A Ph 1, Rndmzd, Dbl-Blinded, Pbo-Controlled, 4-Part Study to Eval the Safety, Tolerability, PK, and PD of TD-1058 Admin by Inhalation of Single (A) and Multiple (B) Ascending Doses in Healthy Subjs and Subjs With IPF (C) and Following Admin Microtracer Doses (D)
A Ph 1, Rndmzd, Dbl-Blinded, Pbo-Controlled, 4-Part Study to Eval the Safety, Tolerability, PK, and PD of TD-1058 Admin by Inhalation of Single (A) and Multiple (B) Ascending Doses in Healthy Subjs and Subjs With IPF (C) and Following Admin Microtracer Doses (D)
This is a Phase 1, 4-part, randomized, double-blinded, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TD-1058 inhaled solution. Part A is a SAD study in healthy subjects, Part B is a MAD study in healthy subjects, Part C is a multiple-dose study in subjects with IPF, and Part D studies lung bioavailability and renal elimination in Healthy Subjects.
A Phase 1, 3-part, randomized, double-blinded, placebo-controlled, first in human study.
Part A is a single ascending dose (SAD) study in up to 5 cohorts of 8 healthy subjects (6 active and 2 placebo).
Part B is a multiple ascending dose (MAD) study in up to 4 cohorts of 8 healthy subjects (6 active and 2 placebo).
Part C is a 28 day multiple-dose study in up to 2 cohorts of 12 IPF subjects (8 active and 4 placebo). The dose levels administered in Part C will not exceed those previously administered in Part B which were shown to be well tolerated.
Part D studies lung bioavailability and renal elimination in Healthy Subjects.
Inclusion Criteria:
Parts A and B:
Healthy, adult, male or female, 18 to 60 years of age, inclusive, at Screening
Body mass index (BMI) ≥ 18.0 and ≤ 30.0 kg/m2 and weighs at least 50 kg at Screening
Medically healthy with no clinically significant medical history, physical examination, spirometry, vital signs or ECGs, as deemed by the Investigator or designee
Forced expiratory volume of 1 second (FEV1) ≥80% predicted at Screening and prior to dosing
No clinically significant abnormalities in the results of laboratory evaluations at Screening and the visit scheduled between Day -7 and Day -2, as applicable, and at the discretion of the Investigator and Sponsor's Medical Monitor.
Pregnancy concerns:
Able to understand the correct technique for the use of the nebulizer device(s) at Screening, Day -1, and prior to dosing on Day 1, as applicable
Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the protocol
Part B Only: Willing to undergo 2 bronchoscopy procedures and must be able to tolerate the bronchoscopy at Screening
Part C (Subjects with IPF):
Male subjects ≥ 45 years and female subjects ≥ 55 years at Screening
Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 and weighs at least 45 kg at Screening
Diagnosis of IPF
Forced expiratory vital capacity (FVC) > 50% predicted and diffusing capacity of the lungs for carbon monoxide (DLCO) > 35% predicted
Subjects with IPF will be those who are not eligible for anti-fibrotic treatment according to NICE criteria or the subjects who are intolerant of or declined immediate commencement of standard first-line therapy with anti-fibrotics.
Pregnancy concerns:
Able to understand the correct technique for the use of the nebulizer device(s) at Screening, and prior to dosing on Day 1, as applicable
Part D (Microtracer):
Healthy, adult, male, 18 to 60 years of age, inclusive, at Screening.
BMI ≥ 18.0 and ≤ 30.0 kg/m2 at Screening and weighs at least 50 kg at Screening.
Medically healthy with no clinically significant medical history, physical examination, spirometry, vital signs or ECGs, as deemed by the Investigator or designee.
FEV1 ≥80% predicted at Screening and prior to dosing.
No clinically significant abnormalities in the results of laboratory evaluations at Screening and Day -1, as applicable and at the discretion of the Investigator and Sponsor's Medical Monitor.
Pregnancy concerns:
Able to understand the correct technique for the use of the nebulizer device(s) at Screening, and prior to dosing on Day 1, as applicable
Exclusion Criteria:
Parts A and B:
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Investigator or designee
Abnormal ECG measurements at Screening (any of the three individual ECG measurements) or prior to dosing indicating a second- or third- degree atrioventricular block, or one or more of the following:
Known personal or family history of congenital long QT syndrome or known family history of sudden death.
Supine resting bradycardia (pulse < 40 beats per minute [bpm]) or a supine resting tachycardia (pulse > 100 bpm) at Screening or prior to dosing on Day 1.
Abnormal renal function as defined by estimated glomerular filtration rate (eGFR) <90mL/min/1.73m^2 at Screening
History of clinically significant hypotensive episodes or symptoms of fainting, dizziness, or light-headedness.
History or symptoms of clinically relevant neurologic disease, including transient ischemic attack, stroke, seizure disorder, or behavioral disturbances.
History of lymphoma, leukemia, or other types of malignancy (except for completely resected squamous or basal cell cancer).
Any signs of respiratory tract infection within 6 weeks of Screening that is deemed clinically significant by the Investigator and Sponsor's Medical Monitor.
Has a current bacterial, parasitic, fungal, or viral infection; any infection requiring hospitalization or intravenous antibiotics within 6 months prior to Screening; any non respiratory tract infection requiring oral or topical antimicrobial treatment within 2 weeks prior to Screening; a history of more than one episode of herpes zoster infection.
Subject has any condition of the oro-laryngeal or respiratory tract (including, but not limited to, prior surgery) that could possibly affect drug administration, deposition, or absorption, or ability to perform lung function measurements (spirometry), as determined by the Investigator or Sponsor.
History or presence of alcoholism or drug abuse within the past 2 years prior to dosing.
Positive urine drugs of abuse test result at Screening or Day -1.
Positive urine or breath alcohol results at Screening or Day -1.
Regular alcohol consumption of > 21 units per week for males or > 14 units per week for females, with one unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine depending on type.
Excessive caffeine intake (i.e., more than 5 cups of coffee/tea per day, or equivalent, on a regular basis).
History of hypersensitivity to drugs, latex allergy, band aids, adhesive dressing, or medical tape, with a clinically significant reaction as determined by the Investigator or designee.
History of severe allergic reaction (including anaphylaxis), or severe hypersensitivity or idiosyncratic reaction to any food, insect or bee sting, or previous status asthmaticus (e.g., acute severe asthma attacks).
History or presence of hypersensitivity or idiosyncratic reaction to TD-1058, related compounds (e.g., ALK5 inhibitors), riboflavin or excipients, including severe milk protein allergy.
Uses or has used tobacco or nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, patches etc.) within 6 months prior to Screening, or has a history of > 5 pack-years.
Subject who has had a live viral vaccine (e.g., measles-mumps-rubella, varicella zoster, herpes zoster, oral polio virus, FluMist, attenuated typhoid fever vaccine, or attenuated rotavirus vaccine) within 8 weeks prior to Screening and/or is unwilling to avoid live viral vaccines for until at-least 8 weeks following completion of the final study visit.
Positive results at Screening for human immunodeficiency virus (HIV), hepatitis A virus (HAV) antibodies (anti-HAV: both immunoglobulin (Ig)G and IgM positive, IgG positive in the absence of IgM positive is acceptable), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV).
Subject who tests positive for active Coronavirus disease 2019 (COVID-19).
Subject who has a history of latent or active tuberculosis, including positive QuantiFeron® Test result at Screening.
Donation of blood (≥ 400 mL) or plasma, or significant blood loss within 56 days prior to the first dosing (including blood sampling requirement volumes from previous study participation)
Participation in another clinical study (including medical device study) and received an investigational product within 90 days for small molecule drugs (or 5 half-lives of the investigational drug if longer than 90 days) or 60 days for biologics (or 5 half-lives of the investigational drug if longer than 60 days) prior to dosing. The 90 day / 60-day / 5 half lives window will be derived from the date of the last dosing in the previous study to Day 1 of the current study.
Subject who, for any reason, is deemed by the Investigator to be inappropriate for this study; or has any condition which would confound or interfere with the evaluation of the safety, tolerability, or PK of the investigational drug; or is unable to comply with the study protocol.
Part C (Subjects with IPF):
Part D (Microtracer):
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Investigator or designee.
Abnormal ECG measurements at Screening (any of the three individual ECG measurements) or prior to dosing indicating a second- or third- degree atrioventricular block, or one or more of the following:
Known personal or family history of congenital long QT syndrome or known family history of sudden death.
Supine resting bradycardia (pulse < 40 bpm) or a supine resting tachycardia (pulse > 100 bpm) at Screening or prior to dosing on Day 1.
History of clinically significant hypotensive episodes or symptoms of fainting, dizziness, or light-headedness.
History or symptoms of clinically relevant neurologic disease, including transient ischemic attack, stroke, seizure disorder, or behavioral disturbances.
History of lymphoma, leukemia, or other types of malignancy (except for completely resected squamous or basal cell cancer).
Any signs of respiratory tract infection within 6 weeks of Screening that is deemed clinically significant by the Investigator and Sponsor's Medical Monitor.
Has a current bacterial, parasitic, fungal, or viral infection; any infection requiring hospitalization or intravenous antibiotics within 6 months prior to Screening; any non-respiratory tract infection requiring oral or topical antimicrobial treatment within 2 weeks prior to Screening; a history of more than one episode of herpes zoster infection.
Subject has any condition of the oro-laryngeal, naso-pharyngeal, or respiratory tract (including, but not limited to, prior surgery, e.g., nasal septal defects, perforation) that could possibly affect drug administration, deposition, or absorption, or ability to perform lung function measurements (spirometry), as determined by the Investigator or Sponsor.
History or presence of alcoholism or drug abuse within the past 2 years prior to dosing.
Positive urine drugs of abuse test result at Screening or Day -1.
Positive urine or breath alcohol results at Screening or Day -1.
Regular alcohol consumption of > 21 units per week, with one unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine depending on type.
Excessive caffeine intake (i.e., more than 5 cups of coffee/tea per day, or equivalent, on a regular basis).
History of hypersensitivity to drugs, latex allergy, band aids, adhesive dressing, or medical tape, with a clinically significant reaction as determined by the Investigator or designee.
History of severe allergic reaction (including anaphylaxis), or severe hypersensitivity or idiosyncratic reaction to any food, insect or bee sting, or previous status asthmaticus (e.g., acute severe asthma attacks).
History or presence of hypersensitivity or idiosyncratic reaction to TD-1058, related compounds (e.g., ALK5 inhibitors), riboflavin or excipients, including severe milk protein allergy.
Uses or has used tobacco or nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, patches etc.) within 6 months prior to Screening, or has a history of > 5 pack-years.
Subject who has had a live viral vaccine (e.g., measles-mumps-rubella, varicella zoster, herpes zoster, oral polio virus, FluMist, attenuated typhoid fever vaccine, or attenuated rotavirus vaccine) within 8 weeks prior to Screening and/or is unwilling to avoid live viral vaccines for until at-least 8 weeks following completion of the final study visit.
Positive results at Screening for HIV, HAV antibodies (anti-HAV: both IgG and IgM positive, IgG positive in the absence of IgM positive is acceptable), HBsAg or HCV.
Subject who tests positive for active COVID-19.
Subject who has a history of latent or active tuberculosis, including positive QuantiFeron® Test result at Screening.
Subject is unable to refrain from or anticipates the use of any medication, herbal remedies, or vitamin supplements
Subject has dietary restrictions incompatible with the diet that can be provided by the study site, in the opinion of the Investigator or designee or is unwilling to refrain from consuming restricted foods and beverages during the study
Donation of blood (≥ 400 mL) or plasma, or significant blood loss within 56 days prior to the first dosing (including blood sampling requirement volumes from previous study participation.
Donation of bone marrow within the last 6 months prior to dosing.
Participation in another clinical study (including medical device study) and received an investigational product within 90 days. The 90-day window will be derived from the date of the last dosing in the previous study to Day 1 of the current study.
Subject for whom the radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeds 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation (Medical Exposure) Regulations 2017 [23], shall participate in the study.
Subjects who have been administered an investigational medicinal product in an absorption, metabolism, and excretion study in the last 12 month