E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042953 |
E.1.2 | Term | Systemic sclerosis |
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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 efficacy of oral STI571 in skin fibrosis in systemic sclerosis (SSc) patients as measured by an improvement in the modified Rodnan Skin Score. •To assess the safety and tolerability of oral STI571 in SSc patients.
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E.2.2 | Secondary objectives of the trial |
•To assess improvement in lung function as measured by CO diffusion capacity (DLCO) and Forced Vital Capacity (FVC). •To assess biomarkers reflecting the direct effects of STI571 on its biological targets. •To determine the PK trough levels of STI571 and its major active metabolite CGP74588 during dose escalation and the maintenance phase of the study. Exploratory objective •To explore alternative biomarkers that may provide additional measures of efficacy of STI571 in skin, plasma/serum and urine samples. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Male and female patients equal to or older than 18 years of age and fulfilling the American College of Rheumatology criteria for systemic sclerosis (SSc). •Diffuse cutaneous SSc (dcSSc) according to the LeRoy criteria with disease duration less than 18 months from the appearance of the first non-Raynaud´s symptom judged by a physician to be part of SSc. •Patients with a MRSS of at least 20 (maximum score 51) in the absence of trunk involvement or a MRSS of at least 16 in patients with trunk involvement •Female patients of childbearing potential must be using two acceptable methods of contraception (e.g., intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.), from the time of screening and for the duration of the study, through study completion. Period abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female patients who report surgical sterilization must have had the procedure at least six (6) months prior to initial dosing. Surgical sterilization procedures should be supported with clinical doumentation made available to the sponsor and noted in the Relevant Medical History / Current medical Conditions section of the CRF. All female patients must have negative pregnancy test results at sreening and at baseline. •Male patients must be using two acceptable methods of contraception, (e.g., spermicidal gel plus condom) for the entire duration of the study, up to the Study Completion visit, and refrain from fathering a child in the three (3) months following last study drug administration. Periodic abstinence and withdrawal are not acceptable methods of contraception. •Able to communicate well with the Investigator, to understand and comply with the requirements of the study. Understand and sign the written informed consent.
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E.4 | Principal exclusion criteria |
1.SSC patients with a MRSS greater than 35. 2.Concurrent connective tissue diseases other than SSc including SSc-like illnesses related to environmental, ingested or injected agents, and also including overlap syndromes and mixed connective tissue disease. 3.Significant pre-existing internal organ damage: •kidneys: •MDRD calculated creatinine clearance < 40 mL/min •renal crisis (acute onset of renal failure, moderate to marked hypertension, and normal urine sediment with mild proteinuria) in the 2 months prior to treatment •lungs: •FVC < 50% predicted •CO diffusion capacity < 40% predicted •heart: •left ventricular ejection fraction < 40% •ECG conduction abnormalities deemed by the Investigator to be clinically significant (including atrio-ventricular blocks, atrial or ventricular arrhythmias, sinus pauses > 3 seconds) •gut: •pseudo-obstruction •mal-absorption requiring parental nutrition. 4.Existing myositis: serum creatine phosphokinase > 3 fold of the upper-limit 5.Conditions that might mimic potential side effects of STI571: •hematological conditions: - thrombocytopenia < 100 x 109/L •neutropenia < 1.5 x 109/L •moderate hepatic insufficiency with transaminase levels >3 fold the upper limit of normal, or bilirubin > 2 fold the upper limit of normal •chronic diarrhea for more than 4 weeks •peripheral edemas 6.Active or opportunistic infection 7.Concurrent interventional medical therapy that might potentially influence the outcome of the disease. Treatment with other potentially disease modifying agents during the last 6 weeks, including prednisone or corticosteroid equivalent in doses higher than 15 mg/d or changes in the prednisone doses during the last 1 month before first dosing. 8.Grapefruit juice should not be drunk whilst patients participate in the study. Special attention should be given to the co-prescription of CYP3A4 inhibitors (e.g. Amiodarone, Diltiazem, Verapamil, macrolide antibiotics, Itraconazole and Ketoconazole), and to some of the drugs metabolized by CYP450 isoenzymes (Phenytoin, Carbamazepin, Rifampicin, Phenobarbital, Saint-John’s Wort, Cyclosporine, Warfarin or Paracetamol). For guidance on drug-drug interactions see Section 6.5.3 on concomitant medication. 9.Other conditions that might be associated with an increased risk to the patient or interfere with successful conduction of the trial: •underlying chronic debilitating diseases such as cancer, •pregnancy, breast feeding or lack of safe contraception (IUD, diaphragm, bilateral tubal ligation, hysterectomy) in women of childbearing potential. 10.Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the patient in case of participation in the study. The Investigator should be guided by evidence of any of the following: •history of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding; •history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection; •history or clinical evidence of pancreatic injury or pancreatitis. 11.Participation in any treatment studies within 3 months prior to dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations. 12.Donation or loss of 400 ml or more of blood within 8 weeks prior to first dosing, or longer if required by local regulation. 13.History of acute or chronic bronchospastic disease (at the discretion of Investigators) 14.History of clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug or drugs similar to the study drug. 15.History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result. 16.A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result. 17.History of drug abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening evaluations at discretion of the investigator. 18.Chronic thromboembolic pulmonary hypertension. 19.Severe systemic arterial hypertension (>180 mm Hg [systolic] or >110 mm Hg [diastolic]) 20.Congenital or acquired valvular or myocardial disease. 21.A past medical history of clinically significant ECG abnormalities. 22.History of autonomic dysfunction (e.g. history of fainting, orthostatic hypotension, sinus arrhythmia). 23.History of myocardial ischemia or infarction. 24.History of heart failure. 25.Disseminated intravascular coagulation (DIC). 26.Sickle cell anemia or other anemia associated with hemoglobin < 10 mg/dL. 27.Evidence of major bleeding or intracranial hemorrhage in the last two years. 28. Hemochromatosis. 29.Ischemic stroke in the last two years. 30.History of other significant illness within four weeks prior dosing.
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage change from baseline in MRSS at time point t is calculated for each patient as % change form baseline(t)=[mRSS(t)-mRSS(baseline)] / mRSS(baseline) |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
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 |
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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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |