| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Asthma and Chronic obstructive pulmonary disease (COPD) | |
| E.1.1.1 | Medical condition in easily understood language | | Asthma and Chronic obstructive pulmonary disease (COPD) | |
| 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 | 20.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10003553 | | E.1.2 | Term | Asthma | | E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders | |
| 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 assess the safety and tolerability of ARO-MUC5AC in patients with asthma and COPD | |
| E.2.2 | Secondary objectives of the trial | Secondary
• To assess the pulmonary safety of ARO-MUC5AC in patients with asthma and COPD using spirometry
• To assess the pharmacokinetics (PK) of ARO-MUC5AC in patients with asthma and COPD
Exploratory
• To assess the pharmacodynamics (PD) of ARO-MUC5AC in patients with asthma and COPD
• To assess the efficacy of ARO-MUC5AC in patients with asthma and COPD | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Inclusion criteria for Patients with Asthma:
1. Male or nonpregnant, nonlactating female volunteers
2. Age 18 to 65 years at Screening
3. Diagnosis of asthma which must have been confirmed and documented (based on source verifiable medical record) for at least 12 months prior to Screening
4. Documented treatment with a total daily dose of inhaled corticosteroids ≥500 mcg
fluticasone propionate dry powder formulation (or equipotent inhaled corticosteroid) for at least 3 months prior to Screening
5. Documented treatment with at least 1 additional maintenance asthma controller medication (eg, a long-acting β2-agonist [LABA], a leukotriene receptor antagonist [LTRA], or a long-acting muscarinic antagonist [LAMA]) for at least 3 months prior to Screening
6. Prebronchodilator ppFEV1 between 40% and 80% inclusive at Screening, prior to sputum induction
7. Stable dose of asthma controller medications for at least 28 days prior to Screening
8. If on allergen-specific immunotherapy, patients must be on a stable maintenance dose for at least 90 days prior to first dose
9. If on biologic therapy for asthma (eg, anti-IgE, anti-IL5/IL5R, anti-IL4R, or anti-thymic stromal lymphopoietin [TSLP]), patients must be on a stable maintenance dose for at least 16 weeks prior to first dose
10. Chest x-ray taken at Screening that, according to the Investigator, excludes significant alternative respiratory disease
11. Able and willing to provide written informed consent prior to the performance of any study-specific procedures
12. BMI between 18.0 and 35.0 kg/m2 at Screening
13. A 12-lead ECG at Screening with no abnormalities that may compromise participant’s safety in this study
14. Nonsmoker (defined as someone who has not smoked a cigarette for at least 6 months) with current nonsmoking status confirmed by urine cotinine at Screening AND previous smoking history prior to 6 months must be <10 pack-years. Subjects may be on nicotine replacement (patch or gum). Nicotine e-cigarettes (vapor) are not permitted. A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the
discretion of the PI
15. Participants of childbearing potential must agree to use highly effective contraception in addition to a condom during the study and for at least 12 weeks following the end of the study or last dose of study drug, whichever is later. Subjects must not donate sperm or eggs during the study and for at least 12 weeks following the end of the study or last dose of study drug, whichever is later
16. Able and willing to comply with all study assessments and adhere to the protocol schedule
17. Able to produce an induced sputum sample at Screening that meets criteria of acceptable quality
Inclusion Criteria for patients with COPD:
1. Male or nonpregnant, nonlactating female
2. Age 40 to 70 years at Screening
3. Diagnosis of COPD for at least 12 months prior to Screening, based on source verifiable medical record, confirmed with a post-bronchodilator ratio of FEV1 to FVC < 0.7 at Screening
4. History of chronic bronchitis elicited on the SGRQ-C at Screening
5. Current smoker or ex-smoker (meaning >1 year of smoking cessation) with a smoking history of ≥ 10 pack-years
6. Post-bronchodilator ppFEV1 between 30% and 80% inclusive at Screening, prior to sputum induction
7. Subjects treated with either single, double, or triple therapy for COPD, as described below:
a. Single therapy consisting of: long-acting beta agonist (LABA) or long-acting muscarinic antagonist (LAMA)
b. Double therapy consisting of: LABA + LAMA, or LABA + inhaled corticosteroid (ICS), or LAMA + ICS / c. Triple therapy consisting of: LABA + LAMA + ICS / d. Please note that additional use of other agents, such as azithromycin or roflumilast, will not exclude the subject
8. All treatments for COPD have been stable for at least one month prior to Screening (meaning no new medications or changes in dose quantity or dose frequency) and subject is willing to continue this treatment regimen without change for study duration.
9. Able and willing to provide written informed consent prior to the performance of any study-specific procedures
10. BMI between 18.0 and 35.0 kg/m2 at Screening
11. A 12-lead ECG at Screening with no abnormalities that may compromise participant’s safety in this study
12. Participants of childbearing potential must agree to use highly effective contraception in addition to a condom during the study and for at least 12 weeks following the end of the study or last dose of study drug, whichever is later. Subjects must not donate sperm or eggs during the study and for at least 12 weeks following the end of the study or last dose of study drug, whichever is later. See Appendix 2 for details.
13. Able and willing to comply with all study assessments and adhere to the protocol schedule
14. Able to produce an induced sputum sample at Screening that meets criteria of acceptable quality | |
| E.4 | Principal exclusion criteria | 1. Acute lower respiratory infection or asthma exacerbation within 30 days prior to 1st dose
2. Acute upper respiratory infection within 7 days prior to 1st dose
3. Positive COVID-19 test during Screening window
4. Prior history of bronchial thermoplasty treatment
5. Diagnosis of vocal cord dysfunction, reactive airways dysfunction syndrome, panic attacks with hyperventilation, or other mimics of asthma
6. Any concomitant pulmonary disease that, in the opinion of the Investigator and/or Medical Monitor, will interfere with the evaluation of the study drug or interpretation of patient safety or study results (including, but not limited to: interstitial lung disease, cystic fibrosis, lung cancer and tuberculosis). Any concomitant pulmonary disease must be discussed with the Medical
Monitor during Screening
7. Known unresolved parasitic infection or prior parasitic infection that has required antiparasitic therapy within 30 days prior to first dose
8. Any history of organ transplant
9. HIV infection, as shown by presence of anti-HIV antibodies (seropositive)
10. Seropositive for HBV or HCV (positive result for anti-HCV antibody must be confirmed with positive HCV RNA test for exclusion)
11. Uncontrolled hypertension (SBP >150 mmHg or DBP >100 mmHg) at Screening
12. A history of Torsades de Pointes, ventricular rhythm disturbances (eg, ventricular tachycardia or fibrillation), pathologic sinus bradycardia (<50 bpm with symptoms), heart block (excluding first-degree block, being PR prolongation only), congenital long QT syndrome, new ST segment elevation or depression, or new Q wave on ECG. Participants with a history of atrial arrhythmias should be discussed with the Medical Monitor
13. A family history of congenital long QT syndrome or unexplained sudden cardiac death
14. Use of medications known to prolong the QTc interval within 30 days prior to first dose (eg, azithromycin)
15. Use of theophylline within 30 days prior to first dose
16. Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction <20%), TIA, or CVA within 24 weeks prior to first dose
17. History of malignancy within the past 2 years except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with other curatively treated malignancies who have no evidence of metastatic disease and >2-year disease-free interval may be entered following approval by the Medical Monitor
18. History of major surgery within 12 weeks prior to first dose
19. Unwilling to limit alcohol consumption to within moderate limits for the duration of the study, as follows: not more than 14 units per week for women and 21 units per week for men (1 unit=150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol)
20. Use of illicit drugs (such as cocaine, PCP) within 1 year prior to Screening or positive urine drug screen at Screening (a urine drug screen deemed positive due to prescription medications or for benzodiazepines, opioids, or marijuana is acceptable and inclusion is at the discretion of the PI). Subjects who smoke or vape prescription THC/marijuana should be discussed with the Medical Monitor
21. Use of an investigational agent or device within 30 days or 5 half-lives (whichever is longer) prior to first dose or current participation in an investigational study
22. Blood donation (500 mL) within 7 days prior to first dose. Donation or loss of whole blood (excluding the volume of blood that will be drawn during the Screening procedures of this study) prior to first dose as follows: 50 mL to 499 mL of whole blood within 30 days, or more than 499 mL of whole blood within 56 days prior to first dose
23. Any finding at Screening or any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or to complete the study, or would put the participant at additional safety risk
24. Participants who are unable to return for all scheduled study visits
25. Any of the following laboratory values at Screening: a. ALT or AST > 2× ULN b. eGFR <60 mL/min/1.73m2
Additional Exclusion criteria only for COPD patients:
1. COPD exacerbation within 30 days prior to 1st dose
2. History of lung volume reduction surgery (either surgical or bronchoscopic) or pneumonectomy
3. Need for chronic (>15 hours/day) oxygen support at Screening
4. Prior history of bronchial thermoplasty treatment
5. Participation in the acute phase of pulmonary rehabilitation (ie started < 4 weeks prior to Screening)
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | | • The incidence and frequency of treatment-emergent adverse events (TEAEs) over time through end of study (EOS) | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | Secondary
• Change from baseline over time through EOS in forced expiratory volume (FEV1) as a safety assessment
• Change from baseline over time through EOS in forced vital capacity (FVC) as a safety assessment
• Plasma PK parameters of ARO-MUC5AC after each dose of study drug
Exploratory
• Change from baseline over time through EOS in mucin 5AC (MUC5AC) and mucin 5B (MUC5B) protein concentrations from induced sputum samples as a PD assessment
• Change from baseline over time through EOS in prebronchodilator and postbronchodilator FEV1 in patients with asthma as an efficacy assessment
• Change from baseline over time through EOS in prebronchodilator and postbronchodilator forced mid-expiratory flow (FEF25-75) in patients with asthma as an efficacy assessment
• Change from baseline over time through EOS in serum total IgE concentrations in patients with asthma as an efficacy assessment
• Change from baseline over time through EOS in plasma periostin in patients with asthma as an efficacy assessment
• Change from baseline over time through EOS in fractional exhaled nitric oxide (FeNO) in patients with asthma as an efficacy assessment
• Change from baseline over time through EOS in blood eosinophil count in patients with asthma as an efficacy assessment
• Change from baseline over time through EOS in mucus symptom assessment in patients with asthma as an efficacy assessment
• Incidence and titer of anti-drug antibodies over time through EOS
• Change from baseline over time through EOS in chest x-ray findings as a safety assessment | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Secondary
• Change in forced expiratory volume (FEV1) and in forced vital capacity (FVC): at all visits
• Plasma PK parameters of ARO-MUC5AC: at visits 2,3,5,7 and 8
Exploratory
• Change in mucin 5AC (MUC5AC) and mucin 5B (MUC5B) protein concentrations: at visits 1, 2, 7, 9, 10, 11, 12 and 14
• Change in pre and post bronchodilator FEV1 and in pre and post bronchodilator forced mid-expiratory flow (FEF25-75): at all visits
• Change in serum total IgE concentrations, in blood eosinophil count, in plasma periostin and in fractional exhaled FeNO: at visits 1, 2, 5, 7, 9, 10, 12 and 14
• Change in mucus symptom assessment: at visits 2, 10 and 14
• Incidence and titer of anti-drug antibodies: at visits 2, 5, 7, 10, 13 and 14
• Change in chest x-ray findings: visit 1 and 14 | |
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | No |
| 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 | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | New Zealand | | Australia | | Korea, Republic of | | Thailand | |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
