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    Summary
    EudraCT Number:2014-004882-26
    Sponsor's Protocol Code Number:ND-L02-s0201-002
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-01-26
    Trial results View 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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBulgarian Drug Agency
    A.2EudraCT number2014-004882-26
    A.3Full title of the trial
    A Phase 1b/2, Open Label, Randomized, Repeat Dose, Dose Escalation Study to Evaluate the Safety, Tolerability, Biological Activity and Pharmacokinetics of ND L02 s0201 Injection, a Vitamin A-coupled Lipid Nanoparticle Containing siRNA Against HSP47, in Subjects with Moderate to Extensive Hepatic Fibrosis (METAVIR F3-4)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the safety and tolerability of multiple doses of ND-L02-s0201 in subjects with moderate to extensive hepatic fibrosis
    A.4.1Sponsor's protocol code numberND-L02-s0201-002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02227459
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNitto Denko Corporation
    B.1.3.4CountryJapan
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNitto Denko Corporation
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNitto Denko Corporation
    B.5.2Functional name of contact pointWenbin Ying, MD, PhD
    B.5.3 Address:
    B.5.3.1Street Address33rd Floor, Tower A, Grand Front Osaka, 4-20 Ofuka-cho, Kita-ku
    B.5.3.2Town/ cityOsaka
    B.5.3.3Post code530-0011
    B.5.3.4CountryJapan
    B.5.4Telephone number+817604357048
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameND-L02-s0201 Injection
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNDT-05-0038
    D.3.9.2Current sponsor codeNDT-05-0038
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Moderate to extensive progressive hepatic fibrosis (METAVIR F3-4)
    E.1.1.1Medical condition in easily understood language
    A progressive increase of scar tissue in the liver due to inflammation
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10019668
    E.1.2Term Hepatic fibrosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the safety and tolerability of once or twice a week ND-L02-s0201 Injection (ND-L02-s0201)
    administered as intravenous (IV) infusions for 5 consecutive weeks to subjects with moderate to extensive hepatic fibrosis (METAVIR F3-4)
    E.2.2Secondary objectives of the trial
    • Evaluate the effect of ND-L02-s0201 on the change of heat shock protein 47 (HSP47) levels detectable by polymerase chain reaction (PCR) in liver biopsies taken before and after therapy,
    • Evaluate the biological activity of ND-L02-s0201 on changes in various markers of collagen metabolism and hepatic fibrosis as determined by histologic examination and collagen quantification of liver biopsy specimens and measurement of collagen synthesis and degradation markers, and
    • Evaluate the pharmacokinetics (PK) of the following components of ND-L02-s0201 after repeat dosing in subjects with moderate to extensive hepatic fibrosis:
    (1) the active small interfering ribonucleic acid (siRNA) ingredient, NDT-05-0038,
    (2) the vitamin A-conjugated targeting agent lipid component (DiVA), and
    (3) the cationic lipid excipient, S104.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject is a male or female between 18 and 75 years of age.
    2. The subject has a diagnosis of METAVIR F3-4 hepatic fibrosis as determined by liver biopsy done within 12 months before screening (Cohort 1) or at the pre-dose biopsy within 6 weeks before treatment (Cohorts 2 and 3). METAVIR (Bedossa & Poynard, 1996) scores are defined as follows:
    F0 = No fibrosis
    F1 = Portal fibrosis without septa
    F2 = Portal fibrosis with rare septa
    F3 = Numerous septa without cirrhosis
    F4 = Cirrhosis
    3. The subject has adequate and stable synthetic hepatic function (albumin ≥ 3 g/dL, international normalized ratio [INR] ≤ 1.4 x upper limit of normal [ULN] and stable by prior medical history).
    4. The subject has adequate and stable hepatic function as measured by alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamate transferase (GGTP), and total bilirubin (ALT/AST ≤ 5 x ULN, ALP ≤ 4 x ULN, GGTP ≤ 4 x ULN, bilirubin ≤ 2x ULN and stable by prior medical history).
    5. The subject has platelet count ≥ 75,000/mm3, hemoglobin ≥ 10 g/dL, and white blood cell count (WBC) > 3000/μL.
    6. The subject has no signs of decompensated liver disease (ascites, hepatic encephalopathy, or variceal bleeding).
    7. The subject has no clinically significant abnormalities on 12-lead electrocardiogram (ECG).
    8. The subject has no other intercurrent medical conditions or infections considered clinically significant by the Investigator.
    9. The subject’s clinical laboratory assessments are within the laboratory limits of normal values or not considered clinically significant by the Investigator.
    10. The subject’s vitamin A levels at screening must be less than or equal to the upper limit of normal (ULN 95 μg/dL or 3.32 μmol/L).
    11. Any male subject, if sexually active, agrees to use barrier contraceptive techniques as defined in the protocol. If female, the subject must be of non-childbearing potential as defined in the protocol.
    12. Subjects who are active substances abusers may be enrolled at the discretion of the Principal Investigator.
    13. The subject is willing and able to provide written informed consent and comply with the study procedures and visit schedule, including follow-up visits.
    E.4Principal exclusion criteria
    1. The subject has any disease or condition which, in the opinion of the Investigator, might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, hepatic, skeletal, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism, or excretion of ND-L02-s0201, or would place the subject at increased risk.
    2. The subject is on ongoing therapy for HCV/HBV, or received therapy for HCV/HBV within 12 weeks prior to administration of study drug.
    3. The subject is on interferon therapy for any disease, or received interferon therapy for any disease within 12 weeks prior to administration of study drug.
    4. The subject has a history of bone disease, including osteoporosis and osteomalacia, Paget’s disease of bone, or a history of unexplained fractures or fractures after minimal trauma.
    5. The subject has alpha-fetoprotein (AFP) ≥ 50 ng/mL or signs of abnormality or hepatocellular carcinoma on ultrasound survey of the liver.
    6. The subject’s laboratory test results include abnormal values considered to be clinically significant by the Investigator.
    7. The subject participated in a concurrent interventional study with the last intervention occurring within 12 weeks prior to administration of study drug.
    8. The subject took vitamin A or vitamin D supplements or multi-vitamins that contain vitamin A or vitamin D between the screening visit and administration of study drug.
    9. The subject has a history, within the last 2 years, of alcohol abuse, significant mental illness, or physical dependence on any opioid.
    10. The subject has, in the opinion of study staff, veins unsuitable for repeated venipuncture or IV infusion (eg, veins that are difficult to locate, access or puncture; veins with a tendency to rupture during or after puncture).
    11. The subject has received recent treatment with alternative therapies, which, in the opinion of the Investigator, could potentially confound clinical or laboratory assessments.
    12. The subject lost more than 500 mL of blood within 56 days prior to administration of study drug.
    13. The subject has a body mass index (BMI) > 38 kg/m2.
    14. The subject has a history of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome-related illness (AIDS).
    15. The subject has a history of malignancy within the last 5 years, with the exception of basal cell carcinoma.
    16. The subject is a woman of childbearing potential.
    17. The subject has a history of hypersensitivity to H2-receptor antagonists.
    18. There is any other reason that, in the opinion of the Investigator or the QDS Medical Monitor, makes the subject unsuitable for enrollment.
    E.5 End points
    E.5.1Primary end point(s)
    Number of participants with serious and non-serious adverse events
    E.5.1.1Timepoint(s) of evaluation of this end point
    After treatment for 5 consecutive weeks and follow-up through week 24
    E.5.2Secondary end point(s)
    • Evaluation of the effect of ND-L02-s0201 on the change of heat shock protein 47 (HSP47) levels detectable by polymerase chain reaction (PCR) in liver biopsies taken before and after therapy,
    • Evaluation of the biological activity of ND-L02-s0201 on changes in various markers of collagen metabolism (weeks 8,12,16,20 and 24) and hepatic fibrosis as determined by histologic examination and collagen quantification of liver biopsy specimens ( within 12 months before screening and within 7 days of last infusion) and measurement of collagen synthesis and degradation markers, and
    • Evaluation of the pharmacokinetics (PK) during week 1 (days 1-4), week 3 (Day 15), and week 5 (day29-32) of the following components of ND-L02-s0201 after repeat dosing in subjects with moderate to extensive hepatic fibrosis:
    (1) the active small interfering ribonucleic acid (siRNA) ingredient, NDT-05-0038,
    (2) the vitamin A-conjugated targeting agent lipid component (DiVA), and
    (3) the cationic lipid excipient, S104.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Change in markers of collagen metabolism will be assessed from before the first treatment to immediately after the last treatment, and at follow up visits at Weeks 8,12,16,20 and 24(or at ET). FibroScan procedures, will be done to assess liver fibrosis before the first treatment, immediately after the last treatment (Week 5), during Follow-up Week 12 and at Week 24 (or at ET).
    Hepatic function laboratory tests will be performed throughout the study.
    Blood samples for the assessment of serum liver fibrosis marker(M2BPGi) will be collected before the first treatment (Week1), after the end of infusion (EOI) of the last treatment(Week5), and during Follow-up at Week12, and at Week24 (or at ET).
    Blood samples will be drawn for PK analysis at multiple time points during the treatment period.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    1b
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Bulgaria
    United States
    E.8.7Trial 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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 24
    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)
    as per the approved local clinical practice
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Nitto Denko Technical Corporation
    G.4.3.4Network Country United States
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-02-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-25
    P. End of Trial
    P.End of Trial StatusCompleted
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