UBT251 Injection Phase Ⅲ Study (OSA-PAP)

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and Safety of UBT251 Injection in Obese Participants With Moderate-to-Severe Obstructive Sleep Apnea (OSA) on Positive Airway Pressure (PAP) Therapy（UNISHAPE-OSA-2）

UBT251 will be compared with placebo (an inactive substance identical in appearance) to evaluate its therapeutic effect in participants with moderate-to-severe obstructive sleep apnea maintained on positive airway pressure therapy.Participants will complete the following study procedures:1. Receive once-weekly subcutaneous injections of either UBT251 or placebo for a total treatment period of 52 weeks, while remaining on stable positive airway pressure therapy;2. Undergo all examinations and tests within the visit windows specified in the trial protocol;3. Undergo assessment of the Apnea-Hypopnea Index (AHI) upon completion of the 52-week treatment period.

Inclusion Criteria:

1. Male or female participants aged 18 to 75 years inclusive at the time of signing the informed consent form.
2. Confirmed diagnosis of obstructive sleep apnea (OSA) based on the International Classification of Sleep Disorders, 3rd Edition, Text Revision (ICSD-3-TR) criteria, with a polysomnography (PSG) showing an Apnea-Hypopnea Index (AHI) ≥ 15 events/hour at screening.
3. Participants who have received stable positive airway pressure (PAP) therapy for at least 3 months prior to screening and who plan to continue PAP therapy throughout the study.
4. Body Mass Index (BMI) ≥ 28 kg/m² at screening.
5. Weight has been stable for 3 months prior to screening (body weight change < 5%) (based on self-report).
6. Participants of childbearing potential and their partners must have no plan for conception from screening until 6 months after completion of the trial, voluntarily use effective contraceptive measures, and have no plan to donate sperm or oocytes within 6 months after trial completion.
7. Willingness to provide written informed consent and strictly comply with the protocol.

Exclusion Criteria:

1. Known hypersensitivity to the investigational drug, its excipients, or other drugs with similar pharmacological activity.
2. Use of any of the following within 3 months prior to screening:

1) GLP-1 receptor agonists or similar drugs with the same target; 2) biguanides, SGLT-2 inhibitors, DPP-4 inhibitors, or any other hypoglycemic agents; 3) weight-influencing medications or anticipated use during the study (including systemic glucocorticoids [excluding non-high-dose use <7 days within 3 months prior to screening and planned use <14 days during the study], tricyclic antidepressants, antipsychotics, mood stabilizers); 4) over-the-counter weight-loss drugs or appetite suppressants (including traditional Chinese medicine, health supplements, meal replacements), prescription weight-loss drugs (e.g., orlistat), or lipolytic injections; 5) stimulants, sedative-hypnotics, opioids, trazodone, or muscle relaxants; 6) over-the-counter or prescription medications that may affect excessive daytime sleepiness assessment.

3.History or evidence of any of the following diseases:

1. . Diagnosed with type 1, type 2 diabetes mellitus or other types of diabetes mellitus (history of gestational diabetes mellitus excluded);

2. . History of acute or chronic pancreatitis or pancreatic surgery;

3. . History of symptomatic gallbladder disease within 1 year prior to screening (excluding participants who underwent cholecystectomy completed at least 3 months before screening without long-term complications); or gallstones and/or bile duct stones detected by abdominal ultrasound at screening, assessed by the investigator to require treatment, likely to require treatment during the study, or other gallbladder lesions judged by the investigator to potentially compromise participant safety;

4. . Personal or family history (first-degree relatives: parents, children, siblings) of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2);

5. . Presence of endocrine disorders that may significantly affect body weight, e.g., Cushing's syndrome, pituitary-hypothalamic injury, hypogonadism; monogenic-obesity or hereditary obesity syndromes; obesity secondary to weight-loss medication reduction/discontinuation, long-term glucocorticoid, growth hormone or antipsychotic use;

6. . History of bariatric surgery or planned bariatric surgery, acupuncture weight-loss treatment, liposuction or abdominal lipolysis during the study, except for:a) Acupuncture weight-loss therapy or liposuction (e.g., abdominal liposuction) performed >1 year prior to screening;b) Gastric band removed >1 year prior to screening;c) Intragastric balloon removed >1 year prior to screening;d) Duodenal-jejunal bypass sleeve removed >1 year prior to screening;

7. . Previous history of depression, or Patient Health Questionnaire-9 (PHQ-9) score ≥15 at screening, or history of severe psychiatric disorders (including but not limited to suicidal ideation, schizophrenia, bipolar disorder);

8. . Positive response to suicidal ideation questions 4 or 5, or any suicidal-behavior-related questions on the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening;

9. . History of clinically significant cardiovascular or cerebrovascular disease within 6 months prior to screening, defined as:a) Myocardial infarction (MI) or unstable angina;b) Cardiac-related surgery (including coronary artery bypass grafting, percutaneous coronary intervention);c) Congestive heart failure (New York Heart Association [NYHA] Class III-IV, see Appendix 2 for details);d) Cerebrovascular accident (old lacunar infarction excluded), including but not limited to hemorrhagic/ischemic stroke or transient ischemic attack;e) Other cardiovascular or cerebrovascular diseases assessed by the investigator that render the subject ineligible for the trial;

10. . Prior sleep-apnea-related surgery or major ENT surgery (including tonsillectomy, adenoidectomy), assessed by the investigator at screening to still influence the occurrence or severity of OSA; or planned sleep-apnea-related or major ENT surgery during the trial.

    Note: Participants with minor prior ENT surgery (e.g., septoplasty) may be considered eligible at the investigator's discretion.

11. . History or presence at screening of clinically relevant medical conditions (other than OSA) or psychiatric disorders associated with insomnia or excessive daytime sleepiness;

12. . Receipt of other active device therapies for OSA besides PAP (e.g., oral appliance) at screening, or other therapies that may interfere with study results per investigator judgment, unless the participant is willing to discontinue such therapies at screening and throughout the study;

13. . Participants who are unable (per investigator judgment) or unwilling to discontinue PAP therapy for 7 days prior to PSG assessment;

14. . History or presence of sleep disorders other than OSA, e.g., central or mixed sleep apnea with ≥50 % central/mixed events, or Cheyne-Stokes respiration;

15. . Prior diagnosis of obesity hypoventilation syndrome or daytime hypercapnia;

16. . Requirement for supplemental oxygen therapy;

17. . Severe craniofacial bony deformities/abnormalities (e.g., micrognathia) significantly compromising the airway at screening; or other significant oral-cranio-maxillofacial or upper-airway anatomical abnormalities affecting breathing as judged by the investigator;

18. . Presence of disorders related to gastric emptying impairment (e.g., gastroparesis, pyloric obstruction, intestinal obstruction), gastrointestinal diseases assessed by the investigator to increase post-dose risk (e.g., severe active ulcer, inflammatory bowel disease, acute gastroenteritis, uncontrolled gastroesophageal reflux disease) at screening; or history of major gastrointestinal surgery (excluding fully recovered procedures such as gastrointestinal polypectomy, appendectomy, cholecystectomy deemed safe for trial participation by the investigator);

19. . Malignancy of any organ system within the past 5 years, regardless of local recurrence or metastasis; except for cured local basal-cell skin carcinoma, cervical carcinoma in-situ, prostate carcinoma in-situ, and radically resected breast ductal carcinoma in-situ with stable disease per investigator assessment;

20. . Major surgery, severe trauma or severe infection within 1 month prior to screening, judged by the investigator to preclude study participation;

21. . Concurrent diseases including respiratory, urinary, neurological, hematological, or immune-system disorders, judged by the investigator to compromise participant safety, efficacy evaluation or compliance.

4.Abnormal laboratory findings at screening meeting any of the following:

1. . HbA1c ≥6.5 % or fasting plasma glucose ≥7.0 mmol/L;

2. . Hepatic or renal impairment: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥3 × upper limit of normal (ULN); total serum bilirubin ≥1.5 × ULN; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² (calculated by CKD-EPI 2021 creatinine-Cystatin C formula, see Appendix 4);

3. . Serum calcitonin ≥50 pg/mL (i.e., 50 ng/L);

4. . Thyroid dysfunction uncontrolled on stable medication doses; or clinically significant abnormal thyroid function requiring initiation of treatment at screening; or thyroid-ultrasound-detected thyroid nodules with TI-RADS ≥4a (or ACR TI-RADS ≥TR4), or nodules likely to require fine-needle aspiration biopsy and/or surgery during the trial per investigator judgment;

5. . Fasting triglycerides ≥5.6 mmol/L;

6. . Serum amylase and/or lipase >2.0 × ULN;

7. . Hemoglobin <90 g/L;

8. . Untreated or poorly controlled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, based on the average of 3 blood-pressure measurements at screening);

9. . Clinically significant electrocardiogram (ECG) abnormalities including:

   a) Second- or third-degree atrioventricular block;b) Long-QT syndrome, or Fridericia-corrected QT (QTcF) >470 ms for female participants, >450 ms for male participants (calculation formula see Appendix 4);c) olff-Parkinson-White syndrome;d) Heart rate <50 bpm or >110 bpm;e) Other severe arrhythmias requiring treatment;

10. . Positive hepatitis B surface antigen with HBV-DNA above upper reference limit; or positive hepatitis-C antibody with HCV-RNA above upper reference limit; or positive HIV antibody; or dual positive syphilis-specific and non-specific antibodies;

11. . Clinically significant abnormalities identified by physical examination, vital-sign assessment, laboratory testing, judged by the investigator to pose substantial risk to participants or interfere with safety and PK evaluations, rendering the subject unsuitable for the trial.

5.Participation in another interventional clinical trial within 3 months prior to screening (excluding subjects who only completed screening without enrollment, or enrolled but did not receive study treatment).

6.Blood loss ≥400 mL (including trauma, blood sampling, blood donation) or receipt of blood/blood-component transfusion within 3 months prior to screening.

7.History of drug or alcohol abuse within 3 months prior to screening; alcohol abuse defined as >7 standard drinks/week for females or >14 standard drinks/week for males (1 standard drink = 150 mL wine = 360 mL beer = 45 mL spirits).

8.Unable to tolerate venipuncture or history of needle/blood phobia. 9.Any other condition deemed unsuitable by the investigator.