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    Summary
    EudraCT Number:2019-003505-96
    Sponsor's Protocol Code Number:ISIS702843-CS2
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-01-21
    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 ConcernedGreece - EOF
    A.2EudraCT number2019-003505-96
    A.3Full title of the trial
    A Phase 2a, Randomized, Open-Label Study to Evaluate the
    Efficacy, Safety, Tolerability, Pharmacokinetics and
    Pharmacodynamics of ISIS 702843 Administered Subcutaneously to
    Patients with Non-Transfusion Dependent β-Thalassemia
    Intermedia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to look at how effective, how safe and how well tolerated a study drug called ISIS 702843 is when given under the skin to patients with Non-Transfusion Dependent β-Thalassemia Intermedia. This study will also look at the movement of ISIS 702843 in the body and how ISIS 702843 affects the body.
    A.4.1Sponsor's protocol code numberISIS702843-CS2
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04059406
    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 codeCA 92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1760603-2387
    B.5.5Fax number+1 760603-2504
    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.3.1Product nameISIS 702843
    D.3.2Product code ISIS 702843
    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 702843
    D.3.9.1CAS number 2273007-95-5
    D.3.9.2Current sponsor codeISIS 702843
    D.3.9.3Other descriptive nameIONIS TMPRSS6-LRx
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    Non-Transfusion Dependent
    β-Thalassemia Intermedia
    E.1.1.1Medical condition in easily understood language
    A form of Thalassemia which does not require regular transfusion therapy. Thalassemia is an inherited blood disorder characterized by the abnormal production of hemoglobin.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10074356
    E.1.2Term Non-transfusion dependent thalassemia
    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
    Evaluate the efficacy of antisense inhibitor of TMPRSS6 (ISIS 702843) by demonstrating an improvement in plasma hemoglobin (Hb) concentration at Week 27 of treatment.
    E.2.2Secondary objectives of the trial
    - Evaluate the efficacy of ISIS 702843 by demonstrating an improvement in Hb concentration at Week 53 of treatment.
    - Proportion of patients who have a ≥ 1.0 mg Fe/g dry weight decrease from Baseline in LIC, comparing the 3 cohorts at Week 53 of treatment.
    - Dosing every 28 days is possible due to the long tissue half-life (2 to 4 weeks) of ISIS 702843 in humans, and the proposed frequency of administration would offer a convenient dose regimen.
    - Evaluate the efficacy of ISIS 702843 by demonstrating an improvement in liver iron concentration (LIC) at Week 53 of treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient must have given written informed consent and be able to comply with all study
    requirements
    2. Aged 18-65 years old, inclusive, at the time of informed consent
    3. Clinical diagnosis of Beta-Thalassemia Intermedia with genotypic confirmation of beta-globin gene mutations including but not limited to Hemoglobin E (HbE)/beta-thalassemia
    4. Patient must be non-transfusion dependent as defined by: No more than 6 transfusions in the past 12-month period, and no transfusions in the 8-week period prior to Day 1
    5. Mean Hb within the range 6.0–10.0 g/dL, inclusive, with this mean based on all Hb measurements taken in the Screening Period that are at least 6 weeks after the most recent transfusion for that patient. This mean must be based on at least two Hb measurements.
    6. LIC within the range of 3.0–20.0 mg Fe/g dry weight, inclusive
    7. Chelators will be permitted provided the patient has been on a stable dose for at least
    3 months prior to Day 1, with LIC > 5.0 mg Fe/g dry weight and serum ferritin
    > 300 ng/mL
    8. Females must be non-pregnant and non-lactating, one of the following: (i) surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), (ii) postmenopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and follicle stimulating hormone [FSH] levels in the
    postmenopausal range for the laboratory involved), (iii) abstinent*, or (iv) if engaged in
    sexual relations of child-bearing potential, the patient must be using a highly effective contraceptive method from the time of signing the informed consent form until at least 13 weeks after the last dose of ISIS 702843.
    Males must be one of the following: (i) surgically sterile, (ii) abstinent*, or (iii) if engaged in sexual relations with a female of child-bearing potential, the patient must be using a highly effective contraceptive method from the time of signing the
    informed consent form until at least 13 weeks after the last dose of ISIS 702843.
    * Abstinence is only acceptable as true abstinence, i.e., when this is in line with the
    preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar,
    ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
    E.4Principal exclusion criteria
    1. Genotypic confirmation of either α-globin gene triplication or sickle hemoglobin (HbS)/beta-thalassemia, as determined by genetic assessment of blood-related disorders
    2. Clinically significant abnormalities in medical history or physical examination, which at the discretion of the PI will pose significant additional risk to the patient in participating in the study
    3. Clinically significant abnormalities in Screening laboratory values that would render a patient unsuitable for inclusion, at the discretion of the PI
    4. Current use of iron-chelation therapy if LIC is 3.0–5.0 mg Fe/g dry weight, inclusive, or if serum ferritin ≤ 300 ng/mL
    5. Symptomatic splenomegaly, including abdominal pain or organ obstruction, or evidence of hypersplenism, such as low white blood cell (WBC) count and/or low platelets
    6. Platelet count < LLN, or platelet count > 1,000 x 109/L
    7. Significant concurrent/recent coagulopathy; history of non-traumatic significant bleeding; history of immune thrombocytopenic purpura (ITP); current use of SC anti-coagulants; history of thrombotic events, including stroke or DVT
    8. Clinically significant renal dysfunction which at the discretion of the PI will pose significant additional risk to the patient in participating in the study
    9. eGFR < 45 mL/min/1.73 m2, using CKD-EPI
    10. Clinically significant liver function test (LFT) abnormalities
    11. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3.0 × ULN
    12. Historical diagnosis of cirrhosis, or current signs and symptoms of cirrhosis
    13. Fasting blood glucose > 2.0 × ULN
    14. Significant PHT defined as tricuspid regurgitation > 3.0 meters per second (m/s) on echocardiography and/or requiring treatment
    15. Uncontrolled hypertension (which for this protocol is considered > 140 mm Hg systolic or > 90 mm Hg diastolic)
    16. Heart failure class 3 or higher (New York Heart Association, NYHA)
    17. Ejection fraction < 50% by echocardiogram, multigated acquisition (MUGA), or cardiac magnetic resonance imaging (MRI)
    18. Patients unable to have MRI performed, for example, because of a pacemaker or implantable cardioverter-defibrillator. (MRI is being used to measure LIC.)
    19. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Day 1
    20. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C (unless treatment has caused the patient to test negative for hepatitis C), or chronic hepatitis B
    21. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
    22. Recent introduction of hydroxyurea (6 months prior to Day 1)
    23. Treatment with or exposure to another investigational drug, biological agent, ASO, small interfering ribonucleic acid (siRNA), or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer; or:
    - Treatment with or exposure to sotatercept (ACE-011), luspatercept (ACE-536), or ruxolitinib within 4 months of Screening
    - Treatment with or exposure to hematopoietic stimulating agents (e.g., EPOs) or any hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) (e.g., roxadustat,
    vadadustat, daprodustat, molidustat, desidustat) within 8 weeks of Day 1
    - Prior bone marrow transplant, stem cell transplant, or gene therapy
    24. Regular use of alcohol within 6 months prior to Screening (> 7 drinks/wk for females, > 14 drinks/wk for males (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL]) of hard liquor)
    25. Surgery associated with significant blood loss within 4 months of Screening, splenectomy within 12 months of Screening, or splenectomy scheduled during the Treatment Period
    26. Use of iron supplements, including iron-containing vitamins, within 4 months of Screening
    27. Pregnant or lactating
    28. Have any other conditions which, in the opinion of the PI, 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)
    Proportion of patients who have a ≥ 1.0 g/dL increase from Baseline in Hb, comparing the 3 cohorts at Week 27 of treatment.
    - Baseline Hb for Analysis is the mean of all Hb measurements taken in the Screening Period and Day 1, pre-dose. Each measurement used for the calculation of Baseline must be taken at least 6 weeks after the most recent transfusion for that patient. Baseline must be based on at least 2 Hb measurements.
    - The value to use for Week 27 of treatment is the mean of the 2 Hb measurements intended to be taken at Day 169 (Week 25) and Day 183 (Week 27); if one of these measurements is missing, then the other measurement will be assigned as the value to use for Week 27 of treatment. For a Hb measurement to be usable for the determination of the value to use for Week 27 of treatment, the sampling must occur at least 6 weeks after the most recent transfusion for that patient.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At week 27 of treatment
    E.5.2Secondary end point(s)
    1. Proportion of patients who have a ≥ 1.5 g/dL increase from Baseline in Hb, comparing the 3 cohorts at Week 53 of treatment.
    - Baseline Hb for Analysis is as defined above for the Primary Endpoint
    - The value to use for Week 53 of treatment is the mean of the 2 Hb measurements intended to be taken at Day 337 (Week 49) and Day 365 (Week 53); if one of these measurements is missing, then the other measurement will be assigned as the value to use for Week 53 of treatment. For a Hb measurement to be usable for the determination of the value to use for Week 53 of treatment, the sampling must occur at least 6 weeks after the most recent transfusion for that patient.
    2. Proportion of patients who have a ≥ 1.0 mg Fe/g dry weight decrease from Baseline in LIC, comparing the 3 cohorts at Week 53 of treatment.
    - Baseline LIC is the LIC measurement taken during the Screening Period
    - The Week 53 value is the LIC measurement intended to be taken at Day 365 (Week 53)
    E.5.2.1Timepoint(s) of evaluation of this end point
    At week 53 of treatment
    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 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.8.2.4Number of treatment arms in the trial3
    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 concerned4
    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
    Australia
    Canada
    Greece
    Lebanon
    Thailand
    Turkey
    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 months5
    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 months5
    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: 32
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 36
    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)
    None
    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 Decision2020-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-03-28
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