RCT (Randomized Control Trial) of TD139 vs Placebo in HV's (Human Volunteers) and IPF Patients

A Placebo-controlled RCT in HV's Investigating the Safety, Tolerability and PK (Pharmacokinetic) of TD139, a Galectin-3 Inhibitor, Followed by an Expansion Cohort Treating Subjects With Idiopathic Pulmonary Fibrosis (IPF)

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.

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.

Part 1 Inclusion Criteria

• 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 the Day 1 dose of study medication 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 Day 1 dose of study medication.
• Subject with a negative urinary drugs of abuse screen, determined within 28 days of the Day 1 dose of study medication, (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 ECG determined within 28 days of the Day 1 dose of study medication.
• Subjects were non smokers or former smokers (having ceased smoking for at least 6 months).
• Subjects with no clinically significant impairment in oxygen saturation.
• Subject satisfied a medical examiner about their fitness to participate in the study.
• Subject provided written informed consent to participate in the study.
• Subject was available to complete the study (including all follow up visits).

Confirmed at Baseline / Prior to First Dose:

• Subject continued to meet all screening inclusion criteria.
• Subject with a negative urinary drugs of abuse screen (including alcohol) prior to dosing.

Exclusion Criteria

• A clinically significant illness or surgery within 8 weeks prior to the Day 1 dose of study medication.
• Significant medical history that, in the Investigator's opinion, may have adversely affected 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 the Day 1 dose of study medication.
• Use of medications known to prolong QT/QTc interval within 14 days prior to the Day 1 dose of study medication.
• Any clinically significant findings of physical examination or laboratory findings at screening.
• A clinically significant history of drug or alcohol abuse.
• Receipt of regular/over the counter medication within 14 days of the Day 1 dose of study medication that may have had 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.

Confirmed at Baseline / Prior to First Dose:

• Development of any exclusion criteria since screening.
• Receipt of any medication since screening that may have had an impact on the safety and objectives of the study (at the Investigator's discretion).

Part 2 Inclusion Criteria

• Male patient or female patient of non childbearing potential with IPF.
• Male patient willing to use a condom, if applicable (unless anatomically sterile or where abstaining from sexual intercourse was in line with the preferred and usual lifestyle of the patient) from the first dose until at least 3 months after receiving the last dose of IMP.
• Aged between 45 and 85 years of age.
• With a forced vital capacity (FVC) ≥ 45% predicted and forced expiratory volume in 1 second (FEV1)/FVC ratio ≥ 0.7.
• Oxygen saturation > 90% by pulse oximetry while breathing ambient air at rest.
• Diffusing capacity of lungs for carbon monoxide (DLCO) > 25%.
• Had 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 high resolution computed tomography (HRCT) findings in particular would have been discussed with a radiologist with respiratory expertise.
• Able to undergo BAL.
• Provided written informed consent to participate in the study.
• Available to complete the study (including all follow up visits).
• Negative urinary drugs of abuse screen, determined within 28 days of the first dose of IMP (N.B. a positive alcohol result could have been repeated at the discretion of the Investigator).
• Negative human immunodeficiency virus (HIV) and hepatitis B surface antigen (Hep B) and hepatitis C virus antibody (Hep C) results.
• No clinically significant abnormalities in 12 lead ECG determined within 28 days of the first dose of IMP.

Confirmed at Baseline / Prior to First Dose:

• Patient continued to meet all screening inclusion criteria. Exclusion Criteria
• Any condition that made 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 first dose.
• Evidence of renal, hepatic, central nervous system, or metabolic dysfunction.
• Evidence of poorly controlled diabetes mellitus (defined as a glycosylated haemoglobin (HbA1c) of > 59 mmol/mol (7.5%).
• Use of systemic immunosuppressants within 30 days of dosing.
• 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., interferon gamma (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 µg beclomethasone dipropionate equivalent per day was acceptable if the dose was anticipated to remain stable during the study.
• History of malignancy, including carcinoma during the preceding 5 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 studies 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 the screening visit.

Confirmed at Baseline / Prior to First Dose:

• Development of any exclusion criteria since the screening visit.