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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Horizon Therapeutics Ireland Designated Activity Company

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

11 Nov 2021 → 24 Feb 2025

Decision date (initial)

2024-08-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Horizon Therapeutics USA, Inc

External identifiers

EU CT number

2023-509782-20-00

EudraCT number

2020-005764-62

ClinicalTrials.gov

NCT04781543

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Others, Efficacy, Safety, Pharmacogenetic

The primary objective is to demonstrate the efficacy of 1 or 2 dose
regimens of HZN-825 versus placebo in subjects with diffuse cutaneous SSc, as determined by a comparison of change in forced vital capacity (FVC) % predicted after 52 weeks of treatment

Secondary objectives 1

1. 1.Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on Health Assessment Questionnaire-Disability Index [HAQ-DI] after 52 weeks of treatment. 2.Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on Physician Global Assessment (MDGA) after 52 weeks of treatment. 3.Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on Patient Global Assessment (PTGA) after 52 weeks of treatment. 4.Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on the Physical Effects subscale of the scleroderma skin patient-reported outcome (SSPRO-18) after 52 weeks of treatment. 5.Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on the Physical Limitations subscale of the SSPRO-18 after 52 weeks of treatment. 6.Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on the modified Rodnan skin score(mRSS), after 52 weeks of treatment. 7. Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on American College of Rheumatology-Composite Response Index in Systemic Sclerosis (ACR-CRISS), defined as improvement from Baseline in mRSS, HAQ-DI, PTGA, MDGA and FVC % predicted after 52 weeks of treatment. 8. Evaluate the effect of 2 dose regimens of HZN-825 versus placebo on ACR-CRISS-20, defined as improvement in ≥3 core set measures from Baseline of ≥20% in mRSS, ≥20% in HAQ-DI, ≥20% in PTGA, ≥20% in MDGA and ≥5% in FVC % predicted after 52 weeks of treatment. 9. Assess safety and tolerability of HZN-825 based on adverse events (AEs), the adverse event of special interest (AESI) (orthostatic hypotension), concomitant medication use, vital signs, 12-lead electrocardiogram (ECG) and clinical safety laboratory evaluations (hematology, chemistry, inflammatory parameters, coagulation panel and urinalysis). 10. Evaluate the pharmacokinetics (PK) of HZN-825

Conditions and MedDRA coding

Diffuse Cutaneous Systemic Sclerosis

Study design 1 period

Regulatory references

Plan to share 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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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 4.Classified as having skin involvement proximal to the elbow and/or 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 in the forearm suitable for repeat biopsy (only applicable to the first 110 subjects for whom biopsy will be performed). 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

1. 1.Positive for anti-centromere antibodies with the exception that subjects who are positive for both anti-centromere and antitopoisomerase 1 antibodies may be enrolled. 2.Diagnosed w/sine scleroderma or limited cutaneous SSc. 3.Diagnosed w/other autoimmune connective tissue diseases ,except for fibromyalgia, scleroderma-associated myopathy & secondary Sjogren's syndrome. 4.Scleroderma renal crisis diagnosed within 6months of the Screening Visit. 5.Any of the following cardiovascular diseases: a. uncontrolled, severe hypertension(≥160/100mmHg) or persistent low blood pressure (systolic blood pressure<90 mmHg) within 6months of Screening, b. myocardial infarction within6months of Screening, c. unstable cardiac angina within6months of Screening. 6.DLCO<40% predicted (corrected for hemoglobin). If severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) exposure is of clinical concern for any subject, consider using a DLCO up to6months before the Screening Visit. 7.Pulmonary arterial hypertension (PAH)by right heart catheterization requiring treatment w/more than1oral 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 within4weeks prior to Screening (topical steroids for dermatological conditions& inhaled/intranasal/intra-articular steroids are allowed). 9.Use of any other non-steroid immunosuppressive agent, small biologic molecule, cytotoxic or antifibrotic drug within4weeks prior to Screening, including cyclophosphamide, azathioprine (Imuran®) or other immunosuppressive or cytotoxic edication. Exceptions include mycophenolate mofetil (CellCept®), mycophenolic acid (Myfortic®), methotrexate and low-dose prednisone, as follows: use of CellCept ≤3g/day, Myfortic ≤2.14g/day, methotrexate ≤20 mg/week and prednisone ≤10 mg/day (or equivalent dosing of glucocorticoids) is allowed. See Table 9.1 for full details. Subjects taking CellCept, Myfortic or methotrexate must have been doing so for≥6months 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 Day1Visit. It is acceptable to be on background low-dose prednisone &anti-malarial drug along with CellCept, Myfortic or methotrexate. Rituximab must not have been used within 6 months of the Day1Visit.Subjects must not be withdrawn from any standard-of-care treatment that is considered necessary for the clinical management of the subject in order to fulfill the trial eligibility requirements. 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 90days or 5half-lives,whichever is longer, prior to Screening or anticipated use during the course of the trial. 12.Malignant condition in the past5years(except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ). Please refer to protocol section 9.3.2 for details

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in FVC % predicted from Baseline to Week 52

Secondary endpoints 1

1. 1.Change from Baseline in HAQ-DI at Week 52. 2.Change from Baseline in MDGA at Week 52. 3.Change from Baseline in PTGA at Week 52. 4.Change from Baseline in the Physical Effects subscale of the SSPRO-18 at Week 52. 5.Change from Baseline in the Physical Limitations subscale of the SSPRO-18 at Week 52. 6.Proportion of subjects with an mRSS decrease of ≥5 points and 25% from Baseline at Week 52. Please refer to protocol section 8.2

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Horizon Therapeutics Ireland Designated Activity Company

Sponsor organisation

Horizon Therapeutics Ireland Designated Activity Company

Address

70 Saint Stephen's Green

City

Dublin 2

Postcode

D02 E2X4

Country

Ireland

Scientific contact point

Organisation

Horizon Therapeutics Ireland Designated Activity Company

Contact name

Arati Kanchi

Public contact point

Organisation

Horizon Therapeutics Ireland Designated Activity Company

Contact name

Arati Kanchi

Third parties 14

Locations

9 EU/EEA countries · 51 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications