A Multiple Dose Study to Evaluate the Effect of SHR-1222 Injection in Postmenopausal Osteoporosis Patients

Study Overview
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Brief Summary
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This is a Multi-Center, Randomized, Double-Blind, Dose Escalation, Placebo Parallel Controlled PhaseⅠClinical study to Evaluate the Safety, Tolerability and Pharmacokinetics, Pharmacodynamics, Immunogenicity with Multiple Subcutaneous Injections of SHR-1222 in Postmenopausal Osteoporosis Patients. The primary objective of this study is to investigate the safety and tolerability of a range of subcutaneous SHR-1222 in postmenopausal osteoporosis patients. Secondary objectives are to determine the pharmacokinetics (PK), pharmacodynamics (PD) profile of SHR-1222 in postmenopausal osteoporosis patients including assessment of immunogenicity.

Official Title
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Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Immunogenicity Study Following Multiple Subcutaneous Injections of SHR-1222 in Postmenopausal Osteoporosis Patients

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: SHR-1222
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent; Age ≥50 and ≤70 years old and post menopause for at least 5 years at the time of screening; Weight ≥40kg at the time of screening; BMD T-score ≤ -2.50 at the lumbar vertebrae, total hip or femoral neck at the time of screening, based on DXA scans; At least 2 vertebrae in the L1-L4 region and at least one hip are evaluable by DXA; Without disease that would significantly affect the study or bring additional health risks at the time of screening or baseline; blood pressure < 150 / 95mmHg, blood fasting blood glucose < 7.0mmol/l, glycosylated hemoglobin < 7%, or total cholesterol < 6.2mmol/l, triglyceride < 3.4mmol/l under the condition of lifestyle improvement rather than drug treatment; If there are other abnormalities in the examination report of the subject, the subject could only be included after investigator approval; Ambulatory. Exclusion Criteria: Any disease affecting bone metabolism; Any severe (SQ3) or more than 2 moderate (SQ2) vertebral fractures, as assessed by the central imaging based on lateral spine x-rays at the time of screening; History of hip fracture; 25 (OH) vitamin D levels < 20 ng/mL at the time of screening. Vitamin D repletion will be permitted and subjects may be rescreened; BMD T-score < -3.50 at the lumber vertebra, total hip or femoral neck at the time of screening, based on DXA scans; Use of the following agents affecting bone metabolism: IV bisphosphonates or denosumab prior to screening; Oral bisphosphonates, PTH analogs, Strontium or fluoride within 12m prior to screening; Hormone replacement therapy within 6m prior to screening; Glucocorticosteroids (inhaled or topical corticosteroids administered more than 2 weeks before the enrollment date are allowed), Anabolic steroids, Calcitriol and available analogues, thiazide diuretics within 3m prior to screening; History of metabolic or bone disease (except osteoporosis) that may interfere with the interpretation of the results, such as hyperprolactinemia, osteosclerosis, Paget's disease, rheumatoid arthritis, osteomalacia, osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, Cushing's disease, hyperprolactinemia, and malabsorption syndrome; Hyperparathyroidism, hypothyroidism, hyperthyroidism, hypothyroidism, hypercalcemia, hypocalcemia, renal failure, etc at the time of screening; Malignancy except non-melanoma skin cancers, cervical or breast ductal carcinoma in situ within the last 5 years; A clinical history of drug allergy or a history of atopic allergic diseases (asthma, urticaria, eczema dermatitis) or a known allergy to experimental or similar experimental drugs; Past medical history of cerebral infarction, ischemic or hemorrhagic stroke; Past medical history of Myocardial infarction, coronary heart disease, angina pectoris, heart failure (cardiac function II-IV), serious arrhythmia (such as atrial fibrillation, pacemaker needed) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or gamma pancreatic acyl transferase (GGT) or total bilirubin, more than 2 x ULN during screening; 3 months prior to screening involved in any drug clinical subjects (except screening failed or not given cinical drugs) or within 5 half-lives of test drug at the time of screening; Any major surgery in 1m prior to screening or a surgery plan during the study; Blood donation or loss more than 400mL or blood transfusion within 3 months prior to screening; Human immunodeficiency virus antibody (HIV-ab), syphilis serological examination, hepatitis b virus surface antigen (HBsAg), hepatitis c virus antibody (HCV-ab) were positive; No history of alcohol and substance abuse or positive urine drug screening; Subjects with any other situation should not be involved, which determined by the researchers.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1：SHR-1222<br>Subcutaneous injection of SHR-1222 dosage 1 monthly × 6 months | Drug: SHR-1222<br>* Pharmaceutical form: water injection Route of administration: subcutaneous injection<br>|
| Experimental: Cohort 2：SHR-1222<br>Subcutaneous injection of SHR-1222 dosage 2 monthly × 6 months | Drug: SHR-1222<br>* Pharmaceutical form: water injection Route of administration: subcutaneous injection<br>|
| Experimental: Cohort 3：SHR-1222<br>Subcutaneous injection of SHR-1222 dosage 3 monthly × 6 months | Drug: SHR-1222<br>* Pharmaceutical form: water injection Route of administration: subcutaneous injection<br>|
| Experimental: Cohort 4：SHR-1222<br>Subcutaneous injection of SHR-1222 dosage 4 every 2 months × 6 months | Drug: SHR-1222<br>* Pharmaceutical form: water injection Route of administration: subcutaneous injection<br>|
| Experimental: Cohort 5：SHR-1222<br>Subcutaneous injection of SHR-1222 dosage 5 every 2 months × 6 months | Drug: SHR-1222<br>* Pharmaceutical form: water injection Route of administration: subcutaneous injection<br>|
| Experimental: Cohort 6：placebo<br>Subcutaneous injection of placebo × 6 months | Drug: Placebo<br>* Pharmaceutical form: water injection Route of administration: subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerance: Number of subjects with adverse events | Number & proportion of subjects with adverse events | Dose administration to 225 days after first dose administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of PK parameter-time to maximum concentration (Tmax) |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PK parameter-maximum concentration (Cmax) |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PK parameter-area under curve (AUC) |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PD parameter-change in serum C-telopeptide (sCTx) from baseline |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PD parameter-change in aminoterminal propeptide type-1 procollagen (P1NP) from baseline |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PD parameter-change in osteocalcin from baseline |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PD parameter-change in bone-specific alkaline phosphatase (BSAP) from baseline |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PD parameter-change in serum totol sclerostin |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PD parameter-change in areal bone mineral density of lumbar spine (L1-L4) from baseline by dualenergy X-ray absorptiometry |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PD parameter-change in areal bone mineral density of collum femoris from baseline by dualenergy X-ray absorptiometry |  | Pre-dose to 225 days after first dose administration | 
| Assessment of PD parameter-change in areal bone mineral density of total hip from baseline by dualenergy X-ray absorptiometry |  | Pre-dose to 225 days after first dose administration | 
| Antidrug antibody |  | Pre-dose to 225 days after first dose administration | 
| Neutralizing Antibody |  | Pre-dose to 225 days after first dose administration |