A multi-center, open-label, Proof of Concept (PoC) study to evaluate the efficacy and tolerability of STI571 for the treatment of fibrosis in patients with systemic sclerosis

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2007-004669-17-GB
• Date of registration: 16/10/2007
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A multi-center, open-label, Proof of Concept (PoC) study to evaluate the efficacy and tolerability of STI571 for the treatment of fibrosis in patients with systemic sclerosis
• Scientific title: A multi-center, open-label, Proof of Concept (PoC) study to evaluate the efficacy and tolerability of STI571 for the treatment of fibrosis in patients with systemic sclerosis
• Date of first enrolment: 15/02/2008
• Target sample size: 27
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-004669-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:

Countries of recruitment

Italy, United Kingdom

Key inclusion & exclusion criteria

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 modified Rodnan Skin Score of at least 20 (maximum score 51) in the absence of trunk involvement or a modified Rodnan Skin Score of at least 16 in patients with trunk involvement
•Female patients of child bearing 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.
•Male patients must be using a two acceptable methods of contraception, (e.g., spermicidal gel plus condom) for the entire duration of the study, up to 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.

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
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1.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.
2.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.
3.Existing myositis: serum creatine phosphokinase > 3 fold of the upper-limit
4.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
5.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.
6.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.
7.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.
8.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.
9.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.
10.Donation or loss of 400 ml or more of blood within 8 weeks prior to first dosing, or longer if required by local regulation.
11.History of acute or chronic bronchospastic disease (at the discretion of Investigators)
12.History of clinically significant drug all

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

Health Condition(s) or Problem(s) studied

Skin fibrosis in systemic sclerosis patients
MedDRA version: 9.1 Level: LLT Classification code 10042953 Term: Systemic sclerosis

Intervention(s)

Trade Name: Glivec
Product Name: Glivec
Product Code: STI571
Pharmaceutical Form: Tablet
INN or Proposed INN: imatinib
CAS Number: 220127-57-1
Current Sponsor code: STI571
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Secondary Objective: Secondary objectives
•To assess improvement in lung functions 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.

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)

Main Objective: •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.

Secondary ID(s)

CSTI571E2205