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    Summary
    EudraCT Number:2012-000833-38
    Sponsor's Protocol Code Number:ISIS329993-CS6
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-05-15
    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 ConcernedUK - MHRA
    A.2EudraCT number2012-000833-38
    A.3Full title of the trial
    A Phase 2 Study to Assess the Antiarrhythmic and Symptomatic Effect of the Second Generation Antisense Oligonucleotide ISIS 329993 Targeting CRP in Patients with Paroxysmal Atrial Fibrillation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects of ISIS 329993, a C Reactive Protein Antisense Oligonucleotide, in patients with sporadic Atrial Fibrillation
    A.3.2Name or abbreviated title of the trial where available
    329993-CS6, Original
    A.4.1Sponsor's protocol code numberISIS329993-CS6
    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 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 number760-603-2684
    B.5.5Fax number7606033891
    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 nameCRP Antisense Oligonucleotide
    D.3.2Product code ISIS 329993
    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 329993
    D.3.9.1CAS number 827355-42-0
    D.3.9.2Current sponsor codeISIS 329993
    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
    Atrial fibrillation (AF)
    E.1.1.1Medical condition in easily understood language
    Atrial fibrillation (AF): a common and distressing cardiac arrhythmia.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10003658
    E.1.2Term Atrial fibrillation
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate whether treatment with ISIS 329993 can reduce AF (Atrial Fibrillation) burden (percentage of time spent in AF as derived from continuous pacemaker monitoring) in subjects with paroxysmal AF
    E.2.2Secondary objectives of the trial
    1. To assess the effect of ISIS 329993 on the total number of AF (Atrial Fibrillation) episodes, average duration of AF per episode, average sinus rhythm duration, and atrial and ventricular rate during AF episodes derived from continuous pacemaker monitoring.

    2. To assess the effect of ISIS 329993 on ventricular rate during sinus rhythm derived from continuous pacemaker monitoring.

    3. To assess the effect of ISIS 329993 on PR, QRS, QT and QTc intervals derived from 12-lead ECG during periods of sinus rhythm.

    4. To assess the effect of ISIS 329993 on measures of Quality of Life as assessed by SF 36, VAS, EHRA grade and AFSS questionnaires.

    5. To assess whether treatment with ISIS 329993 reduces hsCRP in subjects with paroxysmal AF.

    6. To assess the safety, tolerability, and pharmacokinetics (PK) of ISIS 329993 in subjects with paroxysmal AF.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. 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

    2. Males or females aged over 18 years old at the time of informed consent

    3. 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, subject is using an acceptable contraceptive method (refer to Section 6.3.1) from the time that the participant informed consent document is signed until 60 days after the last dose of Study Drug
    b. Males: Surgically sterile, abstinent or if engaged in sexual relations of child-bearing potential, subject is utilizing an acceptable contraceptive method (refer to Section 6.3.1) from the time that the participant informed consent document is signed until 60 days after the last dose of Study Drug

    4. Dual chamber permanent pacemaker implanted at least 3 months prior to screening

    5. Confirmed diagnosis of paroxysmal atrial fibrillation with an AF burden of 1 to 50% at screening, as derived from pacemaker diagnostic algorithms

    6. Able to have pacemaker antiarrhythmic algorithms turned off for the duration of the study

    7. Able to discontinue all Class I and III antiarrhythmic medication for the duration of the study

    8. Therapeutically anticoagulated with Warfarin, and anticipated to be anticoagulated with Warfarin for the duration of the study

    9. High sensitivity C-Reactive Protein (hsCRP) ≥2 mg/L and ≤10 mg/L at screening (2 measurements taken at least 1 week apart) unless pre-approved by Sponsor
    E.4Principal exclusion criteria
    1. Clinically significant abnormalities in medical history (e.g., acute coronary syndrome within six months of screening, major surgery within three months of screening) or physical examination

    2. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a subject unsuitable for inclusion:
    a) Renal Function:
    •Urine protein or blood persistently positive by dipstick
    •Estimated creatinine clearance calculated according to the formula of Cockcroft and Gault <60 mL/min
    b) Liver Function:
    •ALT or AST >1.5 x ULN
    •Total bilirubin >ULN
    c) Hematology:
    •Platelet count <LLN
    •Hemoglobin <10 mg/dL
    •Thyroid function tests indicative of hyperthyroidism

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

    4. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator

    5. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B

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

    7. NYHA class III/ IV heart failure

    8. Impaired left ventricular function of less than 45% determined by echocardiography within 3 months of screening

    9. Moderate or greater mitral regurgitation assessed by echocardiography within 3 months of screening

    10. Permanent AF

    11. Any episode of AF lasting greater than 1 week

    12. Cardiac rhythm disorder other than AF

    13. Endovascular intervention or cardioversion within 4 weeks prior to screening

    14. Any planned major surgery, endovascular intervention or cardioversion within study period

    15. Continuous Amiodarone therapy within 90 days prior to Study Day 1

    16. Treatment with another Study Drug, biological agent, or device within one-month of screening, or five half-lives of study agent, whichever is longer

    17. Treatment with an oligonucleotide within 9 months of screening. Subjects that have previously received only a single dose of an oligonucleotide as part of a clinical study may be included as long as a duration ≥5 half lives of the study oligonucleotide has elapsed since dosing

    18. Use of systemic corticosteroids or other anti-inflammatory medications including non-steroidal anti-inflammatory drugs (NSAIDs)

    19. Use of statins, ACE inhibitors or AT-receptor antagonists unless on a stable regimen for at least 3 months prior to dosing and will remain on a stable regimen for the duration of the study

    20. Uncontrolled hypertension (BP >160/100)

    21. History of bleeding diathesis or coagulopathy

    22. Current or expected use of any anticoagulant apart from Warfarin

    23. Regular use of alcohol within 6 months prior to screening (>7 drinks/week for females, >14 drinks/week for males, 1 drink= 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mLs) of hard liquor) or use of soft drugs (such as marijuana) within 3 months prior to screening or hard drugs (such as cocaine and phencyclidine [PCP]) within 1 year prior to screening, or positive urine drug screen at screening

    24. Subjects must not have smoked tobacco within 6 months of screening and must be expected to not smoke for the duration of the study

    25. Have any other conditions, which, in the opinion of the Investigator would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study
    E.5 End points
    E.5.1Primary end point(s)
    AF burden as assessed by the use of long term beat to beat pacemaker Holter monitoring
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 28 and 56
    E.5.2Secondary end point(s)
    • Total number of AF episodes, average duration of AF per episode, average sinus rhythm duration and atrial and ventricular rate during
    AF episodes

    • Ventricular rate during sinus rhythm

    • Quality of life measures assessed by SF 36, VAS, EHRA grade and AFSS questionnaires

    The effects of treatment with ISIS 329993 vs. Placebo on the following pharmacodynamic measures will be evaluated:
    • hsCRP and other markers of inflammation (for example erythrocyte sedimentation rate (ESR), serum amyloid A (SAA), IL-6, sTNF-R1 and –R2, fibrinogen).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 28 and 56
    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) 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) No
    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 Yes
    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 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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years1
    E.8.9.1In the Member State concerned months1
    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 months1
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 6
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 20
    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
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-05-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-06-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-03-31
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