Clinical trial NCT04534582: Pharmacokinetic, Safety and Immunogenicity Phase I Study of HLX14 Versus Prolia® in Healthy Male Subjects
Official title: A Randomised, Parallel, Single-Dose, Subcutaneous Injection, Phase I Clinical Study Of HLX14 Versus Prolia® (Denosumab) In Chinese Healthy Adult Male Subjects For Comparison In Pharmacokinetic Characteristics, Safety, And Immunogenicity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Male Volunteers
Lead sponsor: Shanghai Henlius Biotech
Sponsor class: INDUSTRY
First posted: 2020-09-01
Enrollment: 252
Sex: MALE
Minimum age (years): 28
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Part I of the study： This is a randomised, single-dose, subcutaneous injection, parallel study designed to compare the PK of HLX14 and EU-sourced Prolia® in healthy Chinese adult male subjects, and to assess the safety, tolerability, and immunogenicity of these 2 drugs.

Part II of the study： This is a randomised, double-blind, four-arm, single-dose, subcutaneous injection, parallel-controlled study to evaluate the PK, PD, safety, tolerability, and immunogenicity between-group following a single subcutaneous injection of HLX14 or US, EU, CN-sourced Prolia®.


Eligibility criteria: Inclusion Criteria:

1. Males aged\> 28 and ≤ 65 years;
2. Body weight ≥ 50 kg, body mass index (BMI) = body weight (kg)/body height2 (m2), BMI ≥ 19 and ≤ 26 kg/m2;
3. With no disease history, or with abnormal prior medical history which has no effect on the trial as judged by the physician;
4. Normal or abnormal without clinical significance in physical examination, vital signs, ECG, chest imaging, clinical laboratory test, etc.;
5. Before the trial, sign the informed consent form (ICF) and have a full understanding of trial content, process, and possible adverse events (AEs); be able to complete the study as per protocol requirements.

Exclusion Criteria:

1. With a history of allergy to study drugs, calcium, and/or vitamin D, or with a history of allergy to drugs or others not suitable for participating in this study as judged by the investigators;
2. With the following clinically significant diseases (including but not limited to digestive system, kidney diseases, liver diseases, nervous diseases, blood system, endocrine system, tumor, respiratory system, immune diseases, mental diseases, cardiovascular and cerebrovascular diseases, or any condition that may affect bone metabolism);
3. With a history of upper respiratory tract infection and other acute infections within 2 weeks prior to screening;
4. Occurred or suffering from osteomyelitis or ONJ (Osteonecrosis of the jaw) previously.

   The dental or jaw disease that is active, requiring oral surgery; or dental or oral surgery wounds have not healed; or planned for invasive dental surgery during the study.
5. Occurrence of fracture or bone-related surgery within 6 months prior to screening;
6. With rash, scar, tattoo, etc. at administration site that may affect drug absorption;
7. Blood donation or massive blood loss (\> 450 mL) within 3 months prior to screening;
8. Use of any prescription drugs, over-the-counter (OTC) drugs, vitamin products, or traditional Chinese medicines within 28 days prior to screening;
9. Participation in any drug clinical trials and use of any investigational/comparator drugs within 3 months prior to screening;
10. Administration of the following drugs affecting bone metabolism:

    1. Administration history of denosumab or its biosimilar products, romosozumab or its biosimilar products, cathepsin K inhibitors, diphosphonates, fluorides, or stronitum;
    2. Administration of the following within 12 months before screening: parathyroid hormone or its derivatives, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERM), tibolone, anabolic steroids, testosterone, androgen, and gonadotropin-releasing hormone agonists (GnRH-a);
    3. Administration of any prescription drug or OTC drug within 6 months or 10 half-lives of drug elimination (whichever is the longer) before screening that may have impact on the objectives of the study at the discretion of the investigator, including but not limited to heparin, warfarin, anticonvulsants (excluding benzodiazepine), systemic ketoconazole, adrenocorticotropic hormone (ACTH), cinacalcet, aluminum, lithium, protease inhibitors (PI), methotrexate (MTX), calcitonin, calcitriol, diuretics, and glucocorticoids for oral administration or injection (daily administration of ≥ 5 mg prednisone or equivalent drugs for more than 10 days);
11. Use of any biological products (excluding vaccine) or monoclonal antibodies within 6 months prior to screening;
12. Vaccination within 1 month prior to screening;
13. With a history of alcohol abuse (14 units of alcohol per week: 1 unit = 285 mL of beer, 25 mL of spirit, or 100 mL of wine), or positive for alcohol breath test;
14. With a history of substance abuse or drug abuse, or positive for drug screen;
15. Positive for tobacco screen;
16. With significant changes in physical activity within 6 months prior to screening, or not agree to abstain from strenuous physical exercise during the trial;
17. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody, or treponema pallidum antibody (TPPA);
18. Abnormal serum calcium level (beyond the laboratory reference range) during the screening;
19. Ear temperature \> 37.5 °C during the screening period; and/or sitting systolic blood pressure (SBP) \> 140 mmHg or \< 90 mmHg, and/or diastolic blood pressure (DBP) \> 90 mmHg or \< 50 mmHg; and/or pulse rate \> 100 beats/min or \< 50 beats/min during the screening.
20. Clinically significant abnormal ECG or QTcF \> 450 ms during screening, or with a prior history of clinically significant abnormal ECG;
21. Unwilling to take adequate contraceptive measures during the study.
22. Subjects who, in the opinion of the investigators, are not eligible to participate in this study.

Primary outcomes:
measure: AUC(0-t)
timeFrame: from 0 to day 274
measure: Cmax
timeFrame: from 0 to day 274
measure: AUC0-inf
timeFrame: from 0 to day 274
Secondary outcomes:
measure: Tmax
timeFrame: from 0 to day 274
measure: CL/F
timeFrame: from 0 to day 274
measure: λz
timeFrame: from 0 to day 274
measure: t1/2
timeFrame: from 0 to day 274
measure: Vd/F
timeFrame: from 0 to day 274
measure: %AUCex
timeFrame: from 0 to day 274
measure: MRT
timeFrame: from 0 to day 274
measure: AUC0-28d and AUC0-112d
timeFrame: from 0 to day 112
measure: AUEC0-t
timeFrame: from 0 to day 274
measure: Imin
timeFrame: from 0 to day 274
measure: Imax
timeFrame: from 0 to day 274
measure: Tmin
timeFrame: from 0 to day 274
Other outcomes:
measure: AEs and SAEs
timeFrame: from 0 to day 274
measure: Physical examination
timeFrame: from 0 to day 274
measure: Vital signs
timeFrame: from 0 to day 274
measure: Injection site reactions
timeFrame: from 0 to day 274
measure: Laboratory tests (haematology, serum chemistry, and urinalysis)
timeFrame: from 0 to day 274
measure: 12-lead ECG
timeFrame: from 0 to day 274
measure: ADA and NAb
timeFrame: from 0 to day 274
Locations:
city: Shanghai
country: China
facility: Huashan Hospital，Fudan University
state: Shanghai
Study officials:
affiliation: Huashan Hospital
name: Jing Zhang, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Li N, Chu N, Zhu L, Wu X, Wei Q, Wang J, Hu X, Yu H, Wang Q, Yuan W, Huang K, Zhang J. Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 versus reference denosumab in healthy males: A randomized phase I study. Clin Transl Sci. 2024 Dec;17(12):e70089. doi: 10.1111/cts.70089.
citation: American Society for Clinical Pharmacology and Therapeutics. Clin Pharmacol Ther. 2022 Mar;111 Suppl 1:S5-S80. doi: 10.1002/cpt.2521. No abstract available.