TD-1058 First-In-Human Study in Healthy Subjects and Subjects With Idiopathic Pulmonary Fibrosis

  • STATUS
    Recruiting
  • days left to enroll
    28
  • participants needed
    96
  • sponsor
    Theravance Biopharma
Updated on 27 April 2021
body mass index
carbon monoxide
spirometry
bronchoscopy
idiopathic pulmonary fibrosis
diffusion capacity of the lung for carbon monoxide

Summary

This is a Phase 1, 3-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, and Part C is a multiple-dose study in subjects with IPF.

Description

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.

Details
Condition Pulmonary Fibrosis, Idiopathic Pulmonary Fibrosis, usual interstitial pneumonia
Treatment Placebo, TD-1058
Clinical Study IdentifierNCT04589260
SponsorTheravance Biopharma
Last Modified on27 April 2021

Eligibility

Yes No Not Sure

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, with the exception that
Liver function tests (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], gamma-glutamyl transferase [GGT], and bilirubin[with the exception below]) must be upper limit of normal (ULN)
Subjects with isolated, stable and asymptomatic bilirubin elevation (e.g., Gilbert's syndrome) may be allowed at the discretion of the PI and sponsor's Medical Monitor
Pregnancy concerns
Female subjects must either of non-childbearing potential or if of childbearing potential, subject must not be pregnant or breastfeeding, and must agree to use a highly effective birth control method during the study and through 30 days after the last dose of study medication
Male subjects must agree to use condoms to prevent potential fetal or partner exposure through seminal fluid, in addition to the use of highly effective pregnancy prevention measures with female partners of childbearing potential during the study and through 30 days after the last dose of study medication
Subjects must agree to not donate ova or sperm through 30 days after the last dose of study medication
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 as determined by a responsible and experienced chest physician and based on established criteria defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias
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
Female subjects must either of non-childbearing potential or if of childbearing potential, subject must not be pregnant or breastfeeding, and must agree to use a highly effective birth control method during the study and through 30 days after the last dose of study medication
Male subjects must agree to use condoms to prevent potential fetal or partner exposure through seminal fluid, in addition to the use of highly effective pregnancy prevention measures with female partners of childbearing potential during the study and through 30 days after the last dose of study medication
Subjects must agree to not donate ova or sperm through 30 days after the last dose of study medication
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
Understands the study procedures in the ICF, and be willing and able to comply with the protocol
Willing to undergo 2 bronchoscopy procedures and must be able to tolerate the bronchoscopy at Screening

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
QRS > 120 msec
QTcF > 450 msec (males) or > 460 msec (females)
PR interval > 220 msec
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 = 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
Subject is unable to refrain from or anticipates the use of any medication, herbal remedies, or vitamin supplements as detailed in protocol
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 as defined in protocol
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
Subject has previously received TD-1058
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)
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). ALT, AST, and total bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Abnormal ECG measurements at Screening (any of the three individual ECG measurements) or prior to dosing indicated by QTcF > 450 msec for males, QTcF > 460 msec for females
IPF exacerbation or upper or lower respiratory tract infection in the 8 weeks prior to dosing
Severe co-existent chronic obstructive pulmonary disease, for example FEV1 < 60% predicted
Currently taking Pirfenidone or Nintedanib or who have received Pirfenidone or Nintedanib within the 30 days prior to the first dosing on Day 1. Subjects using anti-fibrotic therapy as their standard of care treatment are not to be included in the study and must not withdraw existing IPF standard of care treatments in order to fulfil study eligibility criteria
Prescribed long-term continuous home oxygen therapy (those whose use of oxygen is intermittent and for symptom relief only are not excluded)
History of alcohol consumption regularly in excess of: An average weekly intake of > 21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (~125 ml) of wine or 1 (~25 ml) measure of spirits
Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 3 months prior to Screening
History of sensitivity to any of the study medications, or components thereof (i.e., riboflavin) or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation
Subject who has a history of latent or active tuberculosis , including positive QuantiFeron Test result at Screening
Subject who tests positive for active COVID-19
A positive test for HIV antibody
Presence of HBsAg, positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment. Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) RT-PCR test is obtained
Positive urine drugs of abuse test result at Screening or Day 1
Positive urine or breath alcohol results at Screening or Day 1
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
Participated in more than 4 clinical trials within 12 months prior to the first dosing on Day 1
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
Supine resting bradycardia (pulse < 40 beats per minute [bpm]) or a supine resting tachycardia (pulse > 100 bpm) at Screening
Abnormal renal function as defined by eGRF < 60 mL/min/1.73m^2 at Screening
History of lymphoma, leukemia, or other types of malignancy (except for completely resected squamous or basal cell cancer)
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
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
Subject has previously received TD-1058
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