without justification, this will be deemed a serious protocol 
violation. 
9.6.10 
Prior and Concomitant Therapy 
Part 1: Prescribed drugs should not be taken for 14 days before the first dose and throughout 
the duration of the study-dosing period. Over the counter drugs and herbal remedies and 
supplements should not be taken from 14 days prior to the first dose and throughout the 
duration of the study dosing periods.  Prescribed or over the counter drugs and herbal 
remedies and supplements taken during the 14 days before the first dose, and the reason for 
taking them, will be noted in the subject’s CRF.  Inclusion of subjects who have taken 
prescribed or over the counter medication during this period will be reviewed on a case-by-
case basis in relation to the safety aspects and objectives of this study.   
Part 2: Prescribed drugs should not be taken for 14 days before the first dose and throughout 
the duration of the study dosing period, with the exception of those listed in the study 
inclusion/exclusion section. Over the counter drugs and herbal remedies and supplements 
should not be taken from 14 days prior to the first dose and throughout the duration of the 
study dosing periods. Prescribed or over the counter drugs and herbal remedies and 
supplements taken during the 14 days before the first dose, and the reason for taking them, 
will be noted in the subject’s CRF.  Inclusion of subjects who have taken prescribed or over 
the counter medication during this period will be reviewed on a case-by-case basis in relation 
to the safety aspects and objectives of this study.   
Concomitant medication should be avoided throughout the duration of the study dosing 
periods, with the exception of paracetamol (which may be taken as an analgesic to a 
maximum of 2 g in 24 hrs) and ibuprofen (which may be taken as an analgesic to a maximum 
of 1200 mg in 24 hrs [400 mg tds]), with the agreement of the Investigator.   
If intake of concomitant medication becomes necessary for the treatment of an AE during the 
study, the daily dosage, duration and reasons for administration will be recorded on the 
subject’s CRF.  Subjects will inform the Investigator as soon as possible if concomitant 
medication was necessary during out-patient periods and the daily dosage, duration and 
reasons for administration will be recorded on the subject’s CRF. 
All concomitant medication taken during the screening period and between first dose and the 
Post-Study Visit will be recorded in the subject’s CRF. 


 
 
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9.6.11 
Treatment Compliance 
When in the Clinical Unit, doses will be taken under supervision and the exact dosing time 
for each subject will be recorded on the subject’s CRF. For doses administered by the subject 
at home, the dosing time will be recorded in a dosing diary. 
9.7 
Efficacy and Safety Variables 
9.7.1 
Efficacy and Safety Measurements Assessed and Flow Chart 
Pre-study screening assessments will be carried out in the 28 day period before the first dose.  
In Part 1 post-study assessments will be carried out 12-16 days after the final study 
procedure on day 14. 
In Part 2 post-study assessments will be carried out 26 - 30 days after the last day of the 
Study Period. 
All study personnel who have been appropriately trained will carry out study procedures. 
The Study Flow Chart is provided in Table 9.7.1 and Table 9.7.2.  
Where more than one procedure is scheduled for the same time-point, the following order of 
priority will apply:  
1. PK and PD blood sampling (a window of ± 2 min in relation to the nominal time-point is 
allowed) 
2. Vital signs and 12-lead ECG (a window of ± 10 min in relation to the nominal time-point 
is allowed. A window of ± 30 mins will apply to the Day 14, 2h time point in Part 2 to fit 
around the BAL sampling procedure). 
All pre-dose/baseline assessments may be performed within the 30 mins before dosing.  


 
 
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Table 9.7.1 
Part 1 Study Flow Chart  
Visit 
Screening 
Treatment Period  
Post Study 
In-house 
Return Visits 
Day (h) 
(Day -28 to -2) 
Day -1 
Day 1 
Day 2 (24h) 
Day 3 (48h) 
Day 8 (168h) 
Day 14 (312h) 
(Day 26-30) 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Height / Weight / BMI 1 
X 
 
 
 
 
 
 
X 
Medical History & Concurrent 
Conditions 
X 
 
 
 
 
 
 
 
Biochemistry 
Haematology 
Urinalysis 
X 
X 
X2 
X 
 
 
 
X 
Virology  
X 
 
 
 
 
 
 
 
Drugs of Abuse 
X 
X 
 
 
 
 
 
 
12-Lead ECG 
X 
X 
X3 
X 
 
X 
X 
X 
Physical  Examination 
X 
 
 
 
 
 
 
X 
Vital Signs4 
X 
X 
X5 
X 
X 
X 
X 
X 
Spirometry (FEV1 & FVC) 
X 
 
 
 
 
 
 
 
Dose  
 
 
X 
 
 
 
 
 
PK Blood Sampling 
 
 
X6 
X 
X 
 
 
 
PG & Flow Cytometry sampling 
 
X 
X7 
X 
 
 
 
X 
Galectin-3 Blood sampling 
 
X 
X8 
 
X 
 
 
X 
Exhaled Breath Condensate 
 
X 
X9 
 
 
 
 
X 
Adverse Events 
 
 
Concomitant Medication 
X 
 


 
 
 
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Table 9.7.1 Study Flow Chart Footnotes: 
1. Height at Screening Visit only. 
2. Laboratory safety samples will be taken at 6h post-dose. 
3. 12-lead ECG to be measured prior to dosing = 0h and then at 30min and 2h post-dose. 
4. Blood pressure, pulse, O2 saturation, oral temperature, respiratory rate.   
5. Vitals signs will be recorded prior to dosing = 0h and then at 5min, 15min, 30min, 2h, and 6h post-dose. 
6. PK blood sampling will be taken prior to dosing = 0h and then at 15min, 30min, 45min, 1h, 2h, 3h, 4h, 5h, 6h, 12h and 18h post-dose. 
7. Blood sampling for pharmacogenetic analysis (mRNA) and peripheral blood flow cytometry will be taken prior to dosing = 0h and then at 30min, 2h and 18h 
post-dose. 
8. Blood sampling for Galectin-3 analysis will be taken prior to dosing = 0h and then at 5h post-dose. 
9. Exhaled Breath Condensate will be taken prior to dosing = 0h and then at 1.5h post-dose.  


 
 
 
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Table 9.7.2 
Part 2 Study Flow Chart 
Visit 
Screening 
Treatment Period 
Post Study 
Day 
(Day -28 to -2) 
Day -1 
Day 1-3 
Day 4-6 
Day 7 
Day 8-13 
Day 14-15 
(Day 41-45) 
Clinic Visits 
X 
X 
X 
 
X 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Height / Weight / BMI 1 
X 
 
 
 
 
 
 
X 
Medical History & Concurrent 
Conditions 
X 
 
 
 
 
 
 
 
Biochemistry, Haematology, 
Urinalysis  
X 
X 
X2 
 
 
 
X2 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
 
Virology  
X 
 
 
 
 
 
 
 
Drugs of Abuse 
X 
X 
 
 
 
 
 
 
12-Lead ECG 
X 
X 
 
 
X3 
 
X3 
X 
Physical  Examination 
X 
 
 
 
 
 
 
X 
Vital Signs4 
X 
X 
X5 
 
X5 
 
X5 
X 
Spirometry6 
X 
 
 
 
 
 
X7 
X 
DLCO 
X 
 
 
 
 
 
 
 
Dose8 
 
 
X 
X 
X 
X 
X 
 
PK Blood Sampling  
 
 
X9 
 
X9 
 
X9 
 
PG & Flow Cytometry Sampling  
 
 
X10 
 
X10 
 
X10 
 
PBMC analysis 
 
 
X11 
 
 
 
X11 
 
Galectin-3 Blood sampling 
 
X 
X12 
 
X11 
 
X12 
X 
Exhaled Breath Condensate 
 
X 
 
 
 
 
X13 
X 
Bronchoalveolar Lavage 
 
X14 
 
 
 
 
X14 
 
Adverse Events 
 
 
Concomitant Medication 
X 
 


 
 
 
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Table 9.7.2 
Study Flow Chart Footnotes: 
1. Height at Screening Visit only. 
2. Laboratory safety samples will be taken on Day 1 at 6h post-dose, on Day 3 (prior to dosing) and Day 14 at 6h post-dose. 
3. 12-lead ECG to be measured on Day 7 and Day 15. 
4. Blood pressure, pulse, O2 saturation, oral temperature, respiratory rate. 
5. Vitals signs will be recorded on Day 1 prior to dosing = 0h and then at 5min, 15min, 30min, 2h, and 6h post-dose; Day 2,  3 and 7 prior to dosing = 0h; Day 14 prior 
to dosing = 0h and then at 5min, 15min, 30min, 2h, and 6h and 24h post-dose. (A window of ± 30 mins will apply to the Day 14, 2h timepoint in Part 2 to fit around 
the BAL sampling procedure) 
6. Spirometry measurement to be recorded at equivalent time at each timepoint (± 1h). 
7. Spirometry to be performed on Day 14 prior to BAL sampling procedure. 
8. Subjects will be dosed with the IMP at the Clinical Centre during clinic visits and will self administer the IMP on non clinic visit days.   
9. PK blood sampling will be taken on Day 1 prior to dosing = 0h and then at 15min, 30min, 45min, 1h, 2h, 3h, 4h, 5h, 6h and 12h post-dose; Day 2,  3 and 7 prior to 
dosing = 0h; Day 14 prior to dosing = 0h and then at 15min, 30min, 45min, 1h, 2h, 3h, 4h, 5h, 6h, 12h and 24h post-dose. 
10. Blood sampling for pharmacogenetic analysis (mRNA) and peripheral blood flow cytometry will be taken Day 1 prior to dosing = 0h and then at 30 min post-dose, 
Day 7 at 2h post-dose and Day 14 prior to dosing = 0h and then at 30 min post-dose. 
11. Blood sampling for pharmacogenetic analysis of peripheral blood mononuclear cells (PBMCs) will be taken Day 1 prior to dosing = 0h and Day 14 at 30 min post-
dose. 
12. Blood sampling for Galectin-3 analysis will be taken on Day 1 prior to dosing = 0h and then at 5h post-dose, Day 7 (anytime) and Day 14 prior to dosing = 0h. 
13. Exhaled Breath Condensate to be performed on Day 14 between 1h and 2h post-dose. 
14. BAL to be performed on Day 14 between 1h and 4h post-dose. (It is essential post treatment bronchoscopy is performed in the morning.) 
 
 
 
 


 
 
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9.7.1.1 
Demographic and Background Assessments 
Demographic and background assessments will be performed during the study at the time-
points specified in the Study Flow Chart, Table 9.7.1 and Table 9.7.2 and include: 
9.7.1.1.1 Demographics 
Demographic data to be collected include: age, date of birth, gender, race, ethnicity, height, 
weight and BMI.  
Height in metres (to the nearest cm) and weight in kilograms (to the nearest 0.1 kilogram) in 
indoor clothing and without shoes will be measured.  Body Mass Index = Body weight (kg) / 
[Height (m)]2 will be calculated. 
9.7.1.1.2 Medical History and Concurrent Conditions 
Relevant medical history and current conditions will be recorded in the CRF.   
9.7.1.1.3 Physical Examination 
A Physician will perform a physical examination.  The examination will include:  
Ear/nose/throat, 
ophthalmological, 
dermatological, 
cardiovascular, 
respiratory, 
gastrointestinal, central nervous system, lymph nodes and musculoskeletal systems. Other 
body systems can be examined if required, at the discretion of the Investigator. 
9.7.1.1.4 Virology 
Virology screen will include: Hep B, Hep C and HIV.  
Virology will be analysed by the local laboratory according to their local procedures. 
9.7.1.1.5 Drugs of Abuse and Alcohol 
Urine alcohol and drugs of abuse screen will include: Cannabinoids, amphetamines, 
benzodiazepines, opiates and cotinine. 
Drugs of abuse and alcohol samples will be analysed by the local laboratory according to 
their local procedures. 
9.7.1.1.6 Pregnancy Test, Menstrual and Obstetric History 
Part 2 only: Pregnancy tests will be performed on all female subjects regardless of post-
menopausal or sterilised status.  Pregnancy tests will be performed by the local laboratory 
according to their local procedures.   
9.7.1.2 
Compliance with Inclusion/Exclusion Criteria 
The Investigator will assess all participants against the study inclusion and exclusion criteria 
at the Screening Visit.  Compliance will be re-confirmed at Baseline. 
9.7.1.3 
Efficacy Assessments 
Not applicable to this study 


 
 
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9.7.1.4 
Safety Assessments 
Safety assessments will be performed during the study at the time-points specified in the 
Study Flow Charts and include: 
9.7.1.4.1 Adverse Events 
AEs and serious adverse events (SAEs) that occurred during the study along with their 
severity and relationship to study drug will be reported. 
An AE is defined as: 
Any untoward medical occurrence in a patient or clinical study subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment.  
An unexpected adverse reaction is defined as: 
An adverse reaction, the nature, or severity of which is not consistent with the applicable 
product information (e.g. investigator’s brochure for an unapproved investigational product 
or summary of product characteristics (SmPC) for an authorized product) 
AEs will be monitored throughout the study from the first dose through to the follow-up post 
study visit.  All AEs should be recorded, whether considered minor or serious, drug-related or 
not. 
All abnormal laboratory findings considered to be clinically significant must be recorded as 
AEs. 
Recording of Adverse Events 
All of the following details should be recorded in the subject’s CRF for each AE: 
 Full description of AE. 
 Date and time of onset. 
 Date and time of resolution. 
 Severity of event, to be assessed by the investigating physician in accordance with 
the definitions below. 
 Relationship to IMP to be assessed by the investigating physician in accordance 
with the definitions below. 
 Action taken (if any). 
 Outcome and details of any further follow-up. 
Grades of Adverse Event Severity 
The following grades should be used by the investigating physician to describe the severity of 
AEs. 
The following are the only grades which should be used to describe AE severity.  Only 1 
severity grade should be used for each AE (e.g. mild - moderate is not acceptable). 
 


 
 
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SEVERITY OF THE AE 
DEFINITION 
Mild AE 
The AE does not interfere with the subject’s daily routines.  It 
causes no more than slight discomfort 
Moderate AE  
The AE interferes with some aspects of the subject’s daily 
routines. 
Severe AE  
The AE causes inability to carry out the subject’s daily routine. 
Definitions of Adverse Event Causality 
The following definitions should be used by the investigating physician to describe the 
relationship between an AE and the IMP. 
The following are the only definitions, which should be used to describe the relationship 
between AEs and the IMP.  Only 1 relationship definition should be used for each AE (e.g. 
possible-probable is not acceptable). 
RELATIONSHIP 
TO 
IMP 
DEFINITION 
Almost Definite 
 Distinct temporal relationship with drug treatment. 
 Known reaction to agent or chemical group, or predicted by 
known pharmacology. 
 Event cannot be explained by subject’s clinical state or other 
factors. 
Probable 
 Reasonable temporal relationship with drug treatment. 
 Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
 Event cannot easily be explained by subject’s clinical state or 
other factors. 
Possible 
 Reasonable temporal relationship with drug treatment. 
 Event could be explained by subject’s clinical state or other 
factors. 
Unlikely 
 Poor temporal relationship with drug treatment and/or 
 Event easily explained by subject’s clinical state or other 
factors. 
Unrelated 
 Event occurred before dosing or 
 Event or intercurrent illness due wholly to factors other than 
drug treatment. 
Serious Adverse Events 
"SAE", "serious adverse reaction" or "unexpected serious adverse reaction" is defined in 
Statutory Instrument 2004 No. 1031 as any AE, adverse reaction or unexpected adverse 
reaction, respectively, that 
a. results in death, 
b. is life-threatening, 
c. requires hospitalisation or prolongation of existing inpatients’ hospitalisation, 
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e.
consists of a congenital anomaly or birth defect.
Some medical events may jeopardise the subject or may require an intervention to prevent 
one of the above characteristics/consequences. Such events (referred to as ‘important medical 
events’) should also be considered as ‘serious’ in accordance with the definition. 
SAEs must be notified immediately (and within 24 hrs) by telephone or email to 
the Sponsor’s Responsible Physician, XXXXXX (Tel: +XX X X X XXXX, E-mail: 
XXXXXXX), Study Monitor, XXX X X X  (Tel: +XXXX XXXXXX XXXX 
Email: XXXXXXXXX) 
and 
Diamond 
Pharma 
Services 
by 
XXXXXXXXXXX  This should be followed by a written report within 3 working 
days. 
AEs which meet all of the following criteria 
Serious 
Unexpected (i.e. is not consistent with the investigator's brochure) 
There is at least a reasonable possibility that there is a causal relationship between 
the event and the medicinal product  
will be classified as Suspected Unexpected Serious Adverse Reactions (SUSARs) and should 
be reported to the REC and to the MHRA in accordance with applicable regulatory 
requirements for expedited reporting.  It is the Sponsor’s responsibility to report SUSARs to 
the REC and MHRA, although this responsibility will be delegated to the Investigator. 
To ensure no confusion or misunderstanding of the difference between the terms “serious” 
and “severe,” which are not synonymous, the following note of clarification is provided: 
The term “severe” is often used to describe the severity of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This is not the same as “serious,” 
which is based on patient/event outcome or action criteria usually associated with events that 
pose a threat to a patient’s life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
Monitoring of Subjects with Adverse Events 
In the event of any abnormalities considered to be clinically significant by the investigating 
physician, subjects will be followed up with appropriate medical management until: 
It has resolved/returned to normal or baseline. 
The event has stabilized at a level acceptable to the Investigator and is not considered 
to be clinically significant. 
Pregnancy 
Pregnancies must be reported immediately and should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.  


 
 
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Pregnancy outcomes must be collected for females who took the study drug and the female 
partners of any males who took the study drug.  Consent to report information regarding these 
pregnancy outcomes should be obtained from the mother. 
9.7.1.4.2 Laboratory Safety Assessments 
9.7.1.4.2.1 Routine Laboratory Safety Screen 
Routine laboratory safety screen samples will be analysed by the local laboratory according 
to their local procedures. Printed laboratory Reports will include normal reference ranges.   
A decision regarding whether the result outside the reference range is of clinical significance 
or not shall be made by the investigator and the report will be annotated accordingly.  
Clinically significant abnormalities should be recorded on the AE page. The reference ranges 
for local laboratory parameters will also be filed in the Investigator Site File. 
Haematology: Haematology assessments will include: Haemoglobin (HGB), haematocrit 
(HCT), mean cell volume (MCV), mean cell haemoglobin (MCH), mean cell haemoglobin 
concentration (MCHC), red blood cells (RBC), white blood cells (WBC), neutrophils 
(NEUT), lymphocytes (LYMP), monocytes (MONO), eosinophils (EOS), basophils (BASO) 
and platelets (PLT).  
Biochemistry: Biochemistry assessments will include: Total protein (TP), albumin (ALB), 
total bilirubin (BIL-T), alanine transaminase (ALT), aspartate transaminase (AST), gamma 
glutamyl transferase (GGT), glucose (GLU), sodium (NA), potassium (K), bicarbonate 
(HCO3), urea and creatinine (CREA). 
Urinalysis: Urinalysis assessments will include: protein, GLU, specific gravity, ketones, 
urobilinogen, bilirubin, pH and blood).  In the event that the ‘dipstick’ was positive, RBCs, 
WBCs, epithelial cells, crystals, bacteria and casts will be examined microscopically.  The 
microscopy will be performed by the local laboratory according to their local procedures. 
Urinalysis will be performed by the local laboratory according to their local procedures. 
9.7.1.4.3 Vital signs  
Vital signs assessments will include: Systolic and diastolic blood pressure, pulse, O2 
saturation, oral temperature and respiratory rate.   
Measurements will be recorded in the supine position after 5 minutes (mins) rest.  Blood 
pressure, pulse, O2 saturation and temperature will be measured using an automated validated 
device, with an appropriately sized cuff.   
9.7.1.4.4 12-lead ECG 
12-lead ECG assessments will include: Heart rate, PR interval, QRS width, QT interval, and 
QTcB interval. 
ECGs will be recorded in the supine position after 5 mins rest.  
ECG recordings will be made using a MAC 5500 or equivalent.  Each ECG trace should be 
labelled with the study number, subject initials and subject number.  An investigator will 


 
 
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provide an interpretation of each tracing.  Clinically significant abnormalities should be 
recorded on the AE page.  
9.7.1.4.5 Concomitant Medication 
All concomitant medication taken during the screening period and between first dose and the 
Post-Study Visit will be recorded in the subject’s CRF (see Section 9.6.7). 
9.7.1.4.6 Spirometry  
All spirometry evaluations should follow the recommendations of the ATS/ERS 2005[13] .  
The spirometry equipment used during the trial must meet or exceed the minimal ATS/ERS 
recommendations for diagnostic spirometry equipment as defined in the guideline. 
Calibration of the spirometry equipment is mandatory and must be performed before the first 
study measurement. All calibration reports and subject spirometry reports should be stored as 
source data. All staff conducting the spirometry tests must have received appropriate training 
that must be documented. 
All spirometry manoeuvres should be performed in sitting position whilst wearing nose-clips. 
At least three acceptable manoeuvres should be performed for each time point, and the results 
must meet within-test and between-test criteria for acceptability. A maximum of six 
manoeuvres should be performed at any time point. 
Spirometry assessments will include: Forced Expired Volume in 1 second (FEV1), Forced 
Vital Capacity (FVC) and FEV1/FVC.  
9.7.2 
Appropriateness of Measurements 
All measurements performed in the study are standard measurements. 
The total volume of blood to be collected from each subject during the study (approximately 
177 mL in Part 1 and 242 mL in Part 2) is considered acceptable.   
9.7.3 
Primary Efficacy Variable(s) 
Not applicable 
9.7.4 
Drug Concentration Measurements 
Plasma samples for drug concentration measurements will be analysed by the Bioanalytical 
Unit at Simbec according to applicable local SOPs.  
9.7.4.1 
Pharmacokinetic Blood Sampling 
Blood samples (4 mL) for determination of TD139 plasma levels will be taken into K2 
EDTA tubes at the times specified in Table 9.7.1 and Table 9.7.2: 
Immediately upon sampling the sample will be identified with a bar coded label bearing 
details of study number, subject number, sampling time point, sample type and a unique 9 
digit identification number.  The sample will be separated by centrifugation at 1500xg and 
4°C for 10 mins.  Two (2) equal aliquots of plasma will be transferred to polypropylene tubes 
labelled identically to the original blood sample and stored at approximately -20°C pending 


 
 
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analysis. The time at which samples are taken, received into the separating room and placed 
in the freezer will be recorded in the study documentation. 
9.7.4.2 
Drug concentration measurements in BAL  
BAL samples will also be collected for determination of TD139 concentrations in alveolar 
macrophages and BAL fluid (saline). 
See Section 9.7.5.3 for full details of the BAL collection and handling. 
9.7.5 
Pharmacodynamics 
9.7.5.1 
Exhaled Breath Condensate Sampling 
Exhaled breath condensate samples will be collected using a commercially available device. 
The subject will be required to breathe into the device for approximately 10 minutes whilst in 
a seated position. 
Samples will be analysed by the University of Rochester, New York.  Specific instructions on 
sample collection, handling, and shipment will be provided in a set of sampling instructions 
to each site. 
9.7.5.2 
Galectin-3 Blood Sampling 
Blood samples (3 mL) for determination of galectin-3 plasma levels will be taken into K2 
EDTA tubes at the times specified in Table 9.7.1 and Table 9.7.2: 
Immediately upon sampling the sample will be identified with a bar coded label bearing 
details of study number, subject number, sampling time point, sample type and a unique 9 
digit identification number.  The sample will be separated by centrifugation at 1500xg and 
4°C for 10 mins.  Two (2) equal aliquots of plasma will be transferred to polypropylene tubes 
labelled identically to the original blood sample and stored at approximately -20°C pending 
analysis. The time at which samples are taken, received into the separating room and placed 
in the freezer will be recorded in the study documentation. 
9.7.5.3 
Peripheral Blood Flow Cytometry Blood Sampling 
Peripheral blood flow cytometry will be performed by the University of Edinburgh on the 
same sample that is collected for pharmacogenetic analysis (mRNA). See Section 9.7.6 for 
details. 
9.7.5.4 
Bronchoalveolar Lavage (BAL) 
In Part 2 only, BAL fluid samples will be collected for analysis of: 
 Macrophage morphology, 
 Ex-vivo macrophage function,  
 Macrophage phenotypic and mRNA expression pattern,  
 BAL analysis of soluble markers. 


 
 
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BAL samples will also be collected for determination of TD139 concentrations in alveolar 
macrophages and BAL fluid (saline) (see Section 9.7.4.2). 
BAL will be performed by flexible bronchoscopy at each centre’s local facility. Specific 
instructions for performing the bronchoscopy and collecting the BAL samples will be 
provided in a standard operating procedure, to ensure that there is consistency in technique 
between sites. Where possible, the procedure will be performed by the same site Investigator.  
Detailed information on sample handling and shipment requirements will also be contained in 
the standard operating procedure.  
9.7.6 
Pharmacogenetics 
The study includes a pharmacogenetic component. This is mandatory in order for the subject 
to participate in the study. 
A 10 mL whole blood sample will be collected into an EDTA tube at the times specified in 
Table 9.7.1 and Table 9.7.2. After collection, the sample will be inverted several times to 
prevent clotting. These samples will be shipped to the University of Edinburgh for mRNA 
analysis.  
In addition a 20ml blood sample will be collected at the times specified in Table 9.7.1 and 
Table 9.7.2. After collection PBMCs will be extracted by density centrifugation and frozen 
pending analysis. These samples will be shipped to the University of Edinburgh for analysis 
of IPF gene signatures. 
Full information on sample collection, handling, and shipment will be contained in a set of 
study Pharmacogenetic sampling instructions. The sample collection date and exact time 
must be entered on the sample collection CRF page.  
Macrophage phenotypic and mRNA expression pattern analysis will also be performed in 
BAL fluid samples at the University of Edinburgh. See Section 9.7.5.4 for details. 
9.8 
Data Quality Assurance 
At the time the study is initiated, a representative of the Sponsor will thoroughly review the 
Final Protocol and CRFs with the Investigator and staff.  During the course of the study the 
Monitor will visit each Clinical site regularly to check the completeness of the subjects 
records (including the Volunteer (Subject) Master Files (Part 1), Patient Hospital Notes 
(Part 2), laboratory and ECG print-outs), the accuracy of entries into the CRFs, the 
adherence to the Final Protocol and to ICH GCP[3], the progress of enrolment and also to 
ensure the storage, handling and accountability of the IMP.  The Investigator and key study 
personnel will be available to assist the Monitor during these visits. 
The Investigator will give the Monitor, Auditor(s), the REC, and the MHRA direct access to 
relevant clinical records to confirm their consistency with the CRF entries.  No information in 
these records about the identity of the subjects will leave the Clinical sites.  The Sponsor will 
maintain the confidentiality of all subject records. 
Study data will be fully documented in the CRFs, subject diaries (Part 2) and study log-
books.  Dated signatures will be given to account for all interventions in the study by research 
staff. 


 
 
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Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study.  Source data are contained in source documents 
(original records or certified copies). 
For the purposes of Part 1 the source data will be recorded as detailed in Table 9.8.1. 
Table 9.8.1 
Summary of Source Documentation Location (Part 1) 
Data 
Source Document 
Volunteer Master File 
Case Report Form 
Evidence of healthy subject status 
for entry into clinical study 
X 
 
Demographic Data 
 
X 
Medical History 
X 
 
Inclusion and Exclusion Criteria 
 
X 
Informed consents1 
X 
X 
Subject participation in the clinical 
study 
 
X 
Subject number in the clinical study 
 
X 
Adverse Events 
 
X 
Previous and on-going therapy 
X 
 
Concomitant therapy 
 
X 
Results of study examinations (e.g. 
ECGs, Vital signs and Laboratory 
Safety Tests)2 
 
X 
Study Visit dates 
 
X 
Administration of study medication 
 
X 
Plasma PK sample collection times 
 
X 
1. 
Copies of the Informed Consent Form should be present in the volunteer master file.  The original Informed Consent Forms 
will be maintained in the study officer file during the clinical phase and will then be transferred to the Trial manager for 
archiving with the Investigator Site File at the end of the study. 
2. 
The 12-lead ECG trace and Laboratory Safety Test print-out will be stored in the case report form. 
Table 9.8.1 (Part 1) indicates where source data will be recorded but for completeness the 
following information should also be recorded in the volunteer master file/patient hospital 
notes: 
 Clinical Study code. 
 Study visit dates (pre-dose; post-dose). 
 IMP administration (date of last dose). 
 Results of any key safety and efficacy measures from the clinical study that 
should be noted in the opinion of the Investigator. 
 Any concomitant medications used to treat the subject during the study that should 
be noted in the opinion of the Investigator. 
For Part 2 a Summary of Source Documentation Location table will be inserted into the 
study monitoring plan. 
The data collected in the CRFs during the study will be subject to quality control checking by 
clinical staff prior to sign off. 
Part 1 of the study will be subject to an independent audit by the Simbec Quality Assurance 
Unit as outlined in Simbec SOP BD/324/9/01. 


 
 
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Independent clinical quality assurance audits may be performed at any time during or 
following completion of the Study by the Sponsor, or its authorised agents and Regulatory 
Authorities and/or the REC. 
9.9 
Statistical Methods and Determination of Sample Size 
9.9.1 
Statistical and Analytical Plan 
9.9.1.1 
Primary and Secondary Variables for Assessment 
The primary safety assessment variables will be the vital signs data, ECG data, laboratory 
data and the adverse events reported.  
The secondary pharmacokinetic variables will be the following non-compartmental 
pharmacokinetic end-points:  
 Cmax  
 
 
Maximum plasma concentration  
 tmax 
 
 
 
The time to maximum observed concentration sampled during 
 
 
 
 
a dosing interval 
 λz 
 
 
 
Elimination rate constant  
 t1/2 
 
 
 
Terminal half-life  
 AUC0-t 
 
 
Area under the plasma concentration-time curve (AUC) from the 
 
 
 
 
time of dosing to the time of the last observed concentration 
 AUC0- τ  
 
Area under the plasma concentration-time curve (AUC) from the 
 
 
 
 
time of dosing to time t at steady state 
 AUC0-inf  
 
The area under the curve (AUC) extrapolated to infinity from dosing 
 
 
 
 
time, based on the last observed concentration 
 CL/F  
 
 
Plasma clearance, calculated as Dose / AUC0-inf 
 AUC% extrapolated  Residual area 
 
The secondary pharmacodynamic variables will be the peripheral blood flow cytometry data  
and galectin-3 plasma concentration data. 
 
9.9.1.2 
Definition of Evaluability 
All randomised subjects who receive at least one dose of placebo or TD139 will be included 
in the safety analysis. 
All randomised subjects who receive all doses of TD139, have sufficient plasma 
concentration by time profiles and who do not violate the protocol in such a way that may 


 
 
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invalidate or bias the results (major protocol violators) will be included in the 
pharmacokinetic analysis. 
9.9.1.3 
Description of Statistical Methods 
Simbec Research Limited will carry out the statistical analysis.  Full details of the statistical 
analyses of the data will be documented in an agreed statistical analysis plan, which will be 
finalised prior to locking the database and subsequent analysis of the study data. 
The pharmacokinetic parameters of TD139 in plasma will be determined from the individual 
concentration versus time data using WinNonlin Phoenix 32. For the calculation of derived 
pharmacokinetic parameters, concentrations below the limit of quantification (BLQ) will be 
assigned a value of zero. In case of a deviation from the theoretical time, the actual time of 
blood sample will be used in the calculation of the derived pharmacokinetic parameters.  
Derived pharmacokinetic parameters of TD139 in plasma will be listed and summarised for 
each treatment. The descriptive statistics presented will be N, n, arithmetic mean, arithmetic 
standard deviation (SD), coefficient of variation (CV%), minimum, median, maximum and 
geometric mean (with the exception of tmax). The results for tmax will be reverted back to the 
nominal time. 
Mean and individual plasma concentration-time curves of TD139 in plasma will be presented 
for each dose on both linear and semi-logarithmic scales. 
Statistical analysis will be performed using SAS® version 9.1.3 or higher.  
Dose-Proportionality/Independence: Dose proportionality will be assessed by performing a 
regression analysis of the log-transformed Cmax, AUC0-t and AUC0-inf values versus the log-
transformed dose using the power model with a fixed effect for dose and a random effect for 
subject. For each parameter a point estimate and 95% confidence interval will be calculated 
for the slope of the regression line. 
 
The power model is defined as: 
 
loge(Cmax, AUC0-t, AUC0-inf) = α + βloge(Dose) + ε, 
 
where α is the intercept, β is the slope and ε is the error term.  
 
Dose independence will be assessed for t½ and CL/F by performing a regression analysis of 
the untransformed parameters versus dose with a fixed effect for dose and a random effect for 
subject. For each parameter a point estimate and corresponding 95% confidence interval will 
be calculated for the slope of the regression line. 
Derived pharmacokinetic parameters will be presented graphically for mean Cmax, AUC0-t, 
AUC0-inf, t½ and CL/F versus dose. 
The same analysis will be carried out (for Cmax, AUCτ, t½ and CL/F) for Part 2 of the study 
on Days 1, 7 and 14. 


 
 
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Accumulation Assessment: Log-transformed trough levels at pre-dose on Day 2 through to 
Day 14 will be used to establish any accumulation of TD139. The ratio of trough 
concentrations on each consecutive day will be presented and summarized along with a 90% 
confidence interval. The analysis will be done for each dose level. 
Assessment of Steady State: Log-transformed trough concentration levels at pre-dose on 
Days 7, and 14 will be subjected to mixed effects ANOVA with study day as a fixed 
effect and subject as a random effect in order to establish whether and when steady state 
has been attained for each dose level. Back-transformed ratios for the Day 14/Day 7, 
comparisons will be presented along with corresponding 90% CI. 
Additional PK Assessments:  
Alveolar macrophage and BAL fluid concentrations of TD139 will be presented as a data 
listing. 
Drug compartment measurements in BAL and alveolar macrophages will be analysed as per 
the method set out in the study by Naderer et al[1]  (e.g. TD139AM = TD139pellet/VAC 
[where the volume of alveolar cells - VAC, is estimated at 2.42μl/106 cells])[1]. 
PD Assessments:  
Macrophage morphology parameters (ex-vivo macrophage function and BAL soluble 
markers) will be presented as a data listing. 
Exhaled breath condensate data will be presented as a data listing. 
Descriptive statistics of absolute and change from baseline for peripheral blood flow 
cytometry data will be presented at each time point by dose. 
Descriptive statistics of absolute and change from baseline for Galectin-3 plasma 
concentration data will be presented at each time point by dose. 
PG Assessments:  
Macrophage phenotypic, mRNA pattern expression analysis from BAL and analysis of 
peripheral blood mononuclear cells for IPF gene signatures will be presented as a data listing. 
Descriptive statistics of absolute and change from baseline of mRNA expression levels from 
blood leucocytes will be presented at each time point by dose. 
Safety Assessments: 
Vital signs parameters will be listed with any out of normal range values flagged. Descriptive 
statistics of absolute and change from baseline (pre-dose) supine systolic and diastolic blood 
pressure, supine pulse rate, respiration rate, oral temperature and O2 saturation at each time 
point, up to and including Day 15, will be tabulated by dose. 
The mean change from baseline data will also be plotted by dose across time, up to and 
including Day 15. 
12-Lead ECG parameters will be listed with any out of normal range values flagged. 
Descriptive statistics of absolute and change from baseline (pre-dose) heart rate, PR interval, 
QRS interval, QT interval and QTcB interval at each time point, up to and including day 15, 
will be tabulated by dose. 


 
 
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The mean change from baseline data will also be plotted by dose across time, up to and 
including Day 15. 
In addition, frequencies of QTcB data will be calculated according to the following 
categories: 
For absolute values 
 QTcB > 450 mSec 
 QTcB > 480 mSec 
 QTcB > 500 mSec 
For change from baseline 
 QTcB increase > 30 mSec  
 QTcB increase > 60 mSec 
 
All adverse events will be coded using the MedDRA dictionary, version 16.1.  
All adverse events, including those that occur prior to the first administration of the study 
drug, will be listed. Only treatment-emergent adverse events (TEAEs), i.e. existing conditions 
that worsen or events that occur during the course of the study after administration of study 
drug, will be included within the summary tables. Adverse event summaries will be presented 
by treatment and overall (data from all dose groups will be pooled). 
An overall summary of adverse events will be produced including the number of TEAEs; the 
number and percentage of subjects reporting at least one: TEAE, serious TEAE, TEAE 
leading to withdrawal from the study; the number and percentage of subjects reporting 
TEAEs by severity and relationship to study drug.   
The number of TEAEs and the number and percentage of subjects reporting at least one 
TEAE will be tabulated by system organ class (SOC) and preferred term (PT). A subject 
reporting multiple episodes of a particular adverse event within a study period will only 
contribute one count towards the corresponding system organ class and preferred term within 
that study period. 
In addition, the number and percentage of subjects reporting TEAEs will be tabulated by 
maximum severity and strongest relationship to study drug. For the summary of TEAEs by 
severity, if a subject has multiple events occurring within the same SOC or preferred term, 
the event with the highest severity will be counted. Similarly, for TEAEs by relationship to 
study drug, if a subject has multiple events occurring within the same SOC or preferred term, 
the event with the highest association to study drug will be counted.   
Biochemistry, haematology and urinalysis parameters will be listed with any out of normal 
range values flagged. Laboratory test results that are out of normal range will also be 
presented separately along with normal reference ranges. Descriptive statistics of absolute 
and change from baseline (pre-dose) values for each biochemistry and haematology 
parameter at each time point, up to and including day 15, will be tabulated by dose. 


 
 
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Frequencies of the total number of subjects randomised, completed, and prematurely 
discontinued (including reason for discontinuation) from the study will be summarised by 
dose. Additionally the frequency of subjects within each analysis population (safety, PK) will 
be summarised by dose. 
Demographic data will be listed and descriptive statistics will be tabulated for the continuous 
variables age, height, weight and BMI and frequencies for the categorical variable race. 
These descriptive statistics will be presented by dose and overall. 
9.9.2 
Sample Size Calculation 
No formal sample size calculation has been performed. The number of subjects is considered 
sufficient to meet the safety objectives of Part 1 of the study. For Part 2 all PD 
measurements are exploratory and will provide information for a clinical Phase 2b study. 


 
 
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10 
PRACTICAL CONSIDERATIONS 
10.1 
Storage of Data 
The Investigator Site File (ISF) and associated study documentation will be archived for at 
least 5 years after the conclusion of the study (last subject last visit) as per The Medicines for 
Human Use (Clinical Trials) Amendment Regulations 2006 (No. 1928)[4].  The study 
documentation may be transferred to an offsite storage facility during this period but will 
remain under the control of Simbec.   
The Sponsor has delegated the set up and maintenance of the Sponsor Trial Master File 
(TMF) to Simbec.  The TMF will be returned to the Sponsor at the end of the study, who will 
archive it for at least 5 years after the conclusion of the study.   
10.2 
Protocol Amendments 
Changes in the Study Protocol must take the form of written protocol amendments and shall 
require the approval of all persons responsible for the study (see Section 1).  
A protocol amendment is deemed to constitute a substantial protocol amendment if it is 
considered to be likely to affect to a significant degree either: 
a. the safety or physical or mental integrity of the subjects of the study 
b. the scientific value of the study 
c. the conduct or management of the study 
d. the quality or safety of any IMP used in the study. 
Such amendments must be submitted to the REC responsible for the study and the MHRA for 
approval prior to implementation. 
Protocol amendments required for urgent safety reasons may be implemented immediately.  
However, the REC and MHRA must be notified in writing within 3 days of the measures 
taken and the reasons for implementation. 
All other amendments shall be deemed to be non-substantial and as such do not need the prior 
approval of the REC and the MHRA. 
10.3 
Confidentiality 
The Investigators must agree to maintain the confidentiality of the study at all times and must 
not reveal any information relating to the study without express permission from the study 
Sponsor. 
10.4 
Study Report and Publication Policy 
Simbec will investigate and analyse the data generated with all due speed. 
A draft study report will be sent to the Sponsor for review.  The Sponsor will forward any 
comments on the draft study report to the trial manager within 30 days of receipt.  Upon 
receipt of these comments a final, QA approved report will be issued with all due speed.  A 
copy of the report will be forwarded to the Sponsor. 


 
 
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The Investigator will obtain the Sponsor’s written permission before any information 
concerning this study is submitted for publication. 


 
 
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11 
REFERENCES 
[1] 
 Naderer O. et al. Antimicrob. Agents Chemother. 2014, 58(1):419. 
 
[2] 
 World Health Association Declaration of Helsinki. Recommendations guiding 
physicians in biomedical research involving human subjects. Adopted by the 18th 
WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 29th 
WMA General Assembly, Tokyo, Japan, October 1975, 35th WMA General 
Assembly, Venice, Italy, October 1983, 41st WMA General Assembly, Hong 
Kong, September 1989, and 48th WMA General Assembly, Somerset West, 
Republic of South Africa, October 1996, 52nd WMA General Assembly, 
Edinburgh, Scotland, October 2000, 53rd WMA General Assembly, Washington 
2002 (Note of Clarification on Paragraph 29 added), 55th WMA General 
Assembly, Tokyo 2004 (Note for Clarification on Paragraph 30 added), 59th WMA 
General Assembly, Seoul, October 2008 and 64th WMA General Assembly, 
Fortaleza, Brazil, October 2013. 
 
[3] 
 ABPI (The Association of the British Pharmaceutical Industry). Guidelines for 
Phase 1 Clinical Trials. 2012 edition. 
 
[4] 
 ICH (International Conference on Harmonisation) Harmonised Tripartite 
Guideline for Good Clinical Practice (GCP) (CPMP/ICH/135/95) 1996. 
 
[5] 
 The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory 
Instrument 2004 No. 1031) and subsequent amendments. 
 
[6] 
 Insurance and compensation in the event of injury in Phase I clinical trials 2012. 
Guidance developed by the ABPI (The Association of the British Pharmaceutical 
Industry), the BioIndustry Association and the Clinical Contract Research 
Association in consultation with the Department of Health and the National 
Research Ethics Service 
 
[7] 
 Mahendran, S. and Sethi, T. (2012). Treatments in idiopathic pulmonary fibrosis: 
time for a more targeted approach? Q. J. Med. 105:929–934 
 
[8] 
 Woodcock, H.V. and Maher, T.M. (2014). The treatment of idiopathic pulmonary 
fibrosis. F1000Prime Reports. 6:16 
 
 
[9] 
 Navaratnam, V. et al. (2011) The rising incidence of idiopathic pulmonary fibrosis 
in the U.K. Thorax. 66, 462-467 
 
[10] 
 Raghu, G. et al. (2006) Incidence and prevalence of idiopathic pulmonary fibrosis. 
Am. J. Respir. Crit. Care Med. 174, 810-816 
 
[11] 
 Investigator’s Brochure.  


 
 
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[12] 
 European Commission. EudraLex The rules governing medicinal products in the 
European Union – Volume 4: Good Manufacturing Practice Guidelines 
 
[13] 
 ATS/ERS (2005) Taskforce: Standardization Of Lung Function Testing. Available 
from http://www.thoracic.org/statements/resources/pfet/pft1.pdf 
 


 
 
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APPENDIX 1: DECLARATION OF HELSINKI (BRAZIL, 2013) 
DECLARATION OF HELSINKI (BRAZIL, 2013) 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.  
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 
or other health care professionals and never with the research subjects, even though they have given 
consent. 


 
 
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10. 
Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
11. 
Medical research should be conducted in a manner that minimises possible harm to the environment. 
12. 
Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other 
health care professional. 
13. 
Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. 
Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
15. 
Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits  
16. 
In medical practice and in medical research, most interventions involve risks and burdens. 
 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17. 
All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
18. 
Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19. 
Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
20. 
Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 


 
 
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Scientific Requirements and Research Protocols  
21. 
Medical research involving human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected. 
22. 
The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. 
The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence 
and must be duly qualified. It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.  
 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. No 
amendment to the protocol may be made without consideration and approval by the committee. After 
the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.  
Privacy and Confidentiality  
24. 
Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information. 
Informed Consent  
25. 
Participation by individuals capable of giving informed consent as subjects in medical research must 
be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. 
In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods used to deliver the 
information. 
 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 


 
 
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preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.       
 
All medical research subjects should be given the option of being informed about the general outcome 
and results of the study. 
27. 
When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. 
For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised representative. These individuals must not be included in 
a research study that has no likelihood of benefit for them unless it is intended to promote the health 
of the group represented by the potential subject, the research cannot instead be performed with 
persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29. 
When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorised representative. The potential subject’s dissent should be 
respected. 
30. 
Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research  group. In such circumstances the 
physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 
31. 
The physician must fully inform the patient which aspects of their care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never adversely affect the patient-physician relationship. 
32. 
For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, 
storage and/or reuse. There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
 
Where for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine 
the efficacy or safety of an intervention  
 
and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.  


 
 
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Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. 
In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial 
in the trial. This information must also be disclosed to participants during the informed consent 
process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness 
and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration should not be 
accepted for publication. 
Unproven Interventions in Clinical Practice 
37. 
In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available. 
October 2013 
 

SAP_001.pdf: 
Galecto Biotech AB 
Statistical Analysis Plan - Part 1 
A randomised, double-blind, multi centre, placebo-controlled dose 
escalation study in healthy subjects investigating the safety, tolerability 
and pharmacokinetic properties of TD139, a galectin-3 inhibitor, followed 
by an expansion cohort treating subjects with idiopathic pulmonary 
brosis (IPF) 
Clinical Phase I 
Sponsor Protocol Identification: GB-HV-01 
Simbec Protocol Identification: RD 676/25641 
Prepared by: XXXXX XXXX-Statistician I 
Version: Final 
Date: osth February 2015 
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Date 
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Date 
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Simbec Research Ltd
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