Clinical trial NCT05032066: A Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of HZN-825 in Subjects With Idiopathic Pulmonary Fibrosis
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2021-09-02
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: Core Phase: Change in Forced Vital Capacity (FVC) percent (FVC %) predicted from Baseline to Week 52
timeFrame: Baseline to Week 52
measure: 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
timeFrame: Baseline to Week 104
measure: 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
timeFrame: Baseline to Week 104
Secondary outcomes:
measure: Core Phase: Change from baseline in the 6MWT (Six-Minute Walk Test) results to Week 52
timeFrame: Baseline to Week 52
measure: Core Phase: Change from baseline in K-BILD (King's Brief Interstitial Lung Disease) scores to Week 52
timeFrame: Baseline to Week 52
measure: Core Phase: Change from baseline in L-IPF (Living with IPF[Idiopathic Pulmonary Fibrosis]) scores to Week 52
timeFrame: Baseline to Week 52
measure: Core Phase: Change from baseline in LCQ (Leicester Cough Questionnaire) scores to Week 52
timeFrame: Baseline to Week 52
measure: Core Phase: Time to first hospitalization due to respiratory distress up to Week 52
timeFrame: Baseline to Week 52
measure: 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
timeFrame: Baseline to Week 52
measure: Core Phase: Incidence of treatment emergent adverse events (TEAEs)
timeFrame: Day 1 to Week 52
measure: Core Phase: Incidence of serous adverse events (SAEs)
timeFrame: Day 1 to Week 52
measure: Core Phase: Incidence of adverse events of special interest (AESIs): orthostatic hypotension
timeFrame: Day 1 to Week 52
measure: Core Phase: Incidence and frequency of use of concomitant medication(s)
timeFrame: Day 1 to Week 52
measure: Core Phase: Change in abnormal and clinically significant vital signs as reported as TEAEs
timeFrame: Day 1 to Week 52
measure: Core Phase: Change in abnormal clinical safety laboratory test results as reported as TEAEs
timeFrame: Day 1 to Week 52
measure: Core Phase: Change in abnormal and clinically significant 12-lead electrocardiogram (ECG) or echocardiogram measurements as reported as TEAEs.
timeFrame: Day 1 to Week 52
measure: Extension Phase: Incidence of AESIs: orthostatic hypotension
timeFrame: Day 1 to Week 104
measure: Extension Phase: Incidence of TEAEs
timeFrame: Day 1 to Week 104
measure: Extension Phase: Incidence and frequency of use of concomitant medication(s)
timeFrame: Baseline to Week 104
measure: Extension Phase: Change from trial baseline in abnormal and clinically significant vital signs reported as TEAEs
timeFrame: Baseline to Week 104
measure: Extension Phase: Change from trial baseline in abnormal and clinically significant 12-lead ECG) measurements as reported as TEAEs.
timeFrame: Baseline to Week 104
measure: Extension Phase: Change from trial baseline in abnormal clinical safety laboratory test results as reported as TEAEs
timeFrame: Baseline to Week 104
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Palm Springs
country: United States
facility: Palmtree Clinical Research
state: California
city: Clearwater
country: United States
facility: St. Francis Medical Institute
state: Florida
city: Orlando
country: United States
facility: Central Florida Pulmonary Group PA
state: Florida
city: Tamarac
country: United States
facility: DBC Research Corp.
state: Florida
city: Tampa
country: United States
facility: GCP Clinical Research
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lincoln
country: United States
facility: Nebraska Pulmonary Specialties LLC
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Commack
country: United States
facility: Stony Brook Medicine Advanced Specialty Care
state: New York
city: Gastonia
country: United States
facility: Clinical Research of Gastonia
state: North Carolina
city: Shelby
country: United States
facility: Shelby Clinical Research
state: North Carolina
city: Winston-Salem
country: United States
facility: Southeastern Research Center
state: North Carolina
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Rock Hill
country: United States
facility: Clinical Research of Rock Hill
state: South Carolina
city: Franklin
country: United States
facility: Clinical Trials Center of Middle Tennessee
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: El Paso
country: United States
facility: El Paso Pulmonary Association - Elligo
state: Texas
city: McKinney
country: United States
facility: Metroplex Pulmonary and Sleep Medicine Center
state: Texas
city: Milwaukee
country: United States
facility: Northwestern Memorial Hospital
state: Wisconsin
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: STAT Research S.A.
state: Buenos Aires
city: Florencio Varela
country: Argentina
facility: Instituto De Enfermedades Respiratorias E Investigacion Medica
state: Buenos Aires
city: Mar Del Plata
country: Argentina
facility: Instituto Ave Pulmo
state: Buenos Aires
city: San Miguel De Tucumán
country: Argentina
facility: Instituto De Patologías Respiratorias
state: Tucumán
city: Ciudad de Buenos Aires
country: Argentina
facility: Centro Medico Dra de Salvo
city: Santa Fe
country: Argentina
facility: Instituto Del Buen Aire
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Ajax
country: Canada
facility: Dynamic Drug Advancement Ltd.
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Curico
country: Chile
facility: Centro de Investigación Curico
state: Maule
city: Las Condes
country: Chile
facility: Universidad de Los Andes
state: Región-MetropolitanadeSantiago
city: Providencia
country: Chile
facility: Enroll SpA
state: Región-MetropolitanadeSantiago
city: Santiago
country: Chile
facility: Meditek Ltda
state: Región-MetropolitanadeSantiago
city: Ñuñoa
country: Chile
facility: MIRES/MYF estudios cli-nicos
state: Región-MetropolitanadeSantiago
city: Quillota
country: Chile
facility: Centro Respiratorio Integral LTDA. (CENRESIN)
state: Valparaíso
city: Talca
country: Chile
facility: Centro de Investigacion del Maule
city: Valdivia
country: Chile
facility: Clinical Research Chile SpA
city: Marseille
country: France
facility: Hopital Nord AP-HM
state: Bouches-du-Rhône
city: Pessac
country: France
facility: Hopital Haut Leveque
state: Gironde
city: Tours
country: France
facility: Hôpital Bretonneau
state: Indre-et-Loire
city: Hemer
country: Germany
facility: Lungenklinik Hemer
state: Nordrhein-Westfalen
city: Patras
country: Greece
facility: University General Hospital of Patras
state: Achaïa
city: Athens
country: Greece
facility: Evangelismos General Hospital of Athens
state: Attiki
city: Marousi
country: Greece
facility: Athens Medical Center
state: Attiki
city: Ioannina
country: Greece
facility: University General Hospital of Ioannina
city: Iraklio
country: Greece
facility: University General Hospital of Heraklion
city: Larisa
country: Greece
facility: University General Hospital of Larissa
city: Forlì
country: Italy
facility: Presidio Ospedaliero GB Morgagni L Pierantoni
state: Emilia-Romagna
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese
city: Himeji-Shi
country: Japan
facility: National Hospital Organization Himeji Medical Center
state: Hyôgo
city: Naka-Gun
country: Japan
facility: National Hospital Organization Ibarakihigashi National Hospital
state: Ibaraki
city: Yokohama-Shi
country: Japan
facility: Kanagawa Cardiovascular and Respiratory Center
state: Kanagawa
city: Hiroshima
country: Japan
facility: Hiroshima Prefectural Hospital
city: Tokyo
country: Japan
facility: Medical Hospital of Tokyo Medical and Dental University
city: Sakai-Shi
country: Japan
facility: National Hospital Organization Kinki-Chuo Chest Medical Center
state: Ôsaka
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggido
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center-PPDS
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Guadalajara
country: Mexico
facility: CICUM San Miguel
state: Jalisco
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. Jose Eleuterio González
state: Nuevo León
city: Monterrey
country: Mexico
facility: Unidad de Investigación Clínica En Medicina SC
state: Nuevo León
city: Centro
country: Mexico
facility: Oaxaca Site management Organization (OSMO)
state: Oaxaca
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
state: Pomorskie
city: Katowice
country: Poland
facility: PULMAG Grzegorz Gasior Marzena Kociolek Spolka Cywilna
state: Slaskie
city: Kraków
country: Poland
facility: MCM Krakow - PRATIA - PPDS
city: Durban
country: South Africa
facility: KwaPhila Health Solutions
state: Kwazulu - Natal
city: Cape Town
country: South Africa
facility: University of Cape Town Lung Institute (UCTLI)
state: Western Cape
city: Cape Town
country: South Africa
facility: Dr. Ismail Abdullah Private Practice
state: Western Cape
city: L'Hospitalet De Llobregat
country: Spain
facility: Hospital Universitario de Bellvitge
state: Barcelona
city: Pozuelo De Alarcón
country: Spain
facility: Hospital Universitario Quironsalud Madrid
state: Madrid
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Medical University - Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital - PPDS
city: Taipei
country: Taiwan
facility: Far Eastern Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Kocaeli
country: Turkey
facility: Kocaeli University Hospital
city: Liverpool
country: United Kingdom
facility: Connolly Hospital Blanchardstown
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: