NCT04781543

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

Terminated Phase 2 Results posted Last updated 20 March 2026

What this trial tests

Phase 2 trial testing HZN-825 BID in Diffuse Cutaneous Systemic Sclerosis in 301 participants. Terminated before completion.

Timeline

5 November 2021

Primary endpoint
24 February 2025

24 February 2025

Quick facts

Lead sponsor	Amgen
Phase	Phase 2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	301
Start date	5 November 2021
Primary completion	24 February 2025
Estimated completion	24 February 2025
Sites	4 locations across Serbia, Spain

Drugs / interventions tested

• HZN-825 BID — full drug profile →
• Placebo
• HZN-825 QD — full drug profile →

Conditions studied

• Diffuse Cutaneous Systemic Sclerosis — all drugs for Diffuse Cutaneous Systemic Sclerosis →
• Sclerosis, Systemic — all drugs for Sclerosis, Systemic →

Sponsor

Amgen — full company profile →

Who can join

Adults 18 to 75, any sex, with Diffuse Cutaneous Systemic Sclerosis or Sclerosis, Systemic. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in the Modified Rodnan Skin Score (mRSS) at Week 52 Secondary · 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.

Group	Value	95% CI
Fipaxalparant 300 mg QD	-9.3	± 0.9
Fipaxalparant 300 mg BID	-10.7	± 0.9
Placebo	-8.8	± 0.9

Number of Participants Responding to Treatment Based on the Revised Composite Response Index in Systemic Sclerosis (CRISS 25) at Week 52 Secondary · 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.

Group	Value	95% CI
Fipaxalparant 300 mg QD	32
Fipaxalparant 300 mg BID	27
Placebo	33

Change From Baseline in HAQ-DI at Week 52 Secondary · 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 obtaine

Group	Value	95% CI
Fipaxalparant 300 mg QD	-0.19	± 0.063
Fipaxalparant 300 mg BID	-0.17	± 0.065
Placebo	-0.24	± 0.063

Change From Baseline in CGA at Week 52 Secondary · 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.

Group	Value	95% CI
Fipaxalparant 300 mg QD	-1.8	± 0.25
Fipaxalparant 300 mg BID	-2.3	± 0.26
Placebo	-1.8	± 0.25

Change From Baseline in PTGA at Week 52 Secondary · 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.

Group	Value	95% CI
Fipaxalparant 300 mg QD	-0.6	± 0.27
Fipaxalparant 300 mg BID	-0.4	± 0.29
Placebo	-1.2	± 0.28

Change From Baseline in the Physical Effects Subscale of the Scleroderma Skin Patient-reported Outcome (SSPRO-18) at Week 52 Secondary · 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 l

Group	Value	95% CI
Fipaxalparant 300 mg QD	-13.35	± 2.544
Fipaxalparant 300 mg BID	-16.12	± 2.621
Placebo	-14.0	± 2.551

Change From Baseline in the Physical Limitations Subscale of the SSPRO-18 at Week 52 Secondary · 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 parti

Group	Value	95% CI
Fipaxalparant 300 mg QD	-16.67	± 2.633
Fipaxalparant 300 mg BID	-20.15	± 2.713
Placebo	-17.94	± 2.639

Number of Participants With an mRSS Decrease of ≥ 5 Points and 25% From Baseline at Week 52 Secondary · 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.

Group	Value	95% CI
Fipaxalparant 300 mg QD	43
Fipaxalparant 300 mg BID	37
Placebo	41

Number of Participants Who Were Responders at Week 52 Secondary · 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.

Group	Value	95% CI
Fipaxalparant 300 mg QD	41
Fipaxalparant 300 mg BID	33
Placebo	33

Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) and AEs of Special Interest (AESIs) Secondary · 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 consi

TEAEs

Group	Value	95% CI
Fipaxalparant 300 mg QD	87
Fipaxalparant 300 mg BID	84
Placebo	79

AESI

Group	Value	95% CI
Fipaxalparant 300 mg QD	3
Fipaxalparant 300 mg BID	0
Placebo	2

Number of Participants Who Received Concomitant Medication Secondary · 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.

Group	Value	95% CI
Fipaxalparant 300 mg QD	100
Fipaxalparant 300 mg BID	102
Placebo	97

Pre- and Post-dose Plasma Concentrations of Fipaxalparant Secondary · 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.

Day 1 (post-dose)

Group	Value	95% CI
Fipaxalparant 300 mg QD	14800	± 10100
Fipaxalparant 300 mg BID	17100	± 15200

Week 4 (pre-dose)

Group	Value	95% CI
Fipaxalparant 300 mg QD	5840	± 7030
Fipaxalparant 300 mg BID	15600	± 11200

Week 10 (pre or post-dose)

Group	Value	95% CI
Fipaxalparant 300 mg QD	5690	± 7640
Fipaxalparant 300 mg BID	16300	± 11600

Week 16 (pre-dose)

Group	Value	95% CI
Fipaxalparant 300 mg QD	4540	± 5760
Fipaxalparant 300 mg BID	13300	± 8660

Week 16 (post-dose)

Group	Value	95% CI
Fipaxalparant 300 mg QD	16500	± 9660
Fipaxalparant 300 mg BID	22100	± 13100

Week 28 (pre-dose)

Group	Value	95% CI
Fipaxalparant 300 mg QD	3890	± 4220
Fipaxalparant 300 mg BID	13600	± 10800

Week 28 (post-dose)

Group	Value	95% CI
Fipaxalparant 300 mg QD	17000	± 11500
Fipaxalparant 300 mg BID	22800	± 13900

Week 40 (pre-dose)

Group	Value	95% CI
Fipaxalparant 300 mg QD	4960	± 6310
Fipaxalparant 300 mg BID	14400	± 11900

Adverse events — posted to ClinicalTrials.gov

Time frame: Death: From randomization to end of trial (EOT), median (min, max) was 12.0 (1.5, 14.4) months. TEAE: From first dose to last dose + 28 days, median (min, max) duration was 12.8 (1.0, 13.9) months.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Fipaxalparant 300 mg QD

Serious: 9/100 (9%)

Deaths: 0/100

Fipaxalparant 300 mg BID

Serious: 8/102 (8%)

Deaths: 1/101

Placebo

Serious: 5/99 (5%)

Deaths: 1/100

Serious adverse events (37 terms)

Reaction	System	Fipaxalparant 300 mg QD	Fipaxalparant 300 mg BID	Placebo
Appendicitis	Infections and infestations	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—
Cardiac failure	Cardiac disorders	—	—	—
Cardiac failure congestive	Cardiac disorders	—	—	—
Adrenal insufficiency	Endocrine disorders	—	—	—
Colitis ischaemic	Gastrointestinal disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Enteritis	Gastrointestinal disorders	—	—	—
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—
Adverse drug reaction	General disorders	—	—	—
Non-cardiac chest pain	General disorders	—	—	—
Systemic inflammatory response syndrome	General disorders	—	—	—
Pneumonia	Infections and infestations	—	—	—
Septic shock	Infections and infestations	—	—	—
Anaemia postoperative	Injury, poisoning and procedural complications	—	—	—
Clavicle fracture	Injury, poisoning and procedural complications	—	—	—
Femur fracture	Injury, poisoning and procedural complications	—	—	—
Foot fracture	Injury, poisoning and procedural complications	—	—	—
Humerus fracture	Injury, poisoning and procedural complications	—	—	—
Limb injury	Injury, poisoning and procedural complications	—	—	—
Rib fracture	Injury, poisoning and procedural complications	—	—	—
Osteonecrosis	Musculoskeletal and connective tissue disorders	—	—	—
Mucinous adenocarcinoma of appendix	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Neuroendocrine carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Presyncope	Nervous system disorders	—	—	—

Other adverse events (13 terms — click to expand)

Reaction	System	Fipaxalparant 300 mg QD	Fipaxalparant 300 mg BID	Placebo
Urinary tract infection	Infections and infestations	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
COVID-19	Infections and infestations	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—
Headache	Nervous system disorders	—	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Oedema peripheral	General disorders	—	—	—
Gastroenteritis	Infections and infestations	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Skin ulcer	Skin and subcutaneous tissue disorders	—	—	—

Most-reported serious reactions: Appendicitis, Atrial fibrillation, Cardiac failure, Cardiac failure congestive, Adrenal insufficiency, Colitis ischaemic, Constipation, Enteritis.

Data from ClinicalTrials.gov NCT04781543 adverse events section.

Sponsor's own description

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.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches.
   Benfaremo D, Svegliati S, Paolini C, Agarbati S, et al · · 2022 · cited 29× · PMID 35052842 · DOI 10.3390/biomedicines10010163
2. Lysophosphatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis.
   Volkmann ER, Denton CP, Kolb M, Wijsenbeek-Lourens MS, et al · · 2024 · cited 11× · PMID 39009409 · DOI 10.1183/16000617.0015-2024
3. Decoding lysophosphatidic acid signaling in physiology and disease: mapping the multimodal and multinodal signaling networks.
   Nadhan R, Nath K, Basu S, Isidoro C, et al · · 2025 · cited 6× · PMID 41068071 · DOI 10.1038/s41392-025-02423-4
4. Novel Therapeutic Approaches in Connective Tissue Disease-Associated Interstitial Lung Disease.
   Mulcaire-Jones E, Pugashetti JV, Oldham JM, Khanna D. · · 2024 · cited 5× · PMID 38740369 · DOI 10.1055/s-0044-1786155
5. Role of Growth Factors in the Pathogenesis of Systemic-Sclerosis-Associated Fibrosis.
   Mendoza FA, Piera-Velazquez S, Jimenez SA. · · 2025 · PMID 41096861 · DOI 10.3390/ijms26199596