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

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

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.

Study Overview

• Status: Terminated
• Conditions: Diffuse Cutaneous Systemic Sclerosis; Sclerosis, Systemic
• Intervention / Treatment: Drug: Placebo; Drug: HZN-825 QD; Drug: HZN-825 BID

Detailed Description

Acquired from Horizon in 2024.

• Study Type: Interventional
• Enrollment (Actual): 301
• Phase: Phase 2

Contacts and Locations

Study Locations

• Serbia
  • Belgrade, Serbia, 11000
    • Military Medical Academy
  • Belgrade, Serbia, 11000
    • Institute of Rheumatology - PPDS
  • Niška Banja, Serbia, 708120
    • Institute for Treatment and Rehabilitation Niska Banja
• Spain
  • Barcelona, Spain, 08025
    • Hospital de La Santa Creu i Sant Pau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HZN-825 300 mg once daily (QD); One set of 2 HZN-825 150mg tablets in the morning and one set of 2 placebo tablets in the evening.	Drug: HZN-825 QD; 300 mg oral tablets QD
Experimental: HZN-825 300 mg twice daily (BID); One set of 2 HZN-825 150mg tablets in the morning and one set of 2 HZN-825 150mg tablets in the evening.	Drug: HZN-825 BID; 300 mg oral tablets BID
Placebo Comparator: Placebo; One set of 2 placebo tablets in the morning and one set of 2 placebo tablets in the evening.	Drug: Placebo; Placebo BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Forced Vital Capacity Percent (FVC%) Predicted at Week 52	FVC was assessed using a blowing device provided by the Sponsor. The best of 3 efforts was defined as the highest FVC, obtained on any of the 3 blows meeting the American Thoracic Society (ATS) and the European Respiratory Society (ERS) criteria with a maximum of 8 maneuvers. FVC% predicted was calculated by taking the observed FVC measurement and dividing it by a predicted value multiplied by 100 (% FVC predicted = (FVC observed/FVC predicted) x 100). The predicted value is an average of the normal FVC volume for a person of the same sex, ethnicity, age and height.	Baseline and Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Modified Rodnan Skin Score (mRSS) at Week 52	The mRSS is a validated method for estimating skin thickening. Seventeen different body areas were scored as normal (0), mild thickening (1), moderate thickening (2) and severe thickening (3), with a total score range from 0 (best) to 51 (worst). A higher score meant greater disease severity.	Baseline and Week 52
Number of Participants Responding to Treatment Based on the Revised Composite Response Index in Systemic Sclerosis (CRISS 25) at Week 52	According to the Revised CRISS (CRISS 25), participants were considered responders if there was improvement in at least 2 components: ≥5% increase for FVC% predicted and/or ≥25% decrease for mRSS, the Health Assessment Questionnaire - Disability Index (HAQ-DI), the Patient Global Assessment (PTGA), the Clinician Global Assessment (CGA) and worsening in no more than one component: ≥5% decrease FVC% predicted and/or ≥25% increase for mRSS, HAQ-DI, PTGA, CGA, at 52 weeks.	Baseline to Week 52
Change From Baseline in HAQ-DI at Week 52	The HAQ-DI assesses the participant's level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual activities. The HAQ-DI was calculated by scoring the answer to each question in the HAQ from 0 to 3, with 0 representing the ability to do without any difficulty, and 3 representing inability to do. The total HAQ-DI score was obtained by summing the 8 categories scores and dividing by 8. The total HAQ-DI score ranged from 0 to 3. A negative change meant a worsening of functional ability.	Baseline and Week 52
Change From Baseline in CGA at Week 52	The CGA is an 11-point scale ranging from 0 to 10 (0=excellent to 10=extremely poor) on which the physician rated the participant's overall health over the past week. 0 meant an excellent overall health and 10 an extremely poor overall health. A negative change meant an improvement of participant's overall health.	Baseline and Week 52
Change From Baseline in PTGA at Week 52	The PTGA is an 11-point scale ranging from 0 to 10 (0=excellent to 10=extremely poor) on which the participant rated his/her overall health and illness-related pain level over the past week and how much the skin involvement due to scleroderma had interfered with daily activity and how rapidly the skin disease had been progressing over the past month. A negative change meant an improvement of participant's overall health.	Baseline and Week 52
Change From Baseline in the Physical Effects Subscale of the Scleroderma Skin Patient-reported Outcome (SSPRO-18) at Week 52	The SSPRO-18 is an 18-item, patient-reported outcome instrument that specifically assesses skin-related quality of life in patients with SSc. The SSPRO-18 comprises 4 major conceptual constructs-physical effects, emotional effects, physical limitations and social effects. The SSPRO-18 Physical Effects Subscale is a composite score transformed to a 0 - 100 scale of several questions relating to the extent to which specific skin-related symptoms were experienced by the subject. Recall is the past 4 weeks. Higher scores indicate more severe impact of skin problems on the participnt's quality of life. A negative change meant an improvement of the skin-related quality of life.	Baseline and Week 52
Change From Baseline in the Physical Limitations Subscale of the SSPRO-18 at Week 52	The SSPRO-18 is an 18-item, patient-reported outcome instrument that specifically assesses skin-related quality of life in patients with SSc. The SSPRO-18 comprises 4 major conceptual constructs-physical effects, emotional effects, physical limitations and social effects. The SSPRO-18 Physical Limitations Subscale is a composite score transformed to a 0 - 100 scale of several questions relating to the extent to which the condition of the subject's skin and skin tightness limited them physically. Recall is the past 4 weeks. Higher scores indicate more severe impact of skin problems on the participant's quality of life. A negative change meant an improvement of the skin-related quality of life.	Baseline and Week 52
Number of Participants With an mRSS Decrease of ≥ 5 Points and 25% From Baseline at Week 52	The mRSS is a validated method for estimating skin thickening. Seventeen different body areas were scored as normal (0), mild thickening (1), moderate thickening (2) and severe thickening (3), with a total score range from 0 (best) to 51 (worst). A higher score meant greater disease severity.	Baseline and Week 52
Number of Participants Who Were Responders at Week 52	The American College of Rheumatology (ACR)-CRISS is a 2-step process that assigns a probability of improvement for a participants that ranges from 0.0 (no improvement) to 1.0 (marked improvement). Participants were considered responders if thier ACR-CRISS was at least 0.6.	Week 52
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) and AEs of Special Interest (AESIs)	A TEAE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which dose not necessarily have a causal relationship with this treatment. Changes in vital signs, 12-lead electrocardiograms (ECGs) and clinical safety laboratory evaluations were considered TEAEs. An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor may be appropriate. Orthostatic hypotension was considered an AESI.	From first dose to last dose + 28 days, median (min, max) duration was 12.8 (1.0, 13.9) months
Number of Participants Who Received Concomitant Medication	Concomitant medications were defined as any medication that was ongoing, had a start date on or after the first dose of trial drug, or a stop date on or after the first dose date.	From first dose to last dose + 28 days, median (min, max) duration was 12.8 (1.0, 13.9) months
Pre- and Post-dose Plasma Concentrations of Fipaxalparant	Plasma concentrations of fipaxalparant were summarized descriptively by treatment group and time point.	Day 1 (post-dose), Week 4 (pre-dose), Week 10 (anytime at the visit), Weeks 16 and 28 (pre-dose and post-dose) and Weeks 40 and 52 (pre-dose)

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2021
• Primary Completion (Actual): February 24, 2025
• Study Completion (Actual): February 24, 2025

Study Registration Dates

• First Submitted: March 1, 2021
• First Submitted That Met QC Criteria: March 1, 2021
• First Posted (Actual): March 4, 2021

Study Record Updates

• Last Update Posted (Actual): March 20, 2026
• Last Update Submitted That Met QC Criteria: February 27, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Scleroderma
• Additional Relevant MeSH Terms: Connective Tissue Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Scleroderma, Systemic; Scleroderma, Diffuse
• Other Study ID Numbers: HZNP-HZN-825-301; 2020-005764-62 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No