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

• Register: EUCTR
• Last refreshed on: 17 August 2021
• Main ID: EUCTR2020-005764-62-ES
• Date of registration: 11/08/2021
• Prospective Registration: Yes
• Primary sponsor: Horizon Therapeutics Ireland DAC
• Public title: A Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of HZN-825 in Patients with Diffuse Cutaneous Systemic Sclerosis
• Scientific 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
• Date of first enrolment: 11/08/2021
• Target sample size: 300
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-005764-62
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Farah Ali
• Affiliation: Horizon Therapeutics U.S.A., Inc.

• Name: Farah Ali
• Affiliation: Horizon Therapeutics U.S.A., Inc.

Key inclusion & exclusion criteria

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 classificationcriteria 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 byLeRoy and Medsger, 2001).
5. At the time of enrollment, less than 36 months since the onset of the first SSc manifestation, other thanRaynaud's phenomenon.
6. Based on data available through medical history and/or medical records, the subject should have at least 1 ofthe following:
a. disease duration =18 months
b. increase =3 in mRSS units compared with the last visit within the previous 1 month to 6 months
c. involvement of 1 new body area with =2 mRSS units or 2 new body areas with =1 mRSS unit
d. documentation of worsening skin thickening for subjects who did not have mRSS performed during theprevious visit
e. presence of tendon friction rub at Screening
7. Presence of at least 1 of the following features of elevated acute phase reactants at Screening:
• high-sensitivity C-reactive protein (hsCRP) =0.6 mg/dL (=6 mg/L),
• erythrocyte sedimentation rate (ESR) =28 mm/hr,
• platelet count =330 × 109/L (330,000/µL).
8. Skin thickening from SSc in the forearm suitable for repeat biopsy.
9. mRSS units =15 at Screening.
10. FVC =45% predicted at Screening, as determined by spirometry.
11. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of thetrial.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 285
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 15

Exclusion criteria:
1. Positive for anti-centromere antibodies.
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:
a. uncontrolled, severe hypertension (=160/100 mmHg) or persistent low blood pressure (systolic bloodpressure <90 mmHg) within 6 months of Screening,
b. myocardial infarction within 6 months of Screening,
c. unstable cardiac angina within 6 months 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 to 6 monthsbefore the Screening Visit.
7. Pulmonary arterial hypertension (PAH) by right heart catheterization requiring treatment with more than1 oral PAH-approved therapy or any parenteral therapy. Treatment is allowed for erectile dysfunctionand/or Raynaud's phenomenon/digital ulcers.
8. Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening (topical steroids fordermatological conditions and inhaled/ intranasal/intra-articular steroids are allowed).
9. Use of any other non-steroid immunosuppressive agent, small biologic molecule, cytotoxic or anti-fibroticdrug within 4 weeks of Screening,
including cyclophosphamide, azathioprine (Imuran®) or otherimmunosuppressive or cytotoxic medication.
10. Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypicalmycobacterial disease (fungal infections of nail beds are allowed).
11. Use of a United States Food and Drug Administration-approved agent for SSc or an investigational agent forany condition within 90 days or 5
half-lives, whichever is longer, prior to Screening or anticipated useduring the course of the trial.
12. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of theskin or cervical cancer in situ).
13. Women of childbearing potential or male subjects not agreeing to use highly effective method(s) of birthcontrol throughout the trial and for 1
month after last dose of trial drug. Male subjects must refrain fromsperm 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 theInvestigator 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.
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 testfor HBsAb and with presence of hepatitis B virus DNA at Screening; hepatitis C: positive anti-hepatitis Cvirus [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) orpartial thromboplastin time >1.5 ×ULN at Screening.
22. Alanine am

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Diffuse Cutaneous Systemic Sclerosis
MedDRA version: 21.0 Level: LLT Classification code 10042953 Term: Systemic sclerosis System Organ Class: 100000004859

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Code: HZN-825
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: HZN-825
Current Sponsor code: HZN-825
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: From Baseline to Week 52

Main Objective: 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

Primary end point(s): Change in FVC % predicted from Baseline to Week 52

Secondary Objective: 1.Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on Health Assessment Questionnaire-Disability Index 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 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, after 52 weeks of treatment.
7. Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on ACR-CRISS after 52 weeks of treatment.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: From Baseline to Week 52

Secondary end point(s): 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.
7.Responder rate (defined as ACR-CRISS [predicted probability] of at least 0.6) at Week 52.
8.Proportion of subjects 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).

Secondary ID(s)

HZNP-HZN-825-301

NCT04781543

2020-005764-62-DE

Source(s) of Monetary Support

Horizon Therapeutics USA, Inc

Ethics review

Status: Approved
Approval date: 06/07/2021
Contact: