E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diffuse Cutaneous Systemic Sclerosis |
|
E.1.1.1 | Medical condition in easily understood language |
Disease characterized by skin hardening (fibrosis) and problems in many organs of the body. |
|
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 | 100000004859 |
|
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 |
|
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 after 52 weeks of treatment.
3.Evaluate the effect of 2 dose regimens of HZN-825 vs. placebo on Patient Global Assessment 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. |
|
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 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. |
|
E.4 | Principal 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/orRaynaud'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 use during 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 aminotransferase or aspartate aminotransferase >2 × ULN.
23.Estimated glomerular filtration rate <30 mL/min/1.73 m2 at
Screening.
24.Total bilirubin >2 × ULN. Subjects with documented diagnosis of
Gilbert's syndrome may be enrolled iftheir total bilirubin is ≤3.0 mg/dL.
25.Any other condition that, in the opinion of the Investigator, would
preclude enrollment in the trial. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change in FVC % predicted from Baseline to Week 52 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
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). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 |
|
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) | Yes |
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 | 2 |
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 | 76 |
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 |
Canada |
Israel |
Japan |
Korea, Republic of |
Mexico |
Turkey |
United States |
Austria |
Belgium |
France |
Germany |
Greece |
Hungary |
Ireland |
Italy |
Poland |
Portugal |
Romania |
Spain |
Switzerland |
United Kingdom |
Argentina |
|
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
|
|
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 | |
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 |