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    Summary
    EudraCT Number:2012-001831-30
    Sponsor's Protocol Code Number:ISIS420915-CS2
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-19
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-001831-30
    A.3Full title of the trial
    A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A controlled study to assess the effectiveness and safety of study drug, ISIS 420915, in patients with Familial Amyloid Polyneuropathy
    A.3.2Name or abbreviated title of the trial where available
    ISIS 420915-CS2
    A.4.1Sponsor's protocol code numberISIS420915-CS2
    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 SponsorIsis Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportIsis Pharmaceuticals
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIsis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointMatt R. Buck
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Ct.
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number011760603-2684
    B.5.5Fax number011760603-3891
    B.5.6E-mailmbuck@isisph.com
    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 nameHuman Transthyretin Antisense Oligonucleotide
    D.3.2Product code ISIS 420915
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNISIS 420915
    D.3.9.2Current sponsor codeISIS 420915
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    D.3.11.13.1Other medicinal product typeAntisense Oligonucleotide
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Familial Amyloid Polyneuropathy
    E.1.1.1Medical condition in easily understood language
    Familial Amyloid Polyneuropathy
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10057949
    E.1.2Term Familial amyloid polyneuropathy
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of ISIS 420915 as compared to palcebo, given for 65 weeks, as measured by the change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) and inthe Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score, in patients with FAP.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of ISIS 420915 as compared to placebo based on the change from baseline in the following measures:
    • Norfolk QOL-DN questionnaire symptoms domain score in Stage 1 patients and Norfolk QOL-DN questionnaire physical functioning/large fiber neuropathy domain score in Stage 2 patients
    • Modified body mass index (mBMI) and body mass index (BMI)
    • NIS and modified +7
    • NIS+7

    To evaluate the pharmacodynamic (PD) effect of ISIS 420915 as compared to placebo, based on the change from baseline in transthyretin (TTR) and retinol binding protein 4 (RBP4).

    To evaluate the safety and tolerability of ISIS 420915.

    To evaluate the plasma trough levels of ISIS 420915 in all patients and to evaluate the plasma pharmacokinetic parameters of ISIS 420915 in a subset of patients.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Stage 1 and Stage 2 FAP patients with the following:
    a. NIS score >15 and <85
    b. Ability to walk unaided or with the use of no more than one stick/cane
    c. Documented transthyretin variant by genotyping
    d. Documented amyloid deposit by biopsy

    2. Willingness to take vitamin A supplements

    3. Aged 18 to 75 years old at the time of informed consent

    4. Satisfy the following:
    a. Females: Non-pregnant and non-lactating; surgically sterile, post-menopausal, abstinent, or if engaged in sexual relations of child-bearing potential, patient is using an acceptable contraceptive method for 4 weeks prior to, during, and for 3 months after the last dose of Study Drug
    b. Males: Surgically sterile, abstinent, or if engaged in sexual relations of child-bearing potential, patient is utilizing an acceptable contraceptive method during and for 3 months after the last dose of Study Drug

    5. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements
    E.4Principal exclusion criteria
    1. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator

    2. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion:
    a. ALT/AST >1.9 x ULN
    b. Bilirubin ≥1.5 x ULN (patients with bilirubin ≥1.5 x ULN may be allowed on study following discussion with the Study Medical Monitor if indirect bilirubin only is elevated,ALT/AST is not greater than the ULN and genetic testing confirming Gilbert’s disease)
    c. Platelets <100 x 109/L
    d. Persistently positive (2 out of 3 consecutive tests ≥1+) for protein on urine dipstick. In the event of a positive test eligibility may be confirmed by a quantitative total urine protein measurement of <1.0 g/24 hours
    e. Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on urine dipstick. In the event of a positive test eligibility may be confirmed with urine microscopy showing <5 red blood cells per high power field
    f. TSH values outside normal range

    3. Retinol level at screen < LLN

    4. QTcF >470 msec (average of triplicates). QTcF values >470 msec should be confirmed by Sponsor central ECG reader. Patients with a left bundle branch block or pacemaker will not be eligible if QTcF >500 msec (QTcF values >500 msec should be confirmed by Sponsor entral ECG reader)

    5. Uncontrolled hypertension (blood pressure >160/100)

    6. Positive test result for human immunodeficiency virus (HIV), hepatitis B or hepatitis C

    7. Karnofsky performance status ≤50

    8. Renal insufficiency as defined by estimated creatinine clearance calculated according to the formula of CKD-EPI <45 mL/min/1.73 m2 at screen. If the calculated creatinine clearance is thought to be artificially low, a 24-hour urine creatinine clearance can be completed with prior Sponsor approval

    9. Known type 1 or type 2 diabetes mellitus

    10. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease)

    11. Treatment with another investigational drug, biological agent, or device within three-months of screening, or five half-lives of study agent, whichever is longer

    12. If previously treated with Vyndaqel® must have discontinued treatment for 2 weeks prior to Study Day 1. If previously treated with Diflunisal, must have discontinued treatment for 3 days prior to Study Day 1

    13. Previous treatment with any oligonucleotide or siRNA within 12 months of screening

    14. Prior liver transplant or anticipated liver transplant within 1 year of screening

    15. New York Heart Association (NYHA) functional classification of ≥3

    16. Acute coronary syndrome or major surgery within 3 months of screening

    17. Known Primary Amyloidosis

    18. Known Leptomeningeal Amyloidosis

    19. Anticipated survival less than 2 years

    20. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1

    21. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated

    22. Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study
    E.5 End points
    E.5.1Primary end point(s)
    Change in mNIS+7 score from baseline to Week 66 and the change in the Norfolk QOL-DN questionnaire total score from baseline to Week 66
    E.5.1.1Timepoint(s) of evaluation of this end point
    66 Weeks
    E.5.2Secondary end point(s)
    • Change in the Norfolk QOL-DN questionnaire symptoms domain score (Stage 1 patients only) and Norfolk QOL-DN questionnaire physical functioning/large fiber neuropathy domain score (Stage 2 patients only) from baseline to Week 66)

    • Change in the mBMI and BMI from baseline to Week 65

    • Change in NIS and modified +7 from baseline to Week 66

    • Change in NIS+7 score from baseline to Week 66

    E.5.2.1Timepoint(s) of evaluation of this end point
    66 Weeks
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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
    Brazil
    France
    Germany
    Italy
    Portugal
    United Kingdom
    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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    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: 165
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 113
    F.4.2.2In the whole clinical trial 195
    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)
    Standard of Care or patients may choose to participate in the proposed Open Label Extension trial.
    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 Decision2013-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-01
    P. End of Trial
    P.End of Trial StatusCompleted
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