| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Idiopathic Pulmonary Fibrosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| A condition in which the lungs become scarred and breathing becomes increasingly difficult. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021240 |
| E.1.2 | Term | Idiopathic pulmonary fibrosis |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1 (Core Phase): The primary objective is to demonstrate the efficacy of 2 dose regimens of HZN-825 versus placebo in subjects with IPF, as determined by a comparison of change in forced vital capacity (FVC) % predicted after 52 weeks of treatment.
Part 2 (Extension Phase): The primary efficacy objective is to assess the efficacy of HZN 825 in subjects with IPF after 52 weeks of open label treatment.
|
|
| E.2.2 | Secondary objectives of the trial |
Core Phase:
1.Evaluate the effect of 2 dose regimens of PR1 vs PL1 on subjects with decline in FVC% predicted ≥10% from Baseline after 52 w of treatment
2.Evaluate the effect of 2 dose regimens of PR1 vs PL1 on the changes from Baseline in the 6MWT after 52 w of treatment
3.Evaluate the effect of 2 dose regimens of PR1 vs PL1 on the K-BILD after 52 w of treatment
4.Evaluate the effect of 2 dose regimens of PR1 vs PL1 on the L-IPF after 52 w of treatment.
5.Evaluate the effect of 2 dose regimens PR1 vs PL1 on the LCQ after 52 w of treatment.
6.Evaluate the effect of 2 dose regimens of PR1 vs PL1 on the rate of hospitalization due to respiratory distress up to 52 w of treatment.
7.Evaluate the effect of 2 dose regimens of PR1 vs PL1 on the composite endpoint of PFS, where progression includes decline in FVC% predicted ≥10% from Baseline or death over 52 w of treatment.
8.Assess safety and tolerability of PR1 based on AEs, SAEs and AESI
9.Evaluate the PK of PR1 and metabolite(s) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Core Phase:
1. Written informed consent.
2. Male or female ≥18 years of age at Screening.
3. Current diagnosis of IPF, as defined by American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Society (ALAT) guidelines [Raghu et al., 2022] and determined by central review; the date of initial diagnosis of IPF should be ≤7 years prior to Screening.
4. No recent changes or planned changes to the dose or regimen for IPF therapy, defined as:
• Receiving a stable dose of IPF-approved therapy (i.e., nintedanib or pirfenidone) for a minimum of 3 months prior to Day 1 with no plans to change the background regimen during trial participation, or
• Not currently receiving background IPF-approved therapy at Screening (either naïve to IPF-approved therapy or previously discontinued any IPF-approved therapy at least 4 weeks prior to Day 1 or drug-specific, 5 half-lives elimination period if longer than 4 weeks), and with no current plans to restart treatment during trial participation
• Subjects receiving any additional agent for IPF therapy must be on a stable regimen for at least 3 months prior to Day 1 with no current plans to change the treatment regimen during trial participation. Any previously discontinued therapy used to treat IPF must have been discontinued at least 4 weeks prior to Day 1 or 5 half-lives for that specific therapy must have elapsed, whichever is longer, with no plans to restart the therapy during trial participation.
5. Lung HRCT historically performed within 6 months prior to the
Screening Visit and according to the minimum requirements for IPF diagnosis by central review based on subject's HRCT. If an evaluable HRCT is not available within 6 months prior to Screening, an HRCT will be performed at Screening to determine eligibility, according to the same requirements as the historical HRCT. The HRCT must demonstrate a usual interstitial pneumonia or probable usual interstitial pneumonia pattern based on central review vendor interpretation. Histopathology
in combination with HRCT results supportive of an IPF or IPF likely diagnosis according to Raghu et al., 2022 can be submitted to support subject eligibility.
6. HRCT shows ≥10% to <50% parenchymal fibrosis (reticulation) and the extent of fibrotic changes is greater than the extent of emphysema on the most recent HRCT scan (central reviewer determined).
7. Meets all of the following criteria during the Screening Period, as determined by central review:
a. FVC ≥45% predicted of normal
b. forced expiratory volume in 1 second (FEV1)/FVC ≥0.7
c. DLCO corrected for hemoglobin is ≥25% and ≤90% predicted of
normal
8. Estimated minimum life expectancy of ≥30 months for non-IPF related disease, in the opinion of the Investigator.
9. Vaccinations are up to date, according to the Investigator's
discretion, given age, comorbidities and local availability prior to trial drug dosing.
10. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.
Extension Phase:
1. Written informed consent.
2. Completed the Double-blind Treatment Period (Week 52) of the Core Phase of the trial; subjects prematurely discontinued from trial drug in the Core Phase of the trial for reasons other than safety or tolerability may be included at the discretion of the Investigator after completing scheduled visits, including Week 52 assessments.
3. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the Extension Phase of the trial. |
|
| E.4 | Principal exclusion criteria |
Core Phase:
1. Any of the following cardiovascular diseases:
a. uncontrolled, severe hypertension (≥160/100 mmHg), within 6 months of Screening
b. myocardial infarction within 6 months of Screening
c. unstable cardiac angina within 6 months of Screening
2. Interstitial lung disease (ILD) associated with known primary diseases, connective tissue disorders, exposures or drugs.
3. Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are allowed). The subject must be 3 months beyond any acute infection with COVID-19 if there has been a prior infection.
4. Clinically significant pulmonary hypertension requiring chronic medical therapy.
5. Use of any of the following therapies within 4 weeks prior to Screening, during the Screening Period or planned during the trial: prednisone at steady dose >10 mg/day or equivalent or cyclosporine. Prednisone ≤10 mg/day (or equivalent dosing of glucocorticoids) is allowed. Change in regimen or dosage of any immunosuppressant during the Screening Period through the end of trial participation will require consultation with and approval by the trial Medical Monitor.
6. Use of rifampin within 2 weeks prior to Day 1 or planned during the trial.
7. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
8. Women of childbearing potential (WOCBP) or male subjects not agreeing to use highly effective method(s) of birth control throughout the trial and for 4 weeks after last dose of trial drug. Fertile male subjects must use a condom throughout the trial and for 4 weeks after the last dose of trial drug.
9. Pregnant or lactating women and women who plan to become pregnant or breast feed during the trial and within 4 weeks after the last dose of trial drug.
10. Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the subject.
11. Previous enrollment in this trial or participation in a prior HZN-825 or
SAR100842 clinical trial.
12. Known history of positive test for human immunodeficiency virus (HIV).
13. Active hepatitis (any of the following at Screening):
Hepatitis B:
•positive hepatitis B surface antigen
•positive for anti-hepatitis B core antibody (anti HBcAb) and a positive test for hepatitis B surface antibody (HBsAb) and presence of hepatitis B virus DNA
•positive for HBcAb and a negative test for HBsAb and presence of hepatitis B virus DNA
Hepatitis C:
•positive anti hepatitis C virus (anti HCV) and positive HCV RNA.
14. Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis.
15. Previous organ transplant (including allogeneic and autologous marrow transplant).
16. International normalized ratio >2, prolonged prothrombin time >1.5 × the upper limit of normal (ULN) or partial thromboplastin time >1.5 × ULN at Screening.
17. Alanine aminotransferase or aspartate aminotransferase >2.0 × ULN.
18. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at Screening.
19. Total bilirubin >1.5 × ULN. Subjects with documented diagnosis of Gilbert's syndrome may be enrolled if their total bilirubin is ≤3.0 mg/dL.
20.Moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment according to the Child-Pugh scoring system.
21.Any confirmed Grade 3 or higher laboratory abnormality.
22.Any laboratory abnormality at Screening that, in the opinion of the Investigator, would preclude the subject's participation in the trial.
23.Exposure to an experimental drug or experimental vaccine within either 30 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is the longest, prior to Day 1.
24.Any other condition that, in the opinion of the Investigator, would preclude enrollment in the trial.
Extension Phase:
1.Anticipated use of another investigational agent for any condition during the course of the trial.
2.New diagnosis of malignant condition after enrolling in Trial HZNPHZN-825-303 (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
3.Estimated minimum life expectancy ≤18 months, in the opinion of the Investigator.
4.WOCBP or male subjects not agreeing to use highly effective method(s) of birth control throughout the Extension Phase and for 4 weeks after last dose of HZN-825.
5.Pregnant or lactating women.
6.Any other new development of the disease/condition/significant laboratory test abnormality during the course of the Core Phase of the trial, in the opinion of the Investigator, that would potentially put the subject at unacceptable
risk.
7.In the opinion of the Investigator, unlikely to comply with the trial protocol or has a concomitant disease or condition that could interfere with the conduct of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Core Phase: Change in FVC % predicted from Baseline to Week 52.
Extension Phase: Change from both Baselines in FVC % predicted at Week 104. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Core Phase: From Baseline to Week 52.
Extension Phase: From Baselines to Week 104. |
|
| E.5.2 | Secondary end point(s) |
Core Phase:
1. Proportion of subjects with decline in FVC % predicted ≥10% from Baseline at Week 52.
2. Change from Baseline in the 6MWT results to Week 52.
3. Change from Baseline in K-BILD scores to Week 52.
4. Change from Baseline in L-IPF scores to Week 52.
5. Change from Baseline in LCQ scores to Week 52.
6. Time to first hospitalization due to respiratory distress from Baseline up to Week 52.
7. Time to first onset of the composite endpoint of PFS from Baseline up to Week 52, where progression includes decline in FVC % predicted ≥10% or death.
Extension Phase: Safety and Tolerability Endpoints
1. Incidence of TEAEs and the AESI (orthostatic hypotension) in the
Extension Phase.
2. Concomitant medication use in the Extension Phase
3. Change from OLE Baseline in vital signs in the Extension Phase
4. Change from OLE Baseline in 12-lead ECG measurements in the
Extension Phase
5. Change from OLE Baseline in clinical safety laboratory test results in the Extension Phase |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Core Phase: From Baseline to Week 52.
Extension Phase: From Baselines to Week 104 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 52-week Double-blind Treatment Period in the Core Phase and 52 weeks of open-label HZN-825 treatment |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| Chile |
| Japan |
| Korea, Republic of |
| Mexico |
| South Africa |
| Taiwan |
| United States |
| France |
| Germany |
| Greece |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 13 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 27 |
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