Phase II Clinical Study to Evaluate the Efficacy and Safety of XKH001 Injection

Zhejiang Kanova Biopharmaceutical Co., LTD

Status and phase: Not yet enrolling; Phase 2

Conditions: COPD

Treatments: Drug: XKH001Injection; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT07519499

XKH001-04-II

Details and patient eligibility

About

This is a multicenter, randomized, double-blind, placebo-parallel-controlled, two-stage design, Phase II clinical study. This study is divided into two stages. Stage 1 (Phase IIa) has a dosing duration of 24 weeks (treatment period of 28 weeks) and aims to preliminarily evaluate the efficacy, safety, PK characteristics, and immunogenicity of XKH001 Injection in trial participants with moderate to severe COPD. Stage 2 (Phase IIb) has a dosing duration of 48 weeks (treatment period of 52 weeks) and aims to further evaluate the efficacy, safety, PK characteristics, and immunogenicity of XKH001 Injection in trial participants with moderate to severe COPD.

Full description

This is a multicenter, randomized, double-blind, placebo-parallel-controlled, two-stage design, Phase II clinical study. This study is divided into two stages. Stage 1 (Phase IIa) has a dosing duration of 24 weeks (treatment period of 28 weeks) and aims to preliminarily evaluate the efficacy, safety, PK characteristics, and immunogenicity of XKH001 Injection in trial participants with moderate to severe COPD. Stage 2 (Phase IIb) has a dosing duration of 48 weeks (treatment period of 52 weeks) and aims to further evaluate the efficacy, safety, PK characteristics, and immunogenicity of XKH001 Injection in trial participants with moderate to severe COPD.

Stage 1 (Phase IIa) All trial participants who have signed the ICF will enter the Screening Period and undergo corresponding screening investigations. The screening period is a maximum of 28 days.

Eligible trial participants from screening (a total of 75 participants, including 45 with a whole blood EOS count ≥300/μL and 30 with an EOS count <300/μL) will enter the 28-week Treatment Period (dosing with investigational drug or placebo once every 4 weeks for a total of 7 doses), and their eligibility for enrollment will be reconfirmed before randomization. On Day 1, participants will be randomized in a 1:1:1 ratio to two dose groups of the investigational drug XKH001 Injection (300 mg once every four weeks [Q4W] or 600 mg Q4W) or placebo group, with 25 participants in each group, stratified by whole-blood EOS count (≥300/μL vs. <300/μL) during the screening. During the treatment period, trial participants will undergo corresponding efficacy and safety assessments at specified time points (including before each dose administration). Sampling for laboratory tests must be completed before administration.

COPD trial participants who complete the 28-week treatment period will enter an 8-week Follow-up Period and will return to the hospital every 4 weeks (at Weeks 32 and 36) for corresponding safety and efficacy assessments.

During the study, trial participants will also have biological samples collected for PK, immunogenicity, and exploratory biomarker analysis at specified time points (including before each dose administration).

All trial participants should be on stable inhaled maintenance background therapy for COPD for at least 1 month before signing the ICF, during the screening period, and until the end of the study. From the time of signing the ICF until study completion or withdrawal from the study, trial participants must record their use of background therapy in a diary card. Throughout the study, trial participants may use drugs such as Salbutamol/Levalbuterol as needed for symptom relief. Participants must record the time, reason, dosage, and frequency of use in detail in their daily diary card.

Stage 2 (Phase IIb) All trial participants who have signed the ICF will enter the Screening Period and undergo corresponding screening investigations. The screening period is a maximum of 28 days.

Eligible trial participants from screening will enter the 52-week Treatment Period (dosing with investigational drug or placebo Q4W for a total of 13 doses), and their eligibility for enrollment will be reconfirmed before randomization. On D1, trial participants will be randomized in a 1:1:1:1 ratio to 3 dose groups of the investigational drug XKH001 Injection (100 mg Q4W, 300 mg Q4W, 600 mg Q4W) or the placebo group, stratified by whole blood EOS count during the screening period (≥300/μL vs. <300/μL) (tentative). During the treatment period, trial participants will undergo corresponding efficacy and safety assessments at specified time points (including before each dose administration). Sampling for laboratory tests must be completed before administration.

Note: The randomization stratification factor for Stage 2 (Phase IIb) and the sample size estimation for Stage 2 (Phase IIb) will be adjusted based on the results of Stage 1 (Phase IIa).

COPD trial participants who complete the 52-week treatment period will enter a 12-week Follow-up Period and will return to the hospital every 4 weeks (at Weeks 56, 60, and 64) for corresponding safety and efficacy assessments.

During the study, trial participants will also have biological samples collected for PK, immunogenicity, and exploratory biomarker analysis at specified time points (including before each dose administration).

All trial participants should be on stable inhaled maintenance background therapy for COPD for at least 1 month before signing the ICF, during the screening period, and until the end of the study. From the time of signing the ICF until study completion or withdrawal from the study, trial participants must record their use of background therapy in a diary card. Throughout the study, trial participants may use drugs such as Salbutamol/Levalbuterol as needed for symptom relief. Participants must record the time, reason, dosage, and frequency of use in detail in their daily diary card.

Enrollment: 75 estimated patients

Sex: All

Ages: 40 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Trial participants must meet all of the following inclusion criteria to be enrolled in this study:

  1. The trial participant is able to understand the procedures and methods of this study, is willing to sign the ICF and strictly adhere to the clinical study protocol to complete this study, and can independently complete study-related questionnaires;

  2. The trial participant must be aged 40-80 years (inclusive) at the time of signing the ICF, can be either male or female;

  3. The trial participant has a BMI ≥16.0 kg/m2;

  4. Trial participants diagnosed with COPD for ≥12 months (diagnosed according to GOLD 2024) and meeting the following criteria:

     • Current smoker or ex-smoker with a smoking history of ≥10 pack-years (1 pack-year is calculated as: [average number of cigarettes smoked per day × number of years]/20; e.g., 1 pack-year = smoking 20 cigarettes per day for 1 year, or smoking 10 cigarettes per day for 2 years.); Moderate to severe airflow limitation (post-bronchodilator FEV1/FVC <70%, post-bronchodilator FEV1 measurement ≥30% and <80% of predicted value);
     • Documented high risk of exacerbations, defined as ≥2 moderate or ≥1 severe exacerbations in the year prior to screening: A moderate exacerbation is defined as an AECOPD requiring the use of systemic corticosteroids (intramuscular, intravenous, or oral) and/or antibiotics (however, the use of antibiotics alone does not qualify as a moderate exacerbation unless it is documented that the antibiotic use was necessary to treat worsening COPD symptoms); one of the two required moderate exacerbations must have required systemic corticosteroids; a severe exacerbation is defined as an AECOPD requiring hospitalization or observation in an emergency room/urgent care facility for >24 hours;
     • Received inhaled background maintenance therapy [triple therapy (ICS + LABA + LAMA) or dual therapy (LABA + LAMA or ICS + LABA)] for ≥3 months before randomization, with a stable dose for at least 1 month before signing the ICF and during the screening period;

  5. Whole blood EOS count ≥150/μL during the screening period;

  6. Female trial participants of childbearing potential and their male partners, and male trial participants and their female partners, must agree to use an effective method of contraception during the study and for 6 months after the last dose of investigational drug, and have no plans for childbirth, sperm donation, or ovum donation (see Appendix 1: Contraceptive Measures, Definition of Childbearing Potential, and Contraception Requirements for details).

Exclusion criteria

• Trial participants with any of the following cannot be enrolled in this study:

  1. Presence of any respiratory disorder other than COPD, including:

     • Current diagnosis of asthma or a history of asthma according to the GINA or other recognized guidelines;
     • Diagnosis of alpha-1 antitrypsin deficiency;
     • Other concomitant active or clinically significant respiratory disorders that would significantly affect the study: such as active pulmonary tuberculosis, lung cancer (including suspected malignant pulmonary nodule [Category 4]), bronchiectasis, sarcoidosis, pulmonary fibrosis, interstitial lung disease, cystic fibrosis, obliterative bronchiolitis, pulmonary arterial hypertension, etc.;

  2. AECOPD (including mild, moderate, and severe; for definitions of moderate and severe AECOPD, see Inclusion Criterion 4, item 3) and/or respiratory tract infection within 4 weeks prior to screening and before randomization;

  3. Signs and/or symptoms of cor pulmonale and/or right ventricular failure;

  4. Hypercapnia requiring the use of BiPAP;

  5. Currently receiving or planning to start long-term oxygen therapy (>15 hours of oxygen per day) or mechanical ventilation during the study;

  6. Participation or planned participation in an intensive COPD rehabilitation program within 4 weeks prior to screening (trial participants in the maintenance phase of a rehabilitation program may be considered for enrollment);

  7. Planned pulmonary resection or lung volume reduction surgery, or a history of such surgery;

  8. Presence of any Grade ≥2 (NCI-CTCAE version 6.0) lipid profile abnormalities (the influence of physiological factors such as diet should be excluded);

  9. Concomitant autoimmune disease requiring systemic immunosuppressant therapy (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis);

  10. Known or suspected history of an immunosuppressive disease, including a history of invasive opportunistic infections (e.g., TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis), even if the infection has resolved/subsided; or, in the investigator's judgment, a history of abnormally frequent, recurrent, or prolonged infections;

  11. Confirmed active infection parasitic; suspected infection parasitic or high risk of infection, unless clinical assessment and (if necessary) laboratory assessment have ruled out active infection before randomization;

  12. Confirmed acute or chronic infection requiring treatment with systemic antibiotics, antivirals, antifungals, antiparasitic, or antiprotozoals within 4 weeks prior to screening or during the screening period;

  13. Undergone Grade III or IV surgery (as defined in the "Administrative Measures for the Grading of Medical Institution Surgeries", see Appendix 2: Surgical Grading Management for details) within 12 weeks prior to screening (excluding paracentesis biopsy); or planned surgery requiring general anesthesia or hospitalization >1 day during the study;

  14. Presence of other serious diseases that, in the investigator's judgment, may affect the patient's participation in this trial, including but not limited to: diseases that severely affect survival, uncontrolled diabetes mellitus, renal insufficiency requiring dialysis, Child-Pugh Class B/C liver function, demyelination diseases, neurological and psychological disorders, etc.;

  15. Clinically significant cardiovascular disorder within 6 months prior to screening. Cardiovascular disorders include but are not limited to:

      • Two-dimensional echocardiogram showing an LVEF <50%;
      • Acute myocardial infarction;
      • Severe/unstable angina;
      • History of arterial thromboembolism, including but not limited to cerebrovascular accident and transient ischemic attack;
      • Cardiac failure congestive (NYHA functional class >II);
      • Any clinically significant abnormality in rhythm, conduction, or morphology on a resting ECG, complete bundle branch block left, third-degree heart block, second-degree heart block, PR interval >250 msec;
      • Mean resting QTc interval ≥500 msec obtained from 3 ECGs (corrected using Fridericia's formula, see Appendix 3: Calculation Formulas for QTcF and RR for details);
      • Any factor that increases the risk of QTc interval prolongation or arrhythmic events, such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death in a first-degree relative under 40 years of age, or any concomitant medication known to prolong the QT interval;
      • Hypertension not controlled by antihypertensive medication (blood pressure systolic >160 mmHg and/or blood pressure diastolic >100 mmHg);

  16. Trial participants with a neoplasm malignant within 5 years prior to screening or currently (Note: ① Trial participants with carcinoma in situ of the cervix that has been resected, adequately treated, and currently has no evidence of disease recurrence may participate in this study; ② Trial participants with basal cell carcinoma or squamous cell carcinoma of the skin that has been completely resected, adequately treated, and currently has no evidence of disease recurrence may participate in this study);

  17. Patients receiving the following drugs or treatments that are prohibited as concomitant therapy:

      • Prior use of biologics with efficacy in treating COPD, such as Benralizumab, Mepolizumab, Omalizumab, Dupilumab, etc. (for Phase IIb, enrollment may be considered based on use and therapeutic effect, as assessed by the investigator);
      • Received aminophylline, PDE-4 inhibitors, leukotriene receptor antagonists, and other systemic treatments for COPD within 2 weeks or 5 t1/2 (whichever is longer) before the first dose;
      • Received systemic corticosteroids (excluding topical, ophthalmic, or intranasal use of corticosteroids) or systemic immunosuppressants/immunomodulators (e.g., Methotrexate) within 4 weeks before the first dose;
      • Use of Chinese herbal medicines with therapeutic effects on COPD (excluding topical preparations) within 4 weeks before the first dose;
      • Received IVIG therapy or allergen-SIT within 8 weeks or 5 t1/2 (whichever is longer) before the first dose;
      • Received B- and/or T-cell targeted immunosuppressive therapy within 8 weeks or 5 t1/2 (whichever is longer) before the first dose;
      • Planned vaccination with a live or live-attenuated vaccine within 12 weeks before the first dose or during the study;
      • Received other biologics such as anti-TNF monoclonal antibody therapy within 16 weeks or 5 t1/2 (whichever is longer) before the first dose;
      • Received macrolide antibiotic therapy within 6 weeks prior to screening (except for those who had been on a stable dose of macrolide antibiotics for ≥6 months prior to screening and had at least 1 AECOPD during this period).

  18. Received blood products such as human blood albumin, hematopoietic growth factors (e.g., G-CSF), or platelet-increasing therapy within 2 weeks prior to screening;

  19. Any of the following abnormalities in laboratory test results at screening:

      • ANC <1.5 × 109/L;
      • TBIL >1.5 × ULN;
      • AST or ALT >2 × ULN;
      • Creatinine clearance <50 mL/min (calculated by the Cockcroft-Gault formula);
      • PLT <90 × 109/L;
      • HGB <90 g/L;
      • Other clinically significant laboratory test abnormalities that, in the investigator's judgment, make the participant unsuitable for enrollment; Note: If a laboratory test result exceeds the protocol-specified threshold but is suspected to be transient (due to physiological factors, test error, etc.), or is only slightly above the threshold, it may be re-tested once (and only once) during the screening period for clarification. If the re-test result still exceeds the threshold, the trial participant will be a screen failure;

  20. Presence of any of the following infectious diseases:

      • Positive for HBsAg, or negative for HBsAg but positive for HBcAb and positive for HBV-DNA; positive for HCV-Ab and positive for HCV-RNA;
      • Positive for TP-Ab (unless negative on RPR or TRUST);
      • Positive for HIV antibody;

  21. History of severe allergic reaction or known allergy to XKH001 Injection or its excipients;

  22. History of fainting at the sight of blood or from needles;

  23. Pregnant or lactating females;

  24. Blood donation or blood loss of ≥400 mL within 12 weeks prior to screening, or received a transfusion within 4 weeks prior to screening;

  25. Participation in any other clinical study (including drug and device studies) and use of an investigational drug or medical device intervention within 12 weeks or 5 t1/2 (whichever is longer) prior to screening (calculated from the time of the last use of the investigational drug or medical device intervention);

  26. History of alcohol abuse or various drug abuse within 2 years prior to signing the ICF;

  27. Other factors that, in the investigator's opinion, make the participant unsuitable for the study.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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75 participants in 3 patient groups, including a placebo group

XKH001 300mg

Active Comparator group

Description:

XKH001 Injection 300 mg once every four weeks \[Q4W\]

Treatment:

Drug: Placebo

Drug: XKH001Injection

XKH001 600mg

Active Comparator group

Description:

XKH001 Injection 600 mg once every four weeks \[Q4W\]

Treatment:

Drug: XKH001Injection

Placebo group

Placebo Comparator group

Description:

Placebo once every four weeks \[Q4W\]

Treatment:

Drug: Placebo