E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diffuse Cutaneous Systemic Sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
Disease characterized by skin hardening (fibrosis) and problems in many organs of the body. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042953 |
E.1.2 | Term | Systemic sclerosis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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/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. |
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E.4 | Principal exclusion criteria |
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 medication. 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). 13.Women of childbearing potential (WOCBP) or male subjects not agreeing to use highly effective method(s)of birth control throughout the trial and for 4 weeks after last dose of trial drug. Male subjects must refrain from sperm donation and females from egg/ova donation for this same time period. Women are considered of childbearing potential if they are not postmenopausal and not surgically sterile(documented bilateral salpingectomy, bilateral oophorectomy, or hysterectomy).A postmenopausal state is defined as no menses for 12months without an alternative medical cause. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However,in the absence of 12months of amenorrhea, a single FSH measurement is insufficient. Fertile male subjects must use a condom throughout the trial and for4weeks after the last dose of trial drug.A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 14. Pregnant or lactating women. 15.Current drug or alcohol abuse or history of either within the previous2years,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 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in FVC % predicted from Baseline to Week 52 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | 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). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability and dose-ranging |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 72 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Chile |
Switzerland |
Israel |
Japan |
Korea, Republic of |
Mexico |
Serbia |
United Kingdom |
United States |
Austria |
France |
Germany |
Greece |
Italy |
Poland |
Portugal |
Romania |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |