Diffuse Cutaneous Systemic Sclerosis, Sclerosis, Systemic
Conditions
Keywords
Scleroderma
Brief 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.
Detailed description
Acquired from Horizon in 2024.
Interventions
DRUGHZN-825 BID
300 mg oral tablets BID
DRUGPlacebo
Placebo BID
DRUGHZN-825 QD
300 mg oral tablets QD
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Forced Vital Capacity Percent (FVC%) Predicted at Week 52 | Baseline and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Modified Rodnan Skin Score (mRSS) at Week 52 | Baseline and 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. |
| Number of Participants Responding to Treatment Based on the Revised Composite Response Index in Systemic Sclerosis (CRISS 25) at Week 52 | Baseline to 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. |
| Change From Baseline in HAQ-DI at Week 52 | Baseline and 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. |
| Change From Baseline in CGA at Week 52 | Baseline and 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. |
| Change From Baseline in PTGA at Week 52 | Baseline and 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. |
| Change From Baseline in the Physical Effects Subscale of the Scleroderma Skin Patient-reported Outcome (SSPRO-18) at Week 52 | Baseline and 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. |
| Change From Baseline in the Physical Limitations Subscale of the SSPRO-18 at Week 52 | Baseline and 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. |
| Number of Participants With an mRSS Decrease of ≥ 5 Points and 25% From Baseline at Week 52 | Baseline and 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. |
| Number of Participants Who Were Responders at Week 52 | 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. |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) and AEs of Special Interest (AESIs) | From first dose to last dose + 28 days, median (min, max) duration was 12.8 (1.0, 13.9) months | 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. |
| Number of Participants Who Received Concomitant Medication | From first dose to last dose + 28 days, median (min, max) duration was 12.8 (1.0, 13.9) months | 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. |
| Pre- and Post-dose Plasma Concentrations of Fipaxalparant | 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) | Plasma concentrations of fipaxalparant were summarized descriptively by treatment group and time point. |
Countries
Serbia, Spain
Contacts
STUDY_DIRECTORMD
Amgen
Participant flow
Recruitment details
A total of 301 participants were enrolled from November 2021 to February 2025 at 137 trial sites across Argentina, Austria, Chile, France, Germany, Greece, Israel, Italy, Japan, Korea, Mexico, Poland, Portugal, Romania, Serbia, Spain, Switzerland, the United Kingdom and the United States.
Pre-assignment details
This trial planned to evaluate the efficacy, safety, tolerability and pharmacokinetics (PK) of fipaxalparant (HZN-825) administed once a day (QD) or twice a day (BID) compared to placebo over a 52-week period in participants with diffuse cutaneous systemic sclerosis (SSc). A futility analysis was conducted after 50% of the participants completed the Week 52 visit and a decision was made to terminate the trial early.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 263 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 14 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized Unknown or not reported | 1 Participants |
| Race/Ethnicity, Customized White | 238 Participants |
| Sex: Female, Male Female | 234 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 100 | 1 / 101 | 1 / 100 |
| other Total, other adverse events | 58 / 100 | 47 / 102 | 53 / 99 |
| serious Total, serious adverse events | 9 / 100 | 8 / 102 | 5 / 99 |
Outcome results
None listed