E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild to Moderate Chronic obstructive pulmonary disease (COPD) with Chronic Bronchitis |
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E.1.1.1 | Medical condition in easily understood language |
Mild to Moderate Chronic obstructive pulmonary disease (COPD) with Chronic Bronchitis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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). |
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E.2.2 | Secondary 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. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full 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. |
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E.3 | Principal 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 highly effective contraceptive method 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
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary 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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Average of Weeks 13 and 14 |
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E.5.2 | Secondary 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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |