A Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of HZN-825 in Subjects With Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis Clinical Trial

Official title:

A Phase 2b Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of HZN-825 in Subjects With Idiopathic Pulmonary Fibrosis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05032066
• Other study ID #: HZNP-HZN-825-303
• Secondary ID: 2021-001253-32
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: August 25, 2021
• Est. completion date: July 2025

Study information

• Verified date: May 2024
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

HZNP-HZN-825-303 (HARBOR) comprises of 2 parts. Part 1 (Core Phase) is a randomized, double-blind, placebo-controlled, repeat-dose, multicenter trial to evaluate the efficacy, safety and tolerability of HZN-825 in participants with Idiopathic Pulmonary Fibrosis (IPF).

Part 2 (Extension Phase) is an optional, open-label, repeat-dose, multicenter extension of the Core Phase. The trial will include up to an 8-week Screening Period and a 52-week Double-blind Treatment Period in the Core Phase and 52 weeks of open-label HZN-825 treatment in the Extension Phase.

During the Core Phase, participants will be screened within 8 weeks prior to the baseline (Day 1) Visit. Approximately 135 participants who meet the trial eligibility criteria will be randomly assigned in a 1:1:1 ratio on Day 1 to receive HZN-825 300 mg QD, HZN-825 300 mg BID or matching placebo orally for 52 weeks using the following 2 stratification factors:

1. Concomitant use of approved IPF therapy (i.e., nintedanib or pirfenidone): yes or no

2. Forced vital capacity (FVC) % predicted at Baseline: ≥70% or <70%

Participants who complete the 52-week Double blind Treatment Period of the Core Phase of the trial will be invited to extend their participation in the 52-week Extension Phase of the trial.

Description:

Part 1 (Core Phase) The overall objective of the Core Phase is to investigate the efficacy, safety and tolerability of 2 dose regimens of HZN-825, a selective antagonist of lysophosphatidic acid receptor-1 (LPAR1), administered orally once daily (QD) or twice daily (BID) for 52 weeks in the treatment of participants with IPF.

Part 2 (Extension Phase) The overall objective of the Extension Phase is to investigate the long-term efficacy, safety and tolerability of HZN-825, a selective antagonist of LPAR1, administered at a dose of 300 mg BID orally to participants with IPF in a 52-week open-label extension (OLE) following completion of the Core Phase of the trial. The dose for the Extension Phase may be modified based on the results of the Core Phase.

Two types of Baseline are defined for the Extension Phase:

• OLE Baseline, defined as the latest measurement prior to the first dose of HZN-825 in the Extension Phase

• HZN-825 Baseline, defined as the latest measurement prior to the first dose of HZN-825 in either the Core Phase or the Extension Phase. For subjects who received placebo in the Core Phase, OLE Baseline will be the same as HZN-825 Baseline.

Acquired from Horizon in 2024

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 153
• Est. completion date: July 2025
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria in Core Phase:

1. Male or female =18 years of age at Screening.

2. 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 and determined by central review; the date of initial diagnosis of IPF should be =7 years prior to Screening.

3. 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

• Participants 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.

4. Lung high-resolution computed tomography (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 participant'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.

5. 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).

6. Meets all of the following criteria during the Screening Period:

1. FVC =45% predicted of normal

2. forced expiratory volume in 1 second (FEV1)/FVC =0.7

3. Diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for hemoglobin is =25% and =90% predicted of normal

7. Estimated minimum life expectancy of =30 months for non-IPF-related disease, in the opinion of the Investigator.

8. Vaccinations are up to date given age, comorbidities and local availability prior to trial drug dosing.

9. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

Key Inclusion Criteria in Extension Phase:

1. 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.

2. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the Extension Phase of the trial.

Key Exclusion Criteria Core Phase:

1. Any of the following cardiovascular diseases:

1. uncontrolled, severe hypertension (=160/100 mmHg), within 6 months of Screening

2. myocardial infarction within 6 months of Screening

3. unstable cardiac angina within 6 months of Screening

2. Interstitial lung disease (ILD) associated with known primary diseases (e.g., sarcoidosis, amyloidosis and coronavirus disease 2019 [COVID-19]), connective tissue disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus, Sjogren's, dermatomyositis, scleroderma), exposures (e.g., radiation, silica, asbestos and coal dust) or drugs (e.g., amiodarone).

3. Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are allowed). The participant 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. 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. Females must refrain from egg/ova donation for 4 weeks after the last dose of trial drug and males must refrain from sperm donation for 3 months 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 (hepatitis B: positive hepatitis B surface antigen and positive anti-hepatitis B core antibody [anti-HBcAb] and negative hepatitis B surface antibody [HBsAb] or positive for HBcAb with a positive test for HBsAb and with presence of hepatitis B virus DNA at Screening; hepatitis C: positive anti-hepatitis C virus [anti-HCV] and positive RNA HCV).

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 (ALT) or aspartate aminotransferase (AST) >2.0 × ULN.

18. Estimated glomerular filtration rate <30 mL/min/1.73 m^2 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 participant's entry in the trial.

23. Exposure to an experimental drug (with the exception of HZN-825) 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.

Key Exclusion Criteria 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 HZNP-HZN-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.

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• HZN-825
Core Phase: Participants will receive HZN-825 300 mg QD, HZN-825 300 mg BID or matching placebo orally in the morning and evening with a meal for 52 weeks according to randomization schema. Extension Phase: Participants will receive open-label HZN-825 150 mg orally in the morning and evening with a meal for 52 weeks.
• Placebo
Core Phase: Participants will receive HZN-825 300 mg QD, HZN-825 300 mg BID or matching placebo orally in the morning and evening with a meal for 52 weeks according to randomization schema. Extension Phase: Participants who received matching placebo in the Core Phase will receive open-label HZN-825 150 mg orally in the morning and evening with a meal for 52 weeks.

Locations

Country	Name	City	State
Argentina	STAT Research S.A.	Ciudad Autónoma de Buenos Aires	Buenos Aires
Argentina	Centro Medico Dra de Salvo	Ciudad de Buenos Aires
Argentina	Instituto De Enfermedades Respiratorias E Investigacion Medica	Florencio Varela	Buenos Aires
Argentina	Instituto Ave Pulmo	Mar Del Plata	Buenos Aires
Argentina	Instituto De Patologías Respiratorias	San Miguel De Tucumán	Tucumán
Argentina	Instituto Del Buen Aire	Santa Fe
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Box Hill Hospital	Box Hill	Victoria
Canada	Dynamic Drug Advancement Ltd.	Ajax	Ontario
Canada	St. Joseph's Healthcare Hamilton	Hamilton	Ontario
Chile	Centro de Investigación Curico	Curico	Maule
Chile	Universidad de Los Andes	Las Condes	Región-MetropolitanadeSantiago
Chile	MIRES/MYF estudios cli-nicos	Ñuñoa	Región-MetropolitanadeSantiago
Chile	Enroll SpA	Providencia	Región-MetropolitanadeSantiago
Chile	Centro Respiratorio Integral LTDA. (CENRESIN)	Quillota	Valparaíso
Chile	Meditek Ltda	Santiago	Región-MetropolitanadeSantiago
Chile	Centro de Investigacion del Maule	Talca
Chile	Clinical Research Chile SpA	Valdivia
France	Hopital Nord AP-HM	Marseille	Bouches-du-Rhône
France	Hopital Haut Leveque	Pessac	Gironde
France	Hôpital Bretonneau	Tours	Indre-et-Loire
Germany	Lungenklinik Hemer	Hemer	Nordrhein-Westfalen
Greece	Evangelismos General Hospital of Athens	Athens	Attiki
Greece	University General Hospital of Ioannina	Ioannina
Greece	University General Hospital of Heraklion	Iraklio
Greece	University General Hospital of Larissa	Larisa
Greece	Athens Medical Center	Marousi	Attiki
Greece	University General Hospital of Patras	Patras	Achaïa
Italy	Presidio Ospedaliero GB Morgagni L Pierantoni	Forlì	Emilia-Romagna
Italy	Azienda Ospedaliera Universitaria Senese	Siena
Japan	National Hospital Organization Himeji Medical Center	Himeji-Shi	Hyôgo
Japan	Hiroshima Prefectural Hospital	Hiroshima
Japan	National Hospital Organization Ibarakihigashi National Hospital	Naka-Gun	Ibaraki
Japan	National Hospital Organization Kinki-Chuo Chest Medical Center	Sakai-Shi	Ôsaka
Japan	Medical Hospital of Tokyo Medical and Dental University	Tokyo
Japan	Kanagawa Cardiovascular and Respiratory Center	Yokohama-Shi	Kanagawa
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggido
Korea, Republic of	Asan Medical Center-PPDS	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Mexico	Oaxaca Site management Organization (OSMO)	Centro	Oaxaca
Mexico	CICUM San Miguel	Guadalajara	Jalisco
Mexico	Hospital Universitario Dr. Jose Eleuterio González	Monterrey	Nuevo León
Mexico	Unidad de Investigación Clínica En Medicina SC	Monterrey	Nuevo León
Netherlands	Erasmus MC	Rotterdam
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk	Pomorskie
Poland	PULMAG Grzegorz Gasior Marzena Kociolek Spolka Cywilna	Katowice	Slaskie
Poland	MCM Krakow - PRATIA - PPDS	Kraków
South Africa	Dr. Ismail Abdullah Private Practice	Cape Town	Western Cape
South Africa	University of Cape Town Lung Institute (UCTLI)	Cape Town	Western Cape
South Africa	KwaPhila Health Solutions	Durban	Kwazulu - Natal
Spain	Hospital Universitario de Bellvitge	L'Hospitalet De Llobregat	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Quironsalud Madrid	Pozuelo De Alarcón	Madrid
Taiwan	Kaohsiung Medical University - Chung-Ho Memorial Hospital	Kaohsiung City
Taiwan	China Medical University Hospital - PPDS	Taichung
Taiwan	Far Eastern Memorial Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Turkey	Kocaeli University Hospital	Kocaeli
United Kingdom	Connolly Hospital Blanchardstown	Liverpool
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	St. Francis Medical Institute	Clearwater	Florida
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	Stony Brook Medicine Advanced Specialty Care	Commack	New York
United States	El Paso Pulmonary Association - Elligo	El Paso	Texas
United States	Clinical Trials Center of Middle Tennessee	Franklin	Tennessee
United States	Clinical Research of Gastonia	Gastonia	North Carolina
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Nebraska Pulmonary Specialties LLC	Lincoln	Nebraska
United States	Metroplex Pulmonary and Sleep Medicine Center	McKinney	Texas
United States	Northwestern Memorial Hospital	Milwaukee	Wisconsin
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Central Florida Pulmonary Group PA	Orlando	Florida
United States	Palmtree Clinical Research	Palm Springs	California
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Clinical Research of Rock Hill	Rock Hill	South Carolina
United States	Shelby Clinical Research	Shelby	North Carolina
United States	DBC Research Corp.	Tamarac	Florida
United States	GCP Clinical Research	Tampa	Florida
United States	Southeastern Research Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Canada,  Chile,  France,  Germany,  Greece,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  South Africa,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Core Phase: Change in Forced Vital Capacity (FVC) percent (FVC %) predicted from Baseline to Week 52		Baseline to Week 52
Primary	Extension Phase: Change from the Open Label Extension (OLE) baseline, defined as the latest measurement prior to the first dose of HZN-825 in the extension phase in FVC % predicted from Baseline to Week 104		Baseline to Week 104
Primary	Extension Phase: Change from the HZN-825 baseline, defined as the latest measurement prior to the first dose of HZN-825 in either the core phase or the extension phase in FVC % predicted from Baseline to Week 104		Baseline to Week 104
Secondary	Core Phase: Change from baseline in the 6MWT (Six-Minute Walk Test) results to Week 52	The 6-minute walk test measures the distance that a participant can quickly walk on a flat, hard surface in 6 minutes. This test evaluates the global and integrated responses of all the systems involved during exercise, including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units and muscle metabolism. The 6MWT will be performed according to ATS guidelines for the 6MWT.	Baseline to Week 52
Secondary	Core Phase: Change from baseline in K-BILD (King's Brief Interstitial Lung Disease) scores to Week 52	The King's Brief Interstitial Lung Disease Questionnaire is a self-completed health status questionnaire comprising 15 items and a 7-point Likert response scale that was developed and validated specifically for patients with IPF. The questionnaire has 3 domains: psychological, breathlessness, and activities and chest symptoms. The K-BILD domains and total score range from 0 to 100; 100 represents best health status. The minimal clinically important difference for the K-BILD total score as determined by both anchor and distribution methods is a change of 5 units.	Baseline to Week 52
Secondary	Core Phase: Change from baseline in L-IPF (Living with IPF[Idiopathic Pulmonary Fibrosis]) scores to Week 52	The questionnaire evaluates how living with IPF has impacted the quality of life of the participant with IPF. There are two modules, a 15-item symptom module with 3 domains (dyspnea, cough, and energy) all with a 24-hour recall and a 20-item impacts module with 1-week recall. All items in both modules have response options in a 5-point (0-4) numerical rating scale, where 0 = not at all and 4 = all the time.	Baseline to Week 52
Secondary	Core Phase: Change from baseline in LCQ (Leicester Cough Questionnaire) scores to Week 52	The LCQ is a participant-reported questionnaire evaluating the impact of cough on quality of life. The LCQ comprises 19 items and takes 5-10 minutes to complete. Each item assesses symptoms or the impact of symptoms over the last 2 weeks on a 7-point Likert scale. Scores in 3 domains (physical, psychological, and social) are calculated as a mean for each domain (range: 1-7). A total score (range: 3 to 21) is also calculated. Higher scores indicate better quality of life.	Baseline to Week 52
Secondary	Core Phase: Time to first hospitalization due to respiratory distress up to Week 52		Baseline to Week 52
Secondary	Core Phase: Time to first onset of the composite endpoint of PFS (progression-free survival) from Baseline up to Week 52, where progression includes decline in FVC % predicted =10% or death		Baseline to Week 52
Secondary	Core Phase: Incidence of treatment emergent adverse events (TEAEs)		Day 1 to Week 52
Secondary	Core Phase: Incidence of serous adverse events (SAEs)		Day 1 to Week 52
Secondary	Core Phase: Incidence of adverse events of special interest (AESIs): orthostatic hypotension		Day 1 to Week 52
Secondary	Core Phase: Incidence and frequency of use of concomitant medication(s)		Day 1 to Week 52
Secondary	Core Phase: Change in abnormal and clinically significant vital signs as reported as TEAEs		Day 1 to Week 52
Secondary	Core Phase: Change in abnormal clinical safety laboratory test results as reported as TEAEs		Day 1 to Week 52
Secondary	Core Phase: Change in abnormal and clinically significant 12-lead electrocardiogram (ECG) or echocardiogram measurements as reported as TEAEs.		Day 1 to Week 52
Secondary	Extension Phase: Incidence of AESIs: orthostatic hypotension		Day 1 to Week 104
Secondary	Extension Phase: Incidence of TEAEs		Day 1 to Week 104
Secondary	Extension Phase: Incidence and frequency of use of concomitant medication(s)		Baseline to Week 104
Secondary	Extension Phase: Change from trial baseline in abnormal and clinically significant vital signs reported as TEAEs		Baseline to Week 104
Secondary	Extension Phase: Change from trial baseline in abnormal and clinically significant 12-lead ECG) measurements as reported as TEAEs.		Baseline to Week 104
Secondary	Extension Phase: Change from trial baseline in abnormal clinical safety laboratory test results as reported as TEAEs		Baseline to Week 104