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    Summary
    EudraCT Number:2014-001449-26
    Sponsor's Protocol Code Number:6603/1132
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-12-01
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-001449-26
    A.3Full title of the trial
    A Multicenter, Open-label Study of SI-6603 in Patients with Lumbar Disc Herniation (Phase III)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Multicenter, Open-label Study of SI-6603 in Patients with Lumbar Disc Herniation (Phase III)
    A.4.1Sponsor's protocol code number6603/1132
    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 SponsorSeikagaku 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 supportSeikagaku Corporation
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSeikagaku Corporation
    B.5.2Functional name of contact pointClinical Development Department
    B.5.3 Address:
    B.5.3.1Street Address6-1, Marunouchi 1-chome
    B.5.3.2Town/ cityChiyoda-ku, Tokyo
    B.5.3.3Post code100-0005
    B.5.3.4CountryJapan
    B.5.4Telephone number+81(0)-3-5220-8593
    B.5.5Fax number+81(0)-3-5220-8594
    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 nameSI-6603 for Injection
    D.3.4Pharmaceutical form Powder and solution for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntradiscal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCondoliase
    D.3.9.1CAS number 9024-13-9
    D.3.9.2Current sponsor codeSI-6603
    D.3.9.3Other descriptive namechondroitin-sulfate-ABC endolyase
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Lumbar disc herniation
    E.1.1.1Medical condition in easily understood language
    Slipped lumbar disc (herniation)
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level PT
    E.1.2Classification code 10050296
    E.1.2Term Intervertebral disc protrusion
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary study objective is to evaluate the safety of a single dose intervertebral disc injection of SI-6603 at a dose of 1.25 U in patients with lumbar disc herniation, for a 26 week follow-up period.
    E.2.2Secondary objectives of the trial
    The secondary study objective is to evaluate the efficacy of a single dose intervertebral disc injection of SI-6603 at a dose of 1.25 U in patients with lumbar disc herniation, for a 26 week follow-up period.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients who have given their written informed consent to participate in a clinical study based on voluntary agreement after a thorough explanation of the patient's participation is provided to them. Patients must have adequate reading and writing abilities such that they can comprehend and answer the questions on the patient-completed assessments and Informed Consent Form (ICF).
    2. Patients with lumbar disc herniation (L1-L2, L2-L3, L3-L4, L4-L5, or L5-S1) “protrusion type*” or “extrusion type**” in the posterior lateral or central location as assessed by MRI and clinical symptoms corresponding to the level of the impaired nerve root; if the sixth lumbar vertebra (L6) is present, patients with impaired L5 or S1 nerve root and corresponding clinical symptoms
    * ”Protrusion type” is herniation where the nucleus pulposus has disrupted the posterior lateral or central location of annulus fibrosus partially which leads to compression of the nerve root.
    **“Extrusion type” is herniation where the nucleus pulposus has disrupted the posterior lateral or central location of annulus fibrosus completely which leads to compression of the nerve root.
    3. Patients with positive FNS ≤70° (L1-L2, L2-L3, or L3-L4) or SLR ≤70° (L4-L5 or L5-S1) on the symptomatic side
    4. Patients with sciatica or anterior thigh pain/femoral neuropathy in either leg prior to the time of informed consentt
    5. Patients with no improvement from adequate conservative treatment* prior to the time of informed consent
    *Adequate conservative treatment includes pharmacotherapy (e.g., nonsteroidal anti-inflammatory drugs, opiate preparations, or nonopioid analgesics). Physical therapy and/or spinal injection, epidural injection, or nerve block may also be included.
    6. Patients with the worst leg pain (by VAS ≥30 mm) during the past 24 hours at the time of informed consent.
    7. Male or female patients 30 to 70 years of age at the time of informed consent
    8. Female patients are not pregnant and do not plan to become pregnant during the study. Females of childbearing potential must provide a negative serum pregnancy test during the Screening period, must be using reliable contraception, and must continue to use reliable contraception until end of study (reliable methods of contraception are defined in exclusion criterion #6 below). Non-childbearing potential is defined as postmenopausal for at least 2 years or surgical sterilization or hysterectomy at least 3 months before study start.
    E.4Principal exclusion criteria
    1. Patients who have 2 or more symptomatic lumbar disc herniations as assessed by MRI
    Two or more level symptomatic lumbar disc herniations are defined as a patient having clinical symptoms and MRI findings consistent with radiculopathy in more than one nerve root distribution as assessed by the Investigator
    2. Patients with a contraindication to receiving an MRI
    3. Patients in whom a rupture into the posterior longitudinal ligament as assessed by MRI shows sequestration (free fragment) type lumbar disc herniation. Transligamentous extrusion type of disc herniation is allowed.
    4. Patients who previously received SI-6603 administration at any time
    5. Patients who are pregnant, breast-feeding or women of childbearing potential with positive pregnancy tests. Female patients with posthysterectomy and/or bilateral tubal ligation or postmenopausal* do not need to take the pregnancy tests.
    * Postmenopausal is defined as either 12 months of spontaneous amenorrhea, or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.

    6. Sexually active female patients of childbearing potential who are not willing to use adequate contraceptive measures to avoid pregnancy until end of the study. Sexually active male patients who are not willing to use adequate contraceptive measures until end of the study.
    Adequate methods of birth control include the following:
    -- Hormonal contraception (female patients) or use of at least one acceptable double-barrier method
    Acceptable double-barrier methods include the following:
    ------diaphragm plus a spermicidal agent
    -------condoms (male or female) plus a spermicidal agent
    - Vasectomy, intrauterine device, and/or exclusive sexual partner for whom one of the above acceptable methods applies
    7. Patients who have undergone lumbar operation, lumbar percutaneous nucleotomy or lumbar intradiscal therapies (e.g., chemonucleolysis or intradiscal electrothermal treatment) under any of the following conditions:
    - At the affected level of lumbar disc herniation
    - Within the last 2 years at any lumbar spine level other than affected level
    - With symptoms not completely improved by the above procedure at any lumbar spine level other than affected level
    8. Patients with the following medical conditions or diseases:
    -Vertebral body angle formed by flexion ≥5°
    -Neurological disorders including cauda equina syndrome that is severe or that demonstrates rapid progression. Patient with clinically symptomatic neurological deficit (e.g., motor paresis, sphincter dysfunction), warranting an alternative option of care that would be more appropriate for their presentation, will be also excluded.
    -Spondylosis deformans, spondylolisthesis (translation of vertebral body ≥3 mm), spinal deformity, spinal canal stenosis (except for complication of lumbar disc herniation), spinal tumor, ankylosing spondylitis, diskitis, or clinically significant disorders of the lumbar spine other than disc herniation.
    - Osteophyte at lumbar spine (Nathan's classification ≥3rd degree)
    - Cancer: patients who have cancer or a past history of any cancer within 5 years prior to the time of informed consent, with the exception of basal cell or squamous cell carcinoma of the skin curatively treated or localized gynecologic cancer treated by total hysterectomy.
    - Human immunodeficiency virus (HIV) infection or a clinically significant infection
    - A clinically significant disorder such as cerebrovascular disease, pulmonary infarction, ischemic heart disease, cardiac dysrhythmia, myocardial infarction, or congestive heart failure
    - Chronic diseases such as osteoporosis, rheumatoid arthritis, uncontrolled diabetes mellitus, uncontrolled pulmonary disease (asthma), or uncontrolled hypertension
    - Patients who have evidence of major psychiatric disease, mental disorder, drug dependency, alcohol dependency, or substance use disorders.
    - Patients who have a tendency to bleed or with bleeding disorders such as (but not limited to) hemophilia, hypoplastic anemia, cirrhosis of the liver, leukemia and vitamin K deficiency. Patients using medication for purpose of anticoagulation, which cannot be reversed preoperatively will be excluded.
    9. Patients with medical conditions and/or diseases that the Investigator believes could affect the study results or the safe conduct of the study.
    10. Patients who meet any of the following criteria:
    - Hepatic function: AST or ALT: ≥2.5 x upper limit of normal (ULN)
    - Total-bilirubin: ≥1.5 x ULN
    - Renal function: Serum creatinine: ≥1.5 x ULN
    11. Patients who are receiving compensation according to the Workers' Compensation Act or are involved in personal injury litigation due to a lumbar-related injury.
    12. Patients who participated in another clinical study within 4 months prior to the time of informed consent, or who are expected to participate in another study during the period of this study.
    E.5 End points
    E.5.1Primary end point(s)
    The following safety endpoints will be assessed:
    - Occurrences of AEs
    - Stability evaluation of vertebral bodies by X-ray at the times specified in the schedule of events
    ---Translation of vertebral body
    ---Vertebral body angle formed by flexion
    - Changes from baseline in disc height (disc index) assessed by X-ray at the times specified in the schedule of events
    - Changes of disc degeneration, vertebral body endplates, and adjacent bone marrow assessed by MRI at the times specified in the schedule of events
    -----Modic classification
    -----Pfirrmann classification
    - Clinically significant change in vital signs at the times specified in the schedule of events
    - Clinically significant change in clinical laboratory tests at the times specified in the schedule of events
    - Serum anti-SI-6603 IgE antibody and IgG antibody titer at the times specified in the schedule of events
    - Occurrence of post-treatment lumbar surgery other than surgery for lumbar disc herniation at the same level of the investigational drug administration
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of trial
    E.5.2Secondary end point(s)
    The following secondary efficacy endpoints will be assessed at the times specified in the schedule of events and overall time-course, and changes from baseline will be analyzed:
    - Worst leg pain during the past 24 hours assessed by VAS.
    - Worst back pain during the past 24 hours assessed by VAS.
    Functional disability measured by the Oswestry Disability Index (ODI).
    - Change of neurological status from baseline determined by neurological examinations:
    -----Femoral Nerve Stretching (FNS) test for patients with lumbar disc herniation L1-L2, L2-L3, or L3-L4 or
    -----Straight Leg Raising (SLR) test [for patients with lumbar disc herniation L4-L5 or L5-S1, and
    -----Sensation, muscle strength, and deep tendon reflex.
    - Occurrence of post-treatment surgery for lumbar disc herniation at the same level of administration of the investigational drug up to Week 26 including patients who discontinued from the study.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of trial
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    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.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Germany
    Italy
    Romania
    Spain
    United States
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    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: 800
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state210
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 500
    F.4.2.2In the whole clinical trial 1000
    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)
    Subjects will return to the standard of care therapy as determined by their physician.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-03-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-03-17
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