Clinical Trials Register

Summary
EudraCT Number:	2014-004134-26
Sponsor's Protocol Code Number:	sof-crio
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-11-10
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-004134-26

A.3

Full title of the trial

A MULTICENTER, PROSPECTIVE, SINGLE ARM, OPEN-LABEL, PILOT STUDY ON THE BENEFIT/COST/SAFETY PROFILE OF SOFOSBUVIR FOR SYMPTOMATIC MIXED CRYOGLOBULINEMIA

Studio pilota multicentrico, prospettico, a singolo braccio, in aperto, dei profili costi / benefici / sicurezza del sofosbuvir effettuato su pazienti con infezione cronica da virus dell’epatite C (HCV) e crioglobulinemia mista sintomatica

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A multicenter prospective study on the cost / benefit / safety of Sofosbuvir administered to patients with chronic hepatitis C virus and Mixed Cryoglobulinemia

Studio prospettico a cui aderiscono più centri che valuta i costi/benefici/sicurezza del farmaco Sofosbuvir somministrato a pazienti affetti da epatite cronica da virus C e Crioglobulinemia Mista

A.3.2

Name or abbreviated title of the trial where available

sof-crio

A.4.1

Sponsor's protocol code number

sof-crio

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Centro Masve -Università degli Studi di Firenze-AOUC
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Gilead Sciences Int, Ltd.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Università degli Studi di Firenze
B.5.2	Functional name of contact point	Centro Masve
B.5.3	Address:
B.5.3.1	Street Address	Largo Brambilla 3
B.5.3.2	Town/ city	Florence
B.5.3.3	Post code	50134
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390554271063
B.5.5	Fax number	00390557947335
B.5.6	E-mail	masve@unifi.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Sovaldi
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead SCiences Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sofosbuvir
D.3.9.1	CAS number	1190307-88-0
D.3.9.3	Other descriptive name	SOFOSBUVIR
D.3.9.4	EV Substance Code	SUB121170
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

HCV chronic hepatitis and Mixed Cryoglobulinemia

Epatite cronica HCV correlata e Sindrome Crioglobulinemica

E.1.1.1

Medical condition in easily understood language

Patients with chronic hepatitis by hepatitis virus C and mixed cryoglobulinemia

Paziente affetto da epatite cronica da virus C e crioglubulinemia mista

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	PT
E.1.2	Classification code	10008912
E.1.2	Term	Chronic hepatitis C
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10027756
E.1.2	Term	Mixed cryoglobulinemia
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

Valutare la sicurezza (monitoraggio degli eventi avversi) e l’efficacia del farmaco sull’eradicazione dell'HCV, sui livelli di criocrito e sul miglioramento della vasculite (Birmingham Vasculitis Activity Score)

E.2.2

Secondary objectives of the trial

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

Valutazione dei marcatori genetici durante il trattamento antivirale e nel follow up

E.2.3

Trial contains a sub-study

E.3

Principal 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.

Età superiore ai 18 anni; nessun pericolo di vita imminente; nessuna controindicazione al Sofosbuvir o alla ribavirina; consenso informato

E.4

Principal 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 < 3.5 g/dL (35 g/L);
5. Confirmed Platelets < 50 ×109 cells/L;
6. Confirmed Hemoglobin < 12 g/dL (120 g/L) for women and < 13 g/dL (130 g/L) for men;
7. Confirmed Creatinine Clearance (CrCl) ≤50 mL/min (as estimated by MDRD);
8. Alpha fetoprotein (AFP):
a. AFP > 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 compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

4.2.3 Women of Childbearing Potential
Women of childbearing potential include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as:
• Amenorrhea ≥ 12 consecutive months without another cause and a documented serum follicle stimulating hormone (FSH) level >35 mIU/mL or
• Women with irregular menstrual periods and a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL or
• NOTE: FSH level testing is not required for women ≥ 62 years old with amenorrhea of ≥ 1 year
• Women on hormone replacement therapy (HRT)

Women who are using oral contraceptives or other hormonal contraceptives such as vaginal products, skin patches, or implanted or injectable products, or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or who have a sterile (eg, vasectomy) partner should be considered to be of childbearing potential.

Altre coinfezioni virali (HIV, HbsAg positività), tossicodipendenza o alcolismo attivi, gravidanza in atto

E.5 End points

E.5.1

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.

Miglioramento o la scomparsa della CM sia dal punto di vista biochimico che sintomatologico e la risposta virologica sostenuta (SVR)

E.5.1.1

Timepoint(s) of evaluation of this end point

End of treatment (12 weeks- 24 weeks)
Post treatment (12 weeks and 24 weeks)

Fine trattamento (12 - 24 settimane)
Post trattamento (12 - 24 settimane)

E.5.2

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

Valutazione dei marcatori genetici

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 1 -End of treatment (12 weeks- 24 weeks)

Giorno 1 - Fine trattamento (12 - 24 settimane)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

Ultima visita dell'ultimo paziente.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Nessuno

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-02-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-28

P. End of Trial
P.	End of Trial Status	Ongoing

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