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    Summary
    EudraCT Number:2019-001044-22
    Sponsor's Protocol Code Number:ISIS721744-CS2
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-05-05
    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 number2019-001044-22
    A.3Full title of the trial
    A Randomized, Double Blind, Placebo Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second Generation Ligand Conjugated Antisense Inhibitor of Prekallikrein, in Patients with Hereditary Angioedema
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This is a randomized, double-blind, Placebo controlled trial to evaluate the efficacy of ISIS 721744 in Patients with Hereditary Angioedema
    A.4.1Sponsor's protocol code numberISIS721744-CS2
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04030598
    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 SponsorIonis 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 supportIonis Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIonis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointIonis Clinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Court
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number1760603-2387
    B.5.5Fax number1760603-2504
    B.5.6E-mailclinicaltrials@ionisph.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.3.2Product code ISIS 721744
    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 INNnot available yet
    D.3.9.1CAS number 2304701-45-7
    D.3.9.2Current sponsor codeISIS 721744
    D.3.9.3Other descriptive nameISIS 721744
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100mg/mL
    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 type2'-MOE antisense 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
    Hereditary Angioedema
    E.1.1.1Medical condition in easily understood language
    Genetic disease characterized by the occurrence of transitory and recurrent subcutaneous and/or submucosal edemas resulting in swelling and/or abdominal pain
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10019860
    E.1.2Term Hereditary angioedema
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    evaluate the clinical efficacy of antisense inhibitor of prekallikrein (IONIS PKK-LRx) in patients with hereditary angioedema (HAE) type 1 (HAE-1), HAE type 2 (HAE-2), or HAE with normal C1-inhibitor (C1-INH).
    E.2.2Secondary objectives of the trial
    evaluate safety and tolerability of IONIS PKK-LRx in patients with HAE-1/HAE-2 or HAE with normal C1-INH (HAE-nC1-INH) and to evaluate the
    effect of IONIS PKK-LRx on plasma prekallikrein (PKK) and other relevant biomarkers.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1)Documented diagnosis of HAE-1/HAE-2 (for inclusion in Part A) or HAE-nC1-INH (for inclusion in Part B)
    2)Participants must experience a minimum of 2 HAE attacks (assessed by the Angioedema Activity Score [AAS] and confirmed by the Investigator) during the Screening Period. Complete the AAS questionnaire on a daily basis (minimum of 4 daily assessments per week) for the duration of the Screening Period.
    3)Access to, and the ability to use, ≥ 1 acute medication(s) to treat angioedema attacks
    E.4Principal exclusion criteria
    1) Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned procedure during the screening or study periods
    2) Concurrent diagnosis of any other type of recurrent angioedema, including acquired or idiopathic angioedema
    3) History of acquired coagulopathies or bleeding diasthesis
    4) Active infection with HIV, hepatitis C or hepatitis B diagnosed by initial serological testing and confirmed with RNA testing, or prior treatment for hepatitis C. Patients at Screening who test positive by serology, but negative by RNA may be allowed in consultation with the Sponsor Medical Monitor.
    5) Patients with a history of acquired coagulopathies or bleeding diathesis (e.g. thrombocytopenia, disseminated intravascular coagulation, coagulopathy of liver disease, drug-induced platelet dysfunction, hyperfibrinolysis, acquired clotting factor inhibitors) and inherited bleeding disorders (e.g., hemophilia A, hemophilia B, other clotting
    factor deficiencies, qualitative platelet disorders, inherited thrombocytopenia, vascular abnormalities).
    6) Any clinically significant renal or hepatic diseases.
    7) 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
    8) Treatment with another investigational drug or biological agent within 1 month or 5 half-lives, whichever is longer, of screening
    9) Exposure to any of the following medications:
    -Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptive or hormonal replacement therapy) within 4 weeks prior to screening
    -Chronic prophylaxis with lanadelumab within 6 months prior to screening
    -Oligonucleotides (including small interfering ribonucleic acid [RNA]) within 4 months of screening (if single dose received) or within 12 months of screening (if multiple doses received)
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the time-normalized number of HAE attacks (per month) from Week 1 to Week 17.
    E.5.1.1Timepoint(s) of evaluation of this end point
    HAE Attack Assessment will be evaluated from Week 1 to Week 17
    E.5.2Secondary end point(s)
    • The time-normalized number of HAE attacks (per month) from Week 5
    to Week 17
    • The time-normalized number of moderate or severe HAE attacks (per
    month) from Week 5 to Week 17
    • The number of patients with a clinical response (defined as a ≥ 50%, ≥
    70%, or ≥ 90% reduction from Baseline in HAE attack
    rate) by Week 17
    • The number of HAE attacks requiring acute therapy from Week 5 to
    Week 17
    • cHK levels at Weeks 9 and 17
    • PKK activity at Weeks 9 and 17
    • Consumption of on-demand medication at Weeks 9 and 17
    • AE-QoL questionnaire score at Weeks 9 and 17
    E.5.2.1Timepoint(s) of evaluation of this end point
    HAE Attack Assessment will be evaluated from Week 5 to Week 17
    cHK levels will be evaluated at Weeks 9 and 17
    PKK activity will be evaluated at Weeks 9 and 17
    Consumption of on-demand medication will be evaluated at Weeks 9 and 17
    AE-QoL questionnaire score will be evaluated at Weeks 9 and 17
    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) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Netherlands
    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
    The End-of-Trial is defined as 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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    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: 24
    F.1.3Elderly (>=65 years) No
    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 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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 8
    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)
    Eligible patients may elect to enroll in the open label extension (OLE)
    study (ISIS 721744-CS3
    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 Decision2019-12-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-27
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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