HCV chronic hepatitis and Mixed Cryoglobulinemia MedDRA version: 17.1 Level: PT Classification code 10008912 Term: Chronic hepatitis C System Organ Class: 10021881 - Infections and infestations MedDRA version: 17.1 Level: LLT Classification code 10027756 Term: Mixed cryoglobulinemia System Organ Class: 100000004866
Conditions
Interventions
Trade Name: Sovaldi
Pharmaceutical Form: Tablet
INN or Proposed INN: sofosbuvir
CAS Number: 1190307-88-0
Other descriptive name: SOFOSBUVIR
Concentration unit: mg milligram(s)
Concentration type: equa
Sponsors
Centro Masve -Università degli Studi di Firenze-AOUC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1)Signed Written Informed Consent Freely given informed consent must be obtained from patients prior to clinical trial participation including informed consent for any screening procedures conducted to establish patient eligibility for the study. 2)Target Population • Diagnosis of HCV-associated MC syndrome (type II or III) according to published criteria (10) • Seronegative for HIV-Ab and HBsAg; • Eligibility: age>18 yrs. • No limitation for HCV genotype (GT 1, 2, 3, 4, 5, 6) or treatment history (naïve or experienced to IFN-based therapies) 3)Age and Reproductive Status a) Males and females, = 18 years of age; b) Women of childbearing potential (WOCBP) and men must be using an acceptable method of contraception to avoid pregnancy throughout the study. Contraception requirements for WOCBP (see Section 4.2.3 for definition of WOCBP) and men who are sexually active with WOCBP: i. Two (2) separate forms of non-hormonal contraception are required from time of screening, throughout the duration of the on-treatment study period and for at least 24 weeks after the last dose of RBV (or the duration specified by the country-specific RBV label, whichever is longer) in such a manner that pregnancy is minimized. Oral contraceptive pills (OCPs) may not be used in this study as 1 of the 2 effective forms of contraception. Examples of acceptable methods of contraception include: tubal ligation, diaphragm, female condom, intrauterine devices (IUDs), condom with spermicide. ii. Exceptions include: I. WOCBP who are not heterosexually active or who have male partners who have been vasectomized for a minimum of 6 months; II. Sexually active men who are vasectomized for a minimum of 6 months with a history of confirmed azoospermia. c) WOCBP must have a negative serum or urine pregnancy test [minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (HCG)] within 24 hours prior to the start of investigational product. Female patients must agree to the pregnancy testing requirements of this protocol; d) Women must not be breastfeeding; e) Male patients: Requirements (based on RBV label): i. Male patients (unless vasectomized for at least 6 months and with a history of confirmed azoospermia) with female partners who are WOCBP must agree to inform their female partners of the protocol-specified contraception requirement and pregnancy testing recommendations during treatment and post-treatment (ie, 2 forms of contraception and monthly pregnancy testing while the patient is enrolled in the study and 6 months following discontinuation of RBV [or for the post-treatment duration specified in the country-specific RBV label]), and agree to adhere to these recommendations both on-treatment and during the post-treatment follow-up period; ii. Male patients must confirm that their female sexual partners are not pregnant at the time of screening. 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 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 10
Exclusion criteria
Exclusion criteria: 1) Medical History and Concurrent Diseases a) Liver transplant recipients; b) Evidence of decompensated liver disease including, but not limited to, a history or presence of ascites, bleeding varices, or hepatic encephalopathy; c) Documented or suspected HCC as evidenced by previously obtained imaging studies or liver biopsy (or on a screening imaging study/liver biopsy if this was performed); d) Evidence of a medical condition contributing to chronic liver disease other than HCV (such as, but not limited to: hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures); e) History of chronic hepatitis B virus (HBV) as documented by HBV serology (eg, HBsAg-seropositive). Patients with resolved HBV infection may participate (eg, HBsAb-seropositive with concurrent HBsAg-seronegative); f) History of HIV infection; g) Current or known history of cancer (except in situ carcinoma of the cervix or adequately treated basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment; h) Any gastrointestinal disease or surgical procedure that may impact the absorption of study drug; i) Active substance abuse as defined by DSM-IV, Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 1), which in the opinion of the investigator would make the candidate inappropriate for participation in this study; j) Organ transplants (including hematopoietic stem cell transplants) other than cornea and hair; k) Uncontrolled diabetes (any patient with screening HgA1c = 8.5% must be excluded); l) Confirmed uncontrolled hypertension (any screening systolic blood pressure =160 mmHg or diastolic blood pressure =100 mmHg should be excluded unless discussed with the central medical monitor); m) Inability to tolerate oral medication; n) Any other medical, psychiatric and/or social reason which, in the opinion of the investigator, would make the patient inappropriate for the study. o) Coexistence of life-threatening condition(s) unrelated to MC p) Any ongoing infection (eligible after eradication of infection) q)Patient with decompensated cirrhosis 2) Physical and Laboratory Test Findings 1. Confirmed Alanine amino transferase (ALT) > 5xULN 2. Confirmed Total Bilirubin =2 mg/dL, unless subject has a documented history of Gilbert’s disease; 3. Confirmed INR =1.7; 4. Confirmed Albumin 100 ng/mL (>121IU/ml) b. AFP =50 and =100 ng/mL (> 60.5 IU/ml and < 121 IU/ml) requires a second level imaging procedure. 9. Positive HBsAg, HIV-1 or HIV-2 Ab. 3) Allergies and Adverse Drug Reaction a) History of hypersensitivity to drugs with a similar biochemical structure to Sofosbuvir, or RBV. 4) Prohibited Treatment and/or Therapies a) Treatment with anti-CD20 in the previous 6 months. b) Plasmapheresis course in the 2 months preceding enrollment c) High dose corticosteroids and/or immunosuppressive drugs in the 2 months preceding enrollment 6) Sex and Reproductive Status a) Those males and females who do not or cannot meet the requirements outlined in Inclusion Criteria 3; b) Sexually active fertile men whose partners are pregnant at screening are excluded from this study (a contraindication for RBV use). 7) Other Exclusion Criteria a) Patients who are co
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To define the safety in terms of tolerability/adverse events profiles (total, severe, fatal) of Sofosbuvir+Ribavirin treatment in patients with HCV-related MC. To evaluate the clinical and virological response of the association of Sofosbuvir+Ribavirin for the treatment of HCV-associated MC. ;Secondary Objective: To identify biomarkers useful to define and predict the response of the lymphoproliferative disorder (LPD) underlying MC, i.e,: • Peripheral Blood Mononuclear Cells (PBMC) infection; • levels of an appropriate panel of microRNA (miRNAs) in serum and PBMC; • t(14;18) bearing B-cell clone regression; • decrease of the frequency of circulating monoclonal B-cells • decrease of clonal IgH rearrangement ;Primary end point(s): Clinical response: improvement or disappearance of MC laboratory and/or clinical stigmata at the EOT, 12 and 24 weeks of post-treatment follow-up (when possible, also at the different time points 1, 2, 4, 8, 12 ,16, 20 and 24 (see table 6.1.2 and 6.1.3). Virological response: SVR 12; (SVR 24 in case SVR 12 is not available) (when possible at the different time points. ;Timepoint(s) of evaluation of this end point: End of treatment (12 weeks- 24 weeks) Post treatment (12 weeks and 24 weeks) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Evaluation of putative biomarkers at the key visit times (see table 6.1.2 and 6.1.3). Analysis of clinical and virological response according to patient baseline characteristics, including: • Correlation of HCV-RNA clearance (serum and PBMC) with clinical parameters of efficacy • Correlation of virological and clinical data with the pattern of expression on PBMC of a panel of microRNAs previously shown to be correlated with HCV-related LPDs • Decrease of circulating B-cells with t(14;18) Bcl-2/IgH • Decrease of circulating monoclonal B-cells • Decrease of clonal IgH rearrangement ;Timepoint(s) of evaluation of this end point: Day 1 -End of treatment (12 weeks- 24 weeks) | — |
Countries
Italy
Contacts
Public ContactCentro Masve
Università degli Studi di Firenze
Outcome results
None listed