E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic sclerosis associated with interstitial lung disease |
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E.1.1.1 | Medical condition in easily understood language |
Systemic sclerosis is a disease characterized by abnormal and excess fibrosis, a hardening of tissues and organs. |
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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 | 10025109 |
E.1.2 | Term | Lung involvement in systemic sclerosis |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal 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 |
• To assess the safety and tolerability of PRA023 in SSc-ILD • To compare the annual rate of change from Baseline in forced vital capacity (FVC), of PRA023 vs. placebo over 50 weeks |
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E.2.2 | Secondary objectives of the trial |
• To compare the change from Baseline in FVC at Week 50 • To compare the change from Baseline in high-resolution computer tomography (HRCT) at Week 50 • To compare the annual rate of change in percent predicted FVC • To compare proportion of subjects with an improvement in the American College of Rheumatology Combined Response Index in Systemic Sclerosis (ACR CRISS) score at Week 50 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Skin Biopsy Substudy: to assess change in histology and protein expression Pharmacokinetic Substudy: Fully characterize PK of PRA023 in subjects with SSc-ILD
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E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 years of age. 2. Subjects must meet the 2013 ACR/EULAR definition of SSc. 3. Subjects must have had SSc onset (defined by first non-Raynaud symptom) ≤ 5 years (60 months) prior to screening. 4. Subjects must have diffuse cutaneous scleroderma defined as any level of skin thickening proximal to the elbows and knees exclusive of the face and neck. Total mRSS must be 15 to 35 units, inclusive. Subjects must have SSc-related ILD of fibrotic disease in lung confirmed by HRCT ≥ 10% extent of involvement, assessed by central reading. 6. FVC ≥ 45% of predicted normal. 7. Diffusing capacity of lung for carbon monoxide (DLCO) ≥ 45% of predicted normal (corrected for hemoglobin [Hgb]). 8. Meet at least one of the following criteria: a. CRP > upper limit of normal (ULN) b. Erythrocyte sedimentation rate (ESR) > 28 mm/hr c. Positive for anti-topoisomerase (anti-Scl-70) antibody 9. Subjects receiving background therapy must meet drug stabilization requirements, as applicable: a. Either mycophenolate mofetil (not to exceed 3 g/day) or oral or subcutaneous methotrexate (not to exceed 25 mg/week) or azathioprine (not to exceed 150 mg/day) for ≥ 4 months prior to randomization (not more than 1 therapy) and on a stable dose for 4 weeks prior to randomization b. Subjects who have been on nintedanib for ≥ 6 months (and stable dose for at least 4 weeks) prior to randomization may enter the study provided that there has not been any improvement in FVC (% and absolute) from prior to the initiation of nintedanib therapy c. A stable dose of oral corticosteroids (≤ 10 mg/day prednisone equivalent) for 2 weeks prior to randomization. Inhaled and topical corticosteroids are permitted. 10.For subjects who are women of childbearing potential (WOCBP) involved in any sexual intercourse that could lead to pregnancy, the subject has used two highly effective methods of contraception for at least 4 weeks prior to Day 1 and agrees to continue to use two highly effective methods of contraception until at least 12 weeks after the last dose of study drug. 11. Male subjects and/or their partners must use two highly effective methods of contraception from screening to 12 weeks after the last dose of study drug. 12. Male subjects must refrain from sperm donation or banking from randomization to 12 weeks after the last dose of study drug. 13. Able to provide written informed consent and understand and comply with the requirements of the study. |
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E.4 | Principal exclusion criteria |
1. WOCBP and men with female partners of childbearing potential who are unwilling or unable to use two highly effective methods of contraception to avoid pregnancy for the entire study period and for up to 12 weeks after the last dose of study drug. 2.Women who are pregnant or breastfeeding. 3.Women with a positive pregnancy test on enrollment or prior to randomization. 4. Airway obstruction (pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)/FVC < 0.65). 5.Clinically significant pulmonary arterial hypertension (PAH) on right heart catheterization and requiring 2 oral or inhaled therapies or 1 parenteral therapy. 6.Other clinically significant pulmonary abnormalities. 7.History of autologous stem cell or lung transplantation. 8.Positive for serum anti-centromere antibody. 9.Current clinical diagnosis of another inflammatory connective tissue disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, or dermato/polymyositis). Concomitant scleroderma-associated myopathy, fibromyalgia, and secondary Sjögren's are allowed. 10.Subjects who are scheduled or anticipate the need for surgery, aside from dermatologic procedures. 11.Subjects who have a history of clinically significant drug or alcohol abuse. 12.Subjects who are current smoker (including e-cigarettes) / smoking within 6 months of screening. 13.Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal (including severe recurrent aspiration), cardiac, neurological, ophthalmologic, or cerebral disease. Concomitant medical conditions that in the opinion of the Investigator might place the subject at unacceptable risk for participation in this study. 14.Subjects with a history of cancer within the last 5 years (other than non-melanoma skin cell cancers cured by local resection or cervical in situ). Existing non-melanoma skin cell cancers must be removed prior to enrollment. Subjects with carcinoma in situ or localized cervical cancer, treated with definitive surgical intervention, are allowed. 15. Subjects at risk for tuberculosis (TB). Specifically, subjects with: a.A history of active TB which was not successfully treated with completion of treatment;b.Current clinical, radiographic, or laboratory evidence of active TB;c.Latent TB which was not successfully treated. Subjects with a positive TB screening test indicative of latent TB will not be eligible for the study unless active TB infection has been ruled out, and an appropriate course of intervention for latent TB has been initiated at least 2 weeks prior to randomization, and no evidence of active TB during screening. 16.Subjects with any serious infection within the last 3 months, or any chronic bacterial infection (such as chronic pyelonephritis, osteomyelitis, and bronchiectasis). 17.Female subjects who have had a breast cancer screening that is suspicious for malignancy, and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory, or other diagnostic evaluations. 18.Subjects with any active infections (excluding fungal infections of nail beds) including, but not limited to, those that require IV antimicrobial treatment 4 weeks or oral antimicrobial treatment 2 weeks prior to randomization. Subjects with evidence of Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection detected during screening are also excluded, but subjects with successfully treated Hepatitis C with no recurrence for ≥ 1 year are allowed. Subjects with active documented or suspected COVID-19 infection within 4 weeks of randomization or asymptomatic positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test within 2 weeks of randomization are excluded. 19.Subjects who have received any live vaccines within 3 months of the anticipated first dose of study medication or who will have need of a live vaccine at any time during the study or within 12 weeks after the last dose;20. Any of the following lab values: Hgb < 8.0 g/dL (80 g/L);White blood cell (WBC) < 2,500/mm3 (2.5 x 109/L);Neutrophils < 1,000/mm3 (1 x 109/L);Platelets < 100,000/mm3 (100 x 109/L);Serum creatinine > 2 times upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2;Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times ULN;Any other laboratory test results that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study. |
21.Treatment with: a. D-penicillamine, sulfasalazine, cyclosporine, tofacitinib or pirfenidone within 8 weeks of randomization;b.Cyclophosphamide, tocilizumab, abatacept, leflunomide, tacrolimus, or any other approved biologics for rheumatic diseases within 3 months of randomization;c.Rituximab within 6 months of randomization.22.Investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 5 half-lives (whichever is longer) of randomization.23.Prior exposure to PRA023. |
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E.5 End points |
E.5.1 | Primary end point(s) |
_ The proportion of subjects reporting adverse events (AEs), serious adverse events (SAEs), AEs leading to discontinuation, and markedly abnormal laboratory values _ To compare the annual rate of change from Baseline in FVC |
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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) |
_To compare the change from Baseline in FVC _To compare the annual rate of change in percent predicted FVC _To compare the change from Baseline in HRCT _To compare proportion of subjects with an improvement of the ACR CRISS score |
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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 | Yes |
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 | No |
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 | Yes |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
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 |
Switzerland |
Australia |
Canada |
Israel |
United Kingdom |
United States |
Belgium |
France |
Germany |
Hungary |
Italy |
Netherlands |
Norway |
Poland |
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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End of trial in all other participating countries is defined as last subject last visit (LSLV) or the last study procedure, whichever occurs last. |
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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 | 1 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 14 |