A Multicenter Trial to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of HZN-825 in Patients With Diffuse Cutaneous Systemic Sclerosis

Diffuse Cutaneous Systemic Sclerosis Clinical Trial

Official title:

A Randomized, Double-blind, Placebo-controlled, Repeat-dose, Multicenter Trial to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of HZN-825 in Patients With Diffuse Cutaneous Systemic Sclerosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04781543
• Other study ID #: HZNP-HZN-825-301
• Secondary ID: 2020-005764-62
• Status: Recruiting
• Phase: Phase 2
• Start date: April 1, 2021
• Est. completion date: July 2025

Study information

• Verified date: March 2024
• Source: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Contact: HorizonTherapeutics
• Phone: 866-479-6742
• Email: clinicaltrials[@]horizontherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, double-blind, placebo-controlled, repeat-dose, multicenter trial. Participants will be screened within 6 weeks prior to the Baseline (Day 1) Visit. Approximately 300 participants who meet the trial eligibility criteria will be randomized on Day 1 in a 1:1:1 ratio to receive HZN-825 300 mg QD, HZN-825 300 mg BID or placebo for 52 weeks. The trial will include up to a 42-day Screening Period and a 52-week Double-blind Treatment Period. Participants will take their first dose of trial drug at the clinic and will participate in trial visits at Week 4 and every 6 weeks thereafter until Week 52. All participants who complete the Double-blind Treatment Period (Week 52) will be eligible to enter a 52-week extension trial (HZNP-HZN-825-302, NCT05626751). Participants not entering the extension trial will participate in a Safety Follow-up Visit 4 weeks after the last dose of trial drug.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: July 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Written informed consent.

2. Male or female between the ages of 18 and 75 years, inclusive, at Screening.

3. Meets the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc with a total score of =9 (Van den Hoogen et al., 2013).

4. Classified as having skin involvement proximal to the elbow and knee (diffuse cutaneous SSc subset by LeRoy and Medsger, 2001).

5. At the time of enrollment, less than or equal to 72 months (6 years) since the onset of the first SSc manifestation, other than Raynaud's phenomenon.

6. Skin thickening from SSc in the forearm suitable for repeat biopsy.

7. mRSS units =15 at Screening.

8. FVC =45% predicted at Screening, as determined by spirometry.

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

Exclusion Criteria:

1. Positive for anti-centromere antibodies with the exception that subjects who are positive for both anti-centromere and anti-topoisomerase 1 antibodies may be enrolled.

2. Diagnosed with sine scleroderma or limited cutaneous SSc.

3. Diagnosed with other autoimmune connective tissue diseases, except for fibromyalgia, scleroderma-associated myopathy and secondary Sjogren's syndrome.

4. Scleroderma renal crisis diagnosed within 6 months of the Screening Visit.

5. Any of the following cardiovascular diseases:

1. uncontrolled, severe hypertension (=160/100 mmHg) or persistent low blood pressure (systolic blood pressure <90 mmHg) within 6 months of Screening,

2. myocardial infarction within 6 months of Screening,

3. unstable cardiac angina within 6 months of Screening.

6. DLCO <40% predicted (corrected for hemoglobin). If severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure is of clinical concern for any subject, consider using a DLCO up to 6 months before the Screening Visit.

7. Pulmonary arterial hypertension (PAH) by right heart catheterization requiring treatment with more than 1 oral PAH-approved therapy or any parenteral therapy. Treatment is allowed for erectile dysfunction and/or Raynaud's phenomenon/digital ulcers.

8. Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening (topical steroids for dermatological conditions and inhaled/intranasal/intra-articular steroids are allowed).

9. Use of any other non-steroid immunosuppressive agent, small biologic molecule, cytotoxic or anti-fibrotic drug within 4 weeks of Screening, including cyclophosphamide, azathioprine (Imuran®) or other immunosuppressive or cytotoxic medication. Exceptions include mycophenolate mofetil (CellCept®), mycophenolic acid (Myfortic®), methotrexate and low-dose prednisone, as follows: use of CellCept =3 g/day, Myfortic =2.14 g/day, methotrexate =20 mg/week and prednisone =10 mg/day (or equivalent dosing of glucocorticoids) is allowed. Subjects taking CellCept, Myfortic or methotrexate must have been doing so for =6 months and the dose must have been stable for =4 weeks prior to the Day 1 Visit. Prednisone must have been at a stable dose for =8 weeks prior to the Day 1 Visit. It is acceptable to be on background low-dose prednisone and anti-malarial drug along with CellCept, Myfortic or methotrexate. Rituximab must not have been used within 6 months of the Day 1 Visit.

10. Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are allowed) at the time of randomization.

11. Use of a United States Food and Drug Administration-approved agent for SSc or an investigational agent for any condition within 90 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial.

12. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).

13. Women of childbearing potential or male subjects not agreeing to use highly effective method(s) of birth control throughout the trial and for 1 month after last dose of trial drug. Male subjects must refrain from sperm donation and females from egg/ova donation for this same time period.

14. Pregnant or lactating women.

15. 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.

16. Previous enrollment in this trial or participation in a prior HZN-825 or SAR100842 clinical trial.

17. Known history of positive test for human immunodeficiency virus (HIV). HIV testing is optional based on Investigator assessment, institutional practices or local guidelines to rule out suspected HIV or potential for a positive HIV result. Subject consent is required prior to HIV testing.

18. 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).

19. Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis.

20. Previous organ transplant (including allogeneic and autologous marrow transplant).

21. International normalized ratio >2, prolonged prothrombin time >1.5 × the upper limit of normal (ULN) or partial thromboplastin time >1.5 × ULN at Screening.

22. Alanine aminotransferase or aspartate aminotransferase >2 × ULN.

23. Estimated glomerular filtration rate <30 mL/min/1.73 m^2 at Screening.

24. Total bilirubin >2 × ULN. Subjects with documented diagnosis of Gilbert's syndrome may be enrolled if their total bilirubin is =3.0 mg/dL.

25. Any other condition that, in the opinion of the Investigator, would preclude enrollment in the trial.

Related Conditions & MeSH terms

• Diffuse Cutaneous Systemic Sclerosis
• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis
• Sclerosis, Systemic

Intervention

Drug:
• HZN-825 BID
300 mg oral tablets BID
• Placebo
Placebo BID
• HZN-825 QD
300 mg oral tablets QD

Locations

Country	Name	City	State
Argentina	Aprillus Asistencia e Investigacion de Arcis Salud SRL	Ciudad Autónoma de Buenos Aires
Argentina	Clínica Adventista Belgrano	Ciudad Autónoma de Buenos Aires
Argentina	Consultorio Médico Dra. Rivera	Ciudad Autónoma de Buenos Aires
Argentina	Organización Médica de Investigación	Ciudad Autónoma de Buenos Aires
Argentina	Framingham Centro Médico	La Plata	Buenos Aires
Argentina	I.R. Medical Center - Hospital de Dia	Mendoza
Argentina	Consultorios Médicos Dr. Catalán Pellet	Recoleta	Ciudad Autónoma De BuenosAires
Argentina	Centro de Investigaciones Médicas Tucumán	San Miguel de Tucuman	Tucumán
Argentina	Clinica Mayo de U.M.C.B. S.R.L	San Miguel de Tucumán	Tucumán
Argentina	Consultorio de Investigaciones Reumatologicas	San Miguel De Tucumán	Tucumán
Austria	Medizinische Universität Graz	Graz	Steiermark
Austria	Medizinische Universitat Wien (Medical University of Vienna)	Wien
Chile	Centro de Investigación Clínica de la Universidad Católica	Santiago
Chile	Oncocentro APYS	Viña del Mar	Valparaíso
France	Centre Hospitalier Universitaire de Bordeaux, Hopital Pellegrin	Bordeaux	Gironde
France	Hôpital Claude Huriez	Lille	Nord
France	Hopital Cochin	Paris
France	Hôpitaux Universitaires de Strasbourg	Strasbourg	Bas-Rhin
France	Hôpital de Rangueil	Toulouse	Haute-Garonne
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Universitätsklinikum Carl Gustav Carus an der TU Dresden	Dresden
Germany	Universitatsklinikum Dusseldorf	Düsseldorf	Nordrhein-Westfalen
Germany	Friedrich Alexander Universität Erlangen Nürnberg	Erlangen	Bayern
Germany	Universitätsklinikum Freiburg	Freiburg	Baden-Württemberg
Germany	Universität Georg August	Göttingen	Niedersachsen
Germany	Universitatsklinikum Halle (Saale)	Halle	Sachsen-Anhalt
Germany	LMU Klinikum der Universität	München	Bayern
Germany	Universitätsklinikum Würzburg	Würzburg	Bayern
Greece	Laiko General Hospital of Athens	Athens	Attiki
Greece	Laiko General Hospital of Athens	Athina	Attiki
Greece	Ippokratio General Hospital of Thessaloniki	Thessaloniki
Greece	Kianous Stavros	Thessaloniki
Israel	Lady Davis Carmel Medical Center	Haifa
Israel	Rambam Medical Center - PDDS	Haifa
Israel	Meir Medical Center	Kfar Sava	HaMerkaz
Israel	Rabin Medical Center	Petah tikva
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv-Yafo	Tel-Aviv
Israel	Sheba Medical Center	Tel HaShomer
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze	Toscana
Italy	Ospedale Policlinico San Martino	Genova	Liguria
Italy	Ospedale San Raffaele S.r.l. - PPDS	Milano	Lombardia
Italy	Fondazione IRCCS Policlinico San Matteo di Pavia	Pavia	Lombardia
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa
Italy	Fondazione Policlinico Universitario A Gemelli	Roma	Lazio
Italy	Istituto Clinico Humanitas	Rozzano	Lombardia
Italy	Azienda Sanitaria Universitaria Friuli Centrale - PO Universitario Santa Maria della Misericordia	Udine	Friuli-Venezia Giulia
Japan	Juntendo University Hospital	Bunkyo-Ku	Tokyo
Japan	Kyushu University Hospital	Fukuoka
Japan	Saitama Medical University Hospital	Iruma-Gun	Saitama
Japan	Kitasato University Medical Center	Kitamoto-Shi	Saitama
Japan	Kumamoto University Hospital	Kumamoto-Shi	Kumamoto
Japan	Nagasaki University Hospital	Nagasaki-Shi	Nagasaki
Japan	Hokkaido University Hospital	Sapporo-Shi	Hokkaidô
Japan	Sapporo Medical University Hospital	Sapporo-Shi	Hokkaidô
Japan	Tohoku University Hospital	Sendai-shi	Miyagi
Japan	Tokyo Women's Medical University Hospital	Shinjuku-ku	Tokyo
Japan	Osaka University Hospital	Suita-Shi	Ôsaka
Japan	Osaka Medical and Pharmaceutical University Hospital	Takatsuki-Shi	Ôsaka
Japan	Nippon Medical School Hospital	Tokyo
Japan	St. Luke's International Hospital	Tokyo
Japan	Fujita Health University Hospital	Toyoake-shi	Aiti
Korea, Republic of	Chonnam National University Hospital	Gwangju
Korea, Republic of	Hanyang University Seoul Hospital	Seongdong-gu	Seoul Teugbyeolsi
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam	Gyeonggido
Korea, Republic of	Gangnam Severance Hospital, Yonsei University Health System	Seoul
Mexico	Centro de Alta Especialidad En Reumatologia E Investigacion Del Potosi SC	Burócratas del Estado	San Luis Potosí
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran	Ciudad de México	Distrito Federal
Mexico	Centro de Estudios de Investigacion Basica Y Clinica SC	Guadalajara	Jalisco
Mexico	Centro Integral Reumatologia SA de CV	Guadalajara	Jalisco
Mexico	Clinica de Investigacion en Reumatologia y Obesidad	Guadalajara
Mexico	Unidad de Atencion Medica e Investigacion en Salud	Merida	Yucatán
Mexico	CITER, Centro de Investigacion y Tratamiento de las Enfermedades Reumaticas SA de CV	Mexico	Distrito Federal
Mexico	Centro de Investigación y Tratamiento Reumatológico S.C	Miguel Hidalgo	Distrito Federal
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Leids Universitair Medisch Centrum	Leiden	Zuid-Holland
Poland	Malopolskie Centrum Kliniczne	Kraków	Malopolskie
Poland	MCM Krakow - PRATIA	Kraków
Poland	FutureMeds - Lodz - PPDS	Lódz
Poland	Twoja Przychodnia NCM	Nowa Sól	Lubuskie
Poland	Ortopedyczno-Rehabilitacyjny Szpital Kliniczny im. Wiktora Degi	Poznan	Wielkopolskie
Poland	Centrum Medyczne Reuma Park NZOZ	Warszawa	Mazowieckie
Poland	Medicover Integrated Clinical Services sp. z o.o	Warszawa	Mazowieckie
Portugal	Hospital Garcia de Orta	Almada	Setúbal
Portugal	Hospital de Braga	Braga
Portugal	Centro Hospitalar E Universitário de Coimbra EPE	Coimbra
Portugal	Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria	Lisboa
Portugal	Hospital Conde de Bertiandos Unidade Local de Saúde Do Alto Minho	Ponte De Lima
Portugal	Centro Hospitalar de São João, E.P.E.	Porto
Romania	Centrul Medical de Diagnostic si Tratament Ambulator NEOMED SRL	Brasov
Romania	Sf.Maria Clinical Hospital	Bucharest	Bucuresti
Romania	Sf.Maria Clinical Hospital	Bucharest	Bucuresti
Romania	Dr I Cantacuzino Clinical Hospital	Bucuresti
Spain	Hospital Universitario A Coruña	a Coruña
Spain	Hospital de La Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	C.H. Regional Reina Sofia	Cordoba	Córdoba
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario La Paz - PPDS	Madrid
Spain	Hospital de Merida-Avenida d' Antonio Campos Hoyos 26	Merida	Badajoz
Spain	Corporacio Sanitaria Parc Tauli	Sabadell	Barcelona
Spain	Hospital Universitario Marques de Valdecilla	Santander	Cantabria
Spain	Hospital Quironsalud Infanta Luisa	Sevilla
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitario Doctor Peset	Valencia
Switzerland	Inselspital Bern	Bern	Bern (de)
Switzerland	HFR Fribourg Hôpital Cantonal	Fribourg
Switzerland	Kantonsspital St. Gallen	Sankt Gallen
United Kingdom	The Royal Free Hospital	London	London, City Of
United States	Michigan Medicine University of Michigan	Ann Arbor	Michigan
United States	Boston University School Of Medicine	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Metroplex Clinical Research Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	UT Physicians Rheumatology	Houston	Texas
United States	Pacific Arthritis Care Center	Los Angeles	California
United States	UCLA Department of Medicine	Los Angeles	California
United States	University of Miami Miller School of Medicine	Miami	Florida
United States	DelRicht Clinical Research, LLC	New Orleans	Louisiana
United States	Hospital For Special Surgery	New York	New York
United States	Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania
United States	Arizona Arthritis and Rheumatology Research, PLLC	Phoenix	Arizona
United States	IRIS Research and Development LLC	Plantation	Florida
United States	Mayo Clinic - Cancer Center - Rochester - PPDS	Rochester	Minnesota
United States	Stanford University School of Medicine	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Horizon Therapeutics Ireland DAC

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Chile,  France,  Germany,  Greece,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Portugal,  Romania,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in FVC (forced vital capacity) percent predicted from Baseline to Week 52	As measured by a pulmonary function test called a spirometry.	Baseline to Week 52
Secondary	Change from Baseline in HAQ-DI (Health Assessment Questionnaire - Disability Index) at Week 52		Baseline to Week 52
Secondary	Change from Baseline in MDGA (Physician Global Assessment) at Week 52		Baseline to Week 52
Secondary	Change from Baseline in PTGA (Patient Global Assessment) at Week 52		Baseline to Week 52
Secondary	Change from Baseline in the Physical Effects subscale of the scleroderma skin patient-reported outcome (SSPRO-18) at Week 52		Baseline to Week 52
Secondary	Change from Baseline in the Physical Limitations subscale of the scleroderma skin patient-reported outcome SSPRO-18 at Week 52		Baseline to Week 52
Secondary	Proportion of participants with an mRSS (modified Rodnan skin score) decrease of =5 points and 25% from Baseline at Week 52		Baseline to Week 52
Secondary	Responder rate (defined as ACR-CRISS [predicted probability] of at least 0.6) at Week 52	American College of Rheumatology-Composite Response Index in Systemic Sclerosis	Week 52
Secondary	Proportion of participants with an improvement in =3 of 5 core measures from Baseline: =20% in mRSS, =20% in HAQ-DI, =20% in PTGA, =20% in MDGA and =5% for FVC % predicted at Week 52 (ACR-CRISS-20)	American College of Rheumatology-Composite Response Index in Systemic Sclerosis	Baseline to Week 52