Safety and Efficacy of JKN2304 Inhalation Solution in Patients With Moderate to Severe COPD

A Multicenter, Randomized, Double-Blind, Placebo- and Active-Controlled (Open-Label), Phase IIa Clinical Study to Evaluate the Safety and Efficacy of JKN2304 Inhalation Solution in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

The purpose of this Phase IIa study is to evaluate the safety, efficacy, and pharmacokinetics of JKN2304 Inhalation Solution in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD). The study is a multicenter, randomized, double-blind, placebo-controlled, and active-controlled (open-label) trial. Participants are randomized to receive JKN2304 (2 mg once daily or 2 mg twice daily), Placebo, or Formoterol Fumarate Inhalation Solution for a treatment period of 14 days.

This is a multicenter, randomized, double-blind, placebo-controlled, and active-controlled (open-label for the active comparator) Phase IIa clinical study. The study aims to enroll approximately 40 patients with moderate to severe stable Chronic Obstructive Pulmonary Disease (COPD).

The study consists of three periods: a Screening Period (up to 28 days), a Treatment Period (14 days), and a Follow-up Period (7 days).

During the Screening Period, patients undergo wash-out of prohibited medications (e.g., LAMA withdrawn for at least 7 days, LABA for at least 48 hours prior to the reversibility test). Eligible participants are randomized in a 1:1:1:1 ratio to one of the following four treatment arms:

1. JKN2304 Inhalation Solution 2 mg QD (Once Daily): 2 mg active drug in the morning and placebo in the evening.
2. JKN2304 Inhalation Solution 2 mg BID (Twice Daily): 2 mg active drug in the morning and 2 mg active drug in the evening.
3. Placebo Control: Placebo in the morning and placebo in the evening.
4. Active Control: Formoterol Fumarate Inhalation Solution 20 μg BID (Open-label). The primary objective is to evaluate the safety of JKN2304 in COPD patients. Secondary objectives include evaluating the efficacy (assessed by pulmonary function tests such as FEV1) and characterizing the pharmacokinetic (PK) profile of JKN2304.

Safety assessments are conducted throughout the study. Efficacy assessments, including pulmonary function tests, are performed at designated time points (e.g., Day 1 and Day 14). A safety follow-up visit is conducted on Day 21 (7 days after the last dose).

Inclusion Criteria:

1. Able to understand and comply with the trial procedures, voluntarily participate, and sign the informed consent form.
2. Age between 40 and 75 years (inclusive) at the time of signing the informed consent, both males and females.
3. History of exposure to COPD risk factors, such as: smoking history ≥10 pack-years (pack-years = [number of cigarettes per day / 20] x years smoked; use of electronic cigarettes, pipes, or cigars cannot be used to calculate pack-years), or exposure to biomass fuel for ≥10 years.
4. Established diagnosis of COPD according to the GOLD 2024 guidelines prior to screening.
5. History of ≥1 severe Acute Exacerbation of COPD (AECOPD) leading to hospitalization OR ≥2 moderate AECOPDs within 12 months prior to screening; OR, if ≤1 moderate AECOPD within 12 months prior to screening, then baseline mMRC score must be ≥2 and CAT score ≥10.
6. No occurrence of AECOPD within the 4 consecutive weeks prior to screening.
7. Post-bronchodilator (400 µg salbutamol) FEV1/FVC < 0.70, and post-bronchodilator FEV1 percent predicted (ppFEV1) between 30% and 79%.
8. Ability to perform acceptable and reproducible spirometry.
9. Compliance with concomitant medication restrictions (see study protocol section 5.6) and expected to maintain these restrictions during the treatment period.
10. For subjects of childbearing potential (or with partners of childbearing potential), willingness to use effective contraception from signing the informed consent until 3 months after the last dose.

Exclusion Criteria:

1. History of hypersensitivity to the investigational drug or drugs of the same class, or history of bronchospasm.

2. Current diagnosis of bronchial asthma.

3. Current diagnosis of other lung diseases that may impair lung function, including but not limited to: alpha-1 antitrypsin deficiency, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, bronchopulmonary dysplasia, active pulmonary tuberculosis, pulmonary hypertension (except if judged by the investigator to be due to COPD), interstitial lung disease (e.g., pulmonary fibrosis), pneumothorax, etc.

4. Acute lower respiratory tract infection within 4 weeks prior to or during screening.

5. Hospitalization for respiratory disease within 4 weeks prior to or during screening.

6. Clinically significant history of cardiovascular/cerebrovascular disease within 6 months prior to screening, such as congestive heart failure, acute coronary syndrome (including acute myocardial infarction and unstable angina), newly diagnosed atrial fibrillation, supraventricular/ventricular tachycardia, aortic aneurysm, stroke, etc.

7. Poorly controlled hypertension within 6 months prior to screening (defined as failure to achieve target blood pressure despite combination therapy with ≥3 antihypertensive agents) OR confirmed systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg during screening upon repeated measurement; severe arrhythmia requiring antiarrhythmic drug therapy; sinus node dysfunction, Mobitz type II or third-degree atrioventricular block without a pacemaker.

8. Narrow-angle glaucoma, bladder neck obstruction, moderate-to-severe prostatic hyperplasia, or history of acute urinary retention, judged by the investigator as a contraindication to inhaled anticholinergic drugs.

9. Any active malignancy or history of malignancy within 5 years prior to screening, except for cured cancers (e.g., basal cell carcinoma, squamous cell carcinoma of the skin, localized low-risk prostate cancer, papillary thyroid carcinoma) and radically resected carcinoma in situ (e.g., ductal carcinoma in situ of the breast, cervical carcinoma in situ).

10. Laboratory values at screening meeting any of the following:

    1. Neutrophil count (NEUT) < 1.5 x 10^9/L
    2. ALT > 2.5 x ULN OR AST > 2.5 x ULN OR Total Bilirubin > 1.5 x ULN
    3. Creatinine (Cr) > 1.5 x ULN

11. History of long QT syndrome, or QTc > 480 ms at screening (calculated using Fridericia's formula: QTc = QT / RR^0.33).

12. History of lung resection surgery, or lung volume reduction surgery within 12 months prior to screening.

13. On long-term regular oxygen therapy (>12 hours/day) or mechanical ventilation at screening.

14. Initiation of a pulmonary rehabilitation program within 4 weeks prior to screening or planned initiation during the study.

15. Use of long-acting bronchodilators (including LABA and LAMA) prior to screening, if judged by the investigator as unable to discontinue for at least 14 days prior to the first dose or during the study.

16. Use of inhaled corticosteroids (ICS) prior to screening, meeting any of the following:

    1. Planning to continue during the study AND dose stable for <28 days prior to the first dose; OR originally on combination ICS and unwilling to switch to an equivalent dose of monotherapy ICS during the study.
    2. Planning to discontinue during the study AND discontinued for <28 days prior to the first dose.

17. Use of oral theophylline or leukotriene inhibitors prior to screening, meeting any of the following:

    1. Planning to continue during the study AND dose stable for <28 days prior to the first dose.
    2. Planning to discontinue during the study AND discontinued for less than 5 half-lives of the respective drug prior to the first dose.

18. Participation in another clinical trial within 28 days prior to screening or between V1-V3, or within 5 half-lives of the previous investigational drug (whichever is longer; participation defined as having received study drug).

19. History of alcohol abuse (weekly intake >14 units: 1 unit ≡ 285 mL beer, 25 mL spirits, or 100 mL wine) or drug abuse within 6 months prior to screening.

20. History of psychiatric disorder or cognitive impairment.

21. Major surgery within 28 days prior to screening or planned major surgery during the study.

22. Female subjects who are lactating or pregnant, or with positive blood HCG at screening.

23. Any other condition considered by the investigator as unsuitable for participation in this clinical study.