Study Evaluation Rentosertib (INS018_055) Administered Orally in Patients With Idiopathic Pulmonary Fibrosis (IPF)

A Prospective Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Evaluating the Efficacy and Safety of Rentosertib (INS018_055) Administered Orally Over 52 Weeks in Patients With Idiopathic Pulmonary Fibrosis (IPF)

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of Rentosertib (INS018_055) administered orally in Patients with Idiopathic Pulmonary Fibrosis.

The purpose of this study is to evaluate if Rentosertib (INS018_055) works to treat patients with Idiopathic Pulmonary Fibrosis in adults. It will also learn about the safety of Rentosertib (INS018_055).

In this study, Rentosertib (INS018_055) will be compared to a placebo (a look-alike substance that contains no drug) to investigate if Rentosertib (INS018_055) works to treat Idiopathic Pulmonary Fibrosis.

Inclusion Criteria:

1. An informed consent form (ICF) signed and dated at screening (Visit 1), prior to initiation of any study related procedures, and in accordance with ICH-GCP and local legislation.

2. Patients aged ≥40 years at time of signing the ICF.

3. Diagnosis of IPF based on the 2022 ATS/ERS/JRS/ALAT Clinical Practice Guideline, confirmed by an HRCT chest scan within 3 months prior to screening visit.

4. UIP or probable UIP with fibrosis extent >10% at HRCT.

5. Meet all the following criteria during the screening period:

   1. FVC ≥45% predicted of normal
   2. FEV1/FVC ≥0.7
   3. DLCO (corrected for hemoglobin) ≥25% and <80% predicted of normal.

6. Background antifibrotic therapies are allowed, patients may be either:

   1. on a stable therapy with nintedanib or pirfenidone as monotherapy for at least 12 weeks prior to screening visit and during the screening period and are planning to stay on this background treatment after randomization.
   2. not on a treatment with nintedanib or pirfenidone for at least 8 weeks prior to screening visit and during the screening period and do not plan to start or restart antifibrotic therapy.

7. Estimated minimum life expectancy of at least 30 months for non-IPF related disease in the opinion of the investigator.

8. Male patients and female patients of childbearing potential agree to use highly effective contraception/preventive exposure measures from the time of the first dose of the study drug (for the male patient) or the signing of the ICF (for the female patient) until 90 days after the last dose of the study drug.

Exclusion criteria:

1. Interstitial lung disease associated with known primary diseases (eg, autoimmune disease-related interstitial lung diseases, sarcoidosis and amyloidosis), exposures (eg, radiation, silica, asbestos, and coal dust), or drugs (eg, amiodarone).

2. Previous participation in a clinical study with rentosertib (active or placebo).

3. Concurrent participation in another interventional drug, device, or biological investigational research study, or use of an investigational agent within 5 half-lives of the agent (or within 8 weeks when half-life is unknown) prior to screening is not allowed.

4. Pulmonary hypertension that is clinically relevant or severe as deemed by the investigator, or other clinically significant pulmonary abnormalities.

5. Unstable cardiovascular or other disease within 6 months prior to the screening visit or during the screening period.

6. Presence of other clinically significant airway disease that may, in the opinion of the investigator, impact the study safety or efficacy objectives, such as asthma, bronchiectasis, cystic fibrosis, active aspergillosis, active tuberculosis, or other serious concomitant respiratory disorder other than pulmonary fibrosis.

7. Acute exacerbation of IPF within 6 months prior to screening visit and/or during the screening period.

8. Patients with underlying chronic liver disease (Child Pugh A, B, or C hepatic impairment), hepatic steatosis (including non-alcoholic steatohepatitis and/or other types of fatty liver diseases).

9. Patients with Gilbert's disease

10. Relevant chronic or acute infections including human immunodeficiency virus (HIV) and clinically significant viral hepatitis.

11. Aspartate aminotransferase or alanine aminotransferase ≥1.5 × upper limit of normal (ULN), and/or total bilirubin ≥1.5 × ULN, and/or gamma glutamyl transferase ≥3 × ULN, and/or alkaline phosphatase ≥1.5 × ULN at screening.

12. Estimated glomerular filtration rate <60 mL/min/1.73m2 at screening.

13. Patient with 12-lead ECG demonstrating corrected QT interval by Fridericia (QTcF) >450 ms for males and >470 ms for females at screening (Visit 1).

14. Patient with a history of lung volume reduction surgery or lung transplant.

15. Current smoker and/or cotinine (smoking) test positive.

16. History of drug abuse, drug use, or alcohol abuse within the past 3 months.

17. Major surgery performed within 3 months prior to screening visit, during the screening period, or have major surgery planned during the study period.

18. Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening visit.

19. Use of any of the following therapies within 4 weeks prior to screening visit and during the screening period or planned during the study: warfarin and immunosuppressive medications.

20. Patients currently taking endothelin receptor antagonists,phosphodiesterase type 5 inhibitors, soluble guanylate cyclase modulators, prostacyclin analogues and prostanoids, or activin signaling inhibitor.

21. Patients currently on a treatment with nerandomilast within 8 weeks prior to screening visit and during the screening period.

22. Use of any of the following drugs within 2 weeks prior to Visit 1/screening or planned during the duration of the study

    1. Strong and moderate cytochrome P450 3A4 or 1A2 inhibitors/inducers
    2. Medications associated with substantial risk for prolongation of corrected QT interval.

23. Patients who have consumed grapefruit or grapefruit juice, pomelo, Seville orange or Seville orange-containing products within 48 hours before Day 1.

24. Patients who used hormone replacement therapy in the 4 weeks prior to randomization. No hormone replacement therapy use is allowed during the study.

25. Patients with known hypersensitivity or contraindications to serine/threonine kinase inhibitors.

26. Any condition that would interfere with the interpretation of study assessments or impair study participation.

27. Any physical or psychological conditions or circumstance that, in the opinion of the investigator, may make a patient unsuitable for inclusion or unlikely or unable to complete the study or comply with study procedures and requirements.