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    Summary
    EudraCT Number:2020-000210-15
    Sponsor's Protocol Code Number:ION-827359-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:2020-07-15
    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 number2020-000210-15
    A.3Full title of the trial
    A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Safety, Tolerability, and Efficacy of ION-827359 in Patients with Mild to Moderate COPD with Chronic Bronchitis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2a Study to Assess the Safety, Tolerability, and Efficacy of IONIS-ENaCRx in Patients with Pulmonary Disease with Chronic Bronchitis
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberION-827359-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 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
    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
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Court
    B.5.3.2Town/ cityCarlsbad, CA
    B.5.3.3Post code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1760 603 3890
    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 nameantisense inhibitor of ENaC
    D.3.2Product code ION-827359
    D.3.4Pharmaceutical form Inhalation solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNION-827359
    D.3.9.1CAS number 2247669-97-0
    D.3.9.2Current sponsor codeION-827359
    D.3.9.3Other descriptive nameIONIS-ENaCRx
    D.3.9.4EV Substance CodeSUB198784
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 Yes
    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' 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 placeboInhalation solution
    D.8.4Route of administration of the placeboInhalation use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Mild to Moderate Chronic obstructive pulmonary disease (COPD) with Chronic Bronchitis
    E.1.1.1Medical condition in easily understood language
    Mild to Moderate Chronic obstructive pulmonary disease (COPD) with Chronic Bronchitis
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10010952
    E.1.2Term COPD
    E.1.2System Organ Class 100000004855
    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 the effect of IONIS-ENaCRx on forced expiratory volume in 1 second (FEV1) in patients with mild to moderate chronic obstructive pulmonary disease (COPD) with chronic bronchitis (CB).
    E.2.2Secondary objectives of the trial
    - To evaluate the effect of IONIS-ENaCRx on symptoms of CB;
    - To evaluate the effect of IONIS-ENaCRx on quality of life (QoL)in patients of CB;
    - To evaluate the pharmacokinetics (PK) of IONIS-ENaCRx in patients with CB;
    - To evaluate the safety and tolerability of IONIS-ENaCRx compared to placebo.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetic Analysis:
    Approximately 24 patients will have PK analysis. The plasma PK of ION 827359 will be assessed in subjects from the PK subgroup following inhalational administration by nebulization. Non-compartmental PK analysis of ION 827359 will be carried out on each individual subject data set. The maximum observed drug concentration (Cmax) and the time taken to reach maximal concentration (tmax) will be obtained directly from the concentration-time data.

    Fiberoptic Bronchoscopy:
    A subset of approximately 18 subjects will undergo bronchoscopy during the Screening Period, and then after completing the 13 weeks of active treatment. Following informed consent, subjects will be pre-medicated as per the usual practice at the research site.

    HRCT scans:
    A subset of 60 patients will undergo HRCT of their lungs during Screening and on Day 92. Each site performing these scans will be individually trained in the scanning protocol, sending images to the central vendor, and monitoring patients breathing during the scan.
    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 40–70 inclusive at the time of informed consent;
    3. Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or postmenopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and follicle stimulating hormone (FSH) levels in the post-menopausal range for the laboratory involved). Males must be surgically sterile or abstinent*, if engaged in sexual relations with a female of child-bearing potential, the subject must be using a condom in addition to a highly effective contraceptive method by the partner from the time of signing the informed consent form until at least 10 weeks after the last dose of Study Drug (ION‑827359 or placebo):
    a. * 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.
    4. BMI < 35.0 kg/m2;
    5. Patients with a diagnosis of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS):
    a. Ability to perform acceptable and reproducible spirometry;
    b. Post-bronchodilator (4 puffs of albuterol) spirometry at Screening demonstrating the following:
    I. FEV1/ forced vital capacity (FVC) ratio of < 0.70;
    ii. FEV1 ≥ 50% and ≤ 90% of predicted normal
    6. Clinically stable COPD in the 4 weeks prior to Screening (Visit 1);
    7. Current and former smokers with smoking history of ≥ 20 pack years;
    8. Meet SGRQ definition of CB;
    9. CAT score ≥ 10
    E.4Principal exclusion criteria
    1. Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of screening, congestive heart failure, major surgery within 3 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. Urine protein/creatinine (P/C) ratio ≥ 0.3 mg/mg. In the event of P/C ratio above this threshold eligibility may be confirmed by a quantitative total urine protein measurement of < 300 mg/24 hr;
    b. Positive test (including trace) for blood on urinalysis. In the event of a positive test eligibility may be confirmed with urine microscopy showing ≤ 5 red blood cells per high power field;
    c. alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline phosphatase (ALP), serum creatinine, blood urea nitrogen (BUN) > 1.5 × upper limit of normal (ULN);
    d. Platelet count < LLN;
    e. Serum potassium > 5.2 mmol/L;
    f. Estimated GFR < 60 mL/min (as determined by the Cockcroft-Gault Equation for creatinine clearance);
    3. Any active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to first day Study Drug product is administered to the patient (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. Active infection with human immunodeficiency virus (HIV), hepatitis C or hepatitis B;
    6. Uncontrolled hypertension (blood pressure (BP) > 160/100 mm Hg);
    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. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the PI and reviewed by the Sponsor medical monitor;
    8. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer;
    9. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid [siRNA]) within 4 months of screening if single dose received, or within 12 months of screening if multiple doses received;
    10. Clinically important pulmonary disease other than COPD;
    11. Asthma as a primary or main diagnosis according to the Global Initiative for Asthma (GINA) guidelines (GINA 2011) or other accepted guidelines. Patients with a past medical history of asthma (e.g. childhood or adolescence) may be included;
    12. Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization for a COPD exacerbation within 4 weeks prior to enrolment (Visit 1);
    13. Acute upper or lower respiratory infection requiring antibiotics or antiviral medication within 4 weeks prior to enrolment (Visit 1);
    14. Long term oxygen therapy (LTOT);
    15. Patients participating in, or scheduled for, an intensive (active) COPD rehabilitation program (patients who are in the maintenance phase of a rehabilitation program are eligible to take part);
    16. Recent history of, or current drug or alcohol abuse;
    17. Concomitant medication restrictions: Oral anticoagulants, oral steroids (e.g. prednisone or Medrol), theophylline, chronic azithromycin, or roflumilast;
    18. 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;
    19. A positive PCR test for SARS-CoV-2 at any time prior to randomization.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline to the primary time point (defined as the average of Weeks 13 and 14) in FEV1 compared to placebo
    E.5.1.1Timepoint(s) of evaluation of this end point
    Average of Weeks 13 and 14
    E.5.2Secondary end point(s)
    - Change from baseline in the EXACT respiratory symptoms (E-RS) (evaluating respiratory symptoms) daily symptom diary to the primary time point
    - Change from baseline in the COPD assessment test (CAT) to the Week 14 time point
    - Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) to the Week 14 time point
    - Change from baseline in post-bronchodilator FEV1
    - Pharmacokinetics (Section 1.2.3.1)
    - Safety Secondary Endpoints
    - Incidence and severity of treatment-emergent adverse events (TEAE)
    - Abnormal findings in laboratory assessments, electrocardiogram (ECGs), and vital signs
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to 13 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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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 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 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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 years0
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months9
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 180
    F.4.2.2In the whole clinical trial 180
    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)
    Patients will revert back to their primary physician for further evaluation.
    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 Decision2020-08-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-08
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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