A Study to Explore the Therapeutic Effect of HEC585 on Delaying Forced Vital Capacity (FVC) Decline and Tolerance in Progressive Fibrosing Interstitial Lung Disease (PF-ILD) Patients

Study Overview
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Brief Summary
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The main goal of this phase llb study is to compare the efficacy and safety of two doses of HEC585 tablets with placebo which is a look-alike substance that contains no active drug in patients with progressive fibrosing interstitial lung diseases. This study is divided into two stages, i.e. main study stage with 24 weeks treatment duration followed by up to 96 weeks treatment extended study stage.

Official Title
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A Phase IIb, Multi-center, Randomized, Double Blinded, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of HEC585 Tablets in Patients With Progressive Fibrosing Interstitial Lung Disease

Conditions
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Progressive Fibrosing Interstitial Lung Disease (PF-ILD) / Progressive Pulmonary Fibrosis (PPF)

Intervention / Treatment
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* Drug: HEC585 dose A
* Drug: HEC585 dose B
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Volunteer to participate and sign the ICF. Male or female patients' age ≥ 18 years when signing the ICF. Patients with known or unknown etiology (except IPF) and clear pulmonary fibrosis on chest CT have undergone conventional clinical treatment (assessed by the investigator, including follow-up observation) for ≥ 3 months. At least two of the following criteria occurring within 12 months before screening without alternative explanation (such as infection, heart failure, etc.): i) Worsening respiratory symptoms like cough, shortness of breath. ii) Physiological evidence of disease progression (either of the following): absolute FVC (% of predicted) decline ≥ 5%. absolute DLco[Hb corrected] (% of predicted) decline ≥ 10%. iii) Radiological evidence of disease progression (one or more of the following): Increased extent or severity of traction bronchiectasis and bronchiolectasis. New ground-glass opacity with traction bronchiectasis. New fine reticulation. Increased extent or increased coarseness of reticular abnormality. New or increased honeycombing. Increased lobar volume loss. Fibrosing lung disease on HRCT, defined as reticular abnormality with traction bronchiectasis with or without honeycombing, with disease extent of >10% as confirmed by central readers. For patients with underlying connective tissue disease (CTD) should be in the stable status which is defined by no initiation of new therapy, treatment dose adjustment or withdrawal of therapy within 12 weeks prior to randomization. FEV1/FVC ≥ 0.7 before using bronchodilators. %FVC ≥ 45% predicted. Carbon Monoxide Diffusion Capacity (DLCO) corrected for Haemoglobin (Hb) ≥ 30% and ≤ 80% predicted of normal. Fertile female or male subjects agreed and promised to take effective contraception measures from signing the ICF till 30 days after last administration. Subjects are willing and able to comply with the protocol requirements and attend visits assessed by the investigator. Exclusion Criteria: Diagnosis of Idiopathic Pulmonary Fibrosis (IPF). Lung with other clinically significant abnormalities which the investigator assess to have an effect on the results of study. Significant Pulmonary Arterial Hypertension (PAH), such as meeting the following: Previous clinical or echocardiographic evidence of significant right heart failure, History of right heart catheterization showing a cardiac index ≤ 2 L/min/m², or PAH requiring parenteral therapy with epoprostenol/treprostinil. Major extrapulmonary physiological or pathological restriction (e.g. chest wall abnormality, large pleural effusion). Expected to receive lung transplantation during the study. Expected survival time is less than 6 months. History of malignant tumors within 5 years (except for localized cancers such as basal cell carcinoma and carcinoma in situ of cervix). Thyroid dysfunction that the investigator assessed to be clinically significant and needed to be treated. History of unstable or worsening heart disease during the 6 months prior to screening, including but not limited to the following: Unstable cardiac angina, Acute Myocardial infarction, Congestive heart failure (need to be treated in hospital or NYHA III/IV), Uncontrolled Severe Arrhythmias. TBIL >1.2 × ULN, AST or ALT > 1.5 × ULN. CLcr < 50 mL/min. Human immunodeficiency virus (HIV) or treponema pallidum antibody is positive. Uncontrolled hepatitis B virus infection or hepatitis C virus infection. Use of any of the following medications for the treatment of Interstitial Lung Disease (ILD) or influence the effect or safety of investigational drug: Strong inducers or strong inhibitors of CYP3A4 within 4 weeks before randomization. Azathioprine (AZA), cyclosporine, MMF ( > 1.5 g/d or equivalent dose), tripterygium glycosides , hydroxychloroquine, tacrolimus, prednisone > 15mg/day or equivalent systemic glucocorticoid therapy, and the combination of OCS+AZA+NAC within 4 weeks before randomization. Cyclophosphamide within 8 weeks before randomization. Combination of ≤ 15mg/day or equivalent systemic glucocorticoid therapy with ≤ 1.5 g/d or equivalent dose MMF within 12 weeks before randomization. Pirfenidone or nintedanib within 1 months before screening. Rituximab, Adalimumab, Secukinumab, Infliximab, Tocilizumab, Certolizumab, Golimumab, Tofacitinib, Baricitinib, Etanercept, Abatacept within 6 months before randomization. Subjects cannot complete the PFT、6MWT,or questionnaires. Allergic to any component of HEC585 Tablets. Participated in other clinical study and received the last dose within 3 months before screening. Pregnant or breastfeeding. History of smoking (≥ 10 cigarettes/day) within 3 months before screening or are unwilling to quit smoking during the study. History of alcohol or drug abuse within 6 months before the screening. Any condition that, in the opinion of the investigator, would compromise the safety or compliance of the subject, or prevent the subject from completing the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HEC585 tables does A<br> | Drug: HEC585 dose A<br>* taking HEC585 dose A orally once daily, up to 24 weeks in main stage (if applicable); up to 96 weeks in extended stage<br>|
| Experimental: HEC585 tables does B<br> | Drug: HEC585 dose B<br>* taking HEC585 dose B orally once daily, up to 24 weeks in main stage; up to 96 weeks in extended stage<br>|
| Placebo Comparator: placebo<br>Placebo once daily up to 24 weeks in main stage; HEC585 dose A once daily up to 96 weeks in extended stage | Drug: HEC585 dose A<br>* taking HEC585 dose A orally once daily, up to 24 weeks in main stage (if applicable); up to 96 weeks in extended stage<br>Drug: Placebo<br>* taking Placebo orally once daily, up to 24 weeks in main stage<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 24 in FVC (mL) compared with placebo | change in FVC (mL), measured using Spirometer, from baseline to week 24 | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 12 in FVC (mL) compared with placebo | change in FVC (mL), measured using Spirometer, from baseline to week 12 | 12 Weeks | 
| Proportion of subjects with the decline from baseline in FVC (% predicted) > 10% | The proportion of subjects whose %FVC decline from baseline by more than 10% in each treatment group at week 24 | 24 Weeks | 
| Proportion of subjects with the decline from baseline in FVC (% predicted) > 5% | The proportion of subjects whose %FVC decline from baseline by more than 5% in each treatment group at week 24 | 24 Weeks | 
| Changes of DLco (Hb correction) |  | 12 Weeks, 24 Weeks | 
| Changes of 6MWT results |  | 12 Weeks, 24 Weeks | 
| Changes of St George' s Respiratory Questionnaire (SGRQ) | The higher the score, the more serious the impact on life | 12 Weeks, 24 Weeks | 
| Changes of The University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) | Scores range from 0 to 120. The higher the score, the more severe the difficulty in breathing | 12 Weeks, 24 Weeks | 
| Changes of Leicester coughing questionnaire scores | Scores range from 3 to 21. The lower the score, the greater the impact of cough on quality of life | 12 Weeks, 24 Weeks | 
| Changes of HRCT |  | 24 Weeks | 
| Time to first acute ILD exacerbation or death | the time duration from randomization to first acute ILD exacerbation or death whichever occurs first | 24 Weeks | 
| Proportion of subjects with death caused by any reason(s) |  | 24 Weeks | 
| Proportion of subjects with death caused by the respiratory reason |  | 24 Weeks |