Efficacy and Safety of Subcutaneous Injection of XH-02 in the Treatment of Adult Hypoparathyroidism

Official title

Efficacy and Safety of Subcutaneous Injection of mRNA Nucleic Acid Drug XH-02 in the Treatment of Adult Hypoparathyroidism

Overview

XH-02 is an mRNA nucleic acid drug that expresses PTH in the body following intravenous or subcutaneous injection, providing PTH replacement therapy for patients with hypoparathyroidism. Animal studies have shown pharmacodynamic effects of XH-02, with a favorable safety profile. A clinical study of intravenously administered XH-02 has been completed in patients with hypoparathyroidism, yielding clear pharmacodynamic results and demonstrating good safety. This study aims to evaluate the safety and efficacy of subcutaneously injected XH-02 in patients with hypoparathyroidism.

Interventions

• Drug Single subcutaneous injection
  Participants will receive a single dose of XH-02 through subcutaneous injection.
• Drug Multiple subcutaneous injection
  Participants will receive once daily subcutaneous injection of XH-02 for 5 consecutive days.

Primary outcome measures

• Adverse events (safety) [Time frame: From the first dose through 30 days after the last dose for non-serious adverse events, and through 3 months after the last dose for severe adverse events.]

Secondary outcome measures (8)

• PTH(1-84) (efficacy) [Time frame: Single dose: Predose (within one hour before administration), and 4, 8, 12, 18, 24, 30, 36, 48, 60, and 72 hours postdose. Multiple dose: Predose on Day 1 to 5 (before each dose); and 4, 8, 12, 24, 30, 36, 48, 60, and 72 hours after the last dose.]
• PTH (efficacy) [Time frame: Single dose: Predose (within one hour before administration), and 4, 8, 12, 18, 24, 30, 36, 48, 60, and 72 hours postdose. Multiple dose: Predose on Day 1 to 5 (before each dose); and 4, 8, 12, 24, 30, 36, 48, 60, and 72 hours after the last dose]
• Serum calcium (efficacy) [Time frame: Single dose: Predose (within one hour before administration), and 4, 8, 12, 24, 36, 48, and 72 hours postdose. Multiple dose: Predose on Day 1 to 5 (before each dose); and 24, 48, and 72 hours after the last dose]
• Serum phosphorus (efficacy) [Time frame: Single dose: Predose (within one hour before administration), and 4, 8, 12, 24, 36, 48, and 72 hours postdose. Multiple dose: Predose on Day 1 to 5 (before each dose); and 24, 48, and 72 hours after the last dose]
• Serum magnesium (efficacy) [Time frame: Single dose: Predose (within one hour before administration), and 4, 8, 12, 24, 36, 48, and 72 hours postdose. Multiple dose: Predose on Day 1 to 5 (before each dose); and 24, 48, and 72 hours after the last dose]
• 1, 25-Dihydroxyvitamin D3 (efficacy) [Time frame: Single dose: Predose (within one hour before administration); and 24, 48, and 72 hours postdose. Multiple dose: Predose on Day 1, Day 3, Day 5; and 48 hours and 72 hours after the last dose.]
• 24-hour urine calcium (efficacy) [Time frame: Single dose: Predose (within 3 days before administration), and 24, 48, and 72 hours postdose. Multiple dose: Predose on Day 1 to 5 (before each dose), and 24, 48, and 72 hours after the last dose]
• Fractional Excretion of calcium (efficacy) [Time frame: Single dose: Predose (within one hour before administration), and 12, 24, 36, 48, and 72 hours postdose. Multiple dose: Predose on Day 1 to 5 (before each dose), and 24, 48, and 72 hours after the last dose]

Eligibility criteria

Inclusion criteria

• Aged 18-65 years (inclusive of 18 and 65), male or female.
• A history of postoperative chronic hypoparathyroidism (HP) or autoimmune, genetic, or idiopathic HP for at least 26 weeks. HP is confirmed based on a previous occurrence of hypocalcemia accompanied by an inappropriately low serum parathyroid hormone (PTH) level (below the upper limit of the local laboratory's normal range). Note: If the subject does not have a documented diagnosis of chronic HP but has experienced hypocalcemia accompanied by an inappropriately low serum PTH level for at least 26 weeks prior to screening, and the investigator determines that the diagnosis of chronic HP is met, this criterion is considered fulfilled.
• Inadequate control of hypoparathyroidism with conventional treatment (calcium and vitamin D) or intolerance to such treatment.
• At screening, Body Mass Index (BMI) of 17-40 kg/m² (inclusive).
• If aged ≤25 years, radiographic evidence of epiphyseal closure based on X-ray examination of the wrist and hand of the non-dominant hand.

Exclusion criteria

• Impaired response to PTH (pseudohypoparathyroidism), characterized by resistance to PTH and elevated PTH levels during hypocalcemia.
• Known allergies, or a history of allergy to the investigational drug or polyethylene glycol (PEG).
• Any disease other than HP that may affect calcium metabolism, calcium-phosphorus homeostasis, or PTH levels, such as active hyperthyroidism; Paget's disease of bone; severe hypomagnesemia; Type 1 diabetes mellitus or poorly controlled Type 2 diabetes mellitus (HbA1C >9%, HbA1C test results from blood samples collected within 12 weeks prior to screening are acceptable); severe and chronic liver or kidney disease; Cushing's syndrome; multiple myeloma; active pancreatitis; malnutrition; rickets; recent prolonged immobilization; active malignancy (except for low-risk well-differentiated thyroid cancer or non-melanoma skin cancer); active hyperparathyroidism; history of parathyroid cancer within 5 years prior to screening; acromegaly; or multiple endocrine neoplasia.
• History of vaccination within 4 weeks prior to enrollment, or planned vaccination during the study period.
• Women who are pregnant or breastfeeding.
• Patients with high-risk thyroid cancer requiring TSH suppression to <0.2 mIU/L within the past 2 years, or those with a history of malignancy.
• Subjects requiring long-term use of diuretics, phosphate binders (except calcium supplements), digoxin, lithium, methotrexate, biotin >30 μg/day, or systemic corticosteroids (except as replacement therapy). Patients requiring long-term use of hormones or immunosuppressants (e.g., for rheumatic or autoimmune diseases) will not be enrolled in this study. Note: Subjects who can discontinue these medications during the study may be enrolled, but they must be discontinued for at least 5.5 half-lives prior to Visit 1 blood sample collection. Biotin must be discontinued for at least 1 day prior to screening blood sample collection. These medications are prohibited throughout the study.
• Use of PTH-like drugs (either commercially available or obtained through participation in a clinical trial), including PTH (1-84), PTH (1-34), or other N-terminal fragments or analogs of PTH, or PTH-related protein, within 4 weeks prior to screening.
• Participation in any other interventional trial and receipt of investigational drug or device within 8 weeks prior to screening, or still within 5.5 half-lives of the drug from a previously participated trial.
• Presence of uncontrolled hypertension at baseline, or a history of the following cardiovascular or cerebrovascular diseases, including: (1) Unstable angina; (2) Arrhythmia requiring medication or severe arrhythmia; (3) Myocardial infarction; (4) Class III or higher heart failure (per NYHA classification), second-degree or higher atrioventricular block; (5) Cerebral infarction (except lacunar infarction), cerebral hemorrhage, or other such conditions.
• Increased risk of osteosarcoma, for example, having Paget's disease of bone or unexplained elevated alkaline phosphatase, genetic disorders predisposing to osteosarcoma, or previous exposure to high-dose external beam radiation or implant radiotherapy to the skeleton.
• Abnormal laboratory test results meeting any of the following criteria: Blood routine: Neutrophil count (NEUT#) <1.5×10⁹/L; Platelet count (PLT) <90×10⁹/L; Hemoglobin (Hb) <90g/L; Eosinophil count (EOS#) >0.5×10⁹/L. Liver and kidney function: Total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) exceeding the normal range; eGFR <60 ml/min/1.73m².
• Any other medical or other condition that, in the investigator's judgment, might affect the conduct of the study or interfere with the study results, or might increase the risk to the subject.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking Union Medical College Hospital — Beijing

Publications

• Cao J, Choi M, Guadagnin E, Soty M, Silva M, Verzieux V, Weisser E, Markel A, Zhuo J, Liang S, Yin L, Frassetto A, Graham AR, Burke K, Ketova T, Mihai C, Zalinger Z, Levy B, Besin G, Wolfrom M, Tran B, Tunkey C, Owen E, Sarkis J, Dousis A, Presnyak V, Pepin C, Zheng W, Ci L, Hard M, Miracco E, Rice L, Nguyen V, Zimmer M, Rajarajacholan U, Finn PF, Mithieux G, Rajas F, Martini PGV, Giangrande PH. m PMID 34035281
• Rejnmark L, Ayodele O, Lax A, Mu F, Swallow E, Gosmanova EO. The risk of chronic kidney disease development in adult patients with chronic hypoparathyroidism treated with rhPTH(1-84): A retrospective cohort study. Clin Endocrinol (Oxf). 2023 Apr;98(4):496-504. doi: 10.1111/cen.14813. Epub 2022 Aug 28. PMID 35974422
• Chen KS, Gosmanova EO, Curhan GC, Ketteler M, Rubin M, Swallow E, Zhao J, Wang J, Sherry N, Krasner A, Bilezikian JP. Five-year Estimated Glomerular Filtration Rate in Patients With Hypoparathyroidism Treated With and Without rhPTH(1-84). J Clin Endocrinol Metab. 2020 Oct 1;105(10):e3557-65. doi: 10.1210/clinem/dgaa490. PMID 32738041
• Khan AA, Koch CA, Van Uum S, Baillargeon JP, Bollerslev J, Brandi ML, Marcocci C, Rejnmark L, Rizzoli R, Shrayyef MZ, Thakker R, Yildiz BO, Clarke B. Standards of care for hypoparathyroidism in adults: a Canadian and International Consensus. Eur J Endocrinol. 2019 Mar;180(3):P1-P22. doi: 10.1530/EJE-18-0609. PMID 30540559
• Khan AA, Rubin MR, Schwarz P, Vokes T, Shoback DM, Gagnon C, Palermo A, Marcocci C, Clarke BL, Abbott LG, Hofbauer LC, Kohlmeier L, Pihl S, An X, Eng WF, Smith AR, Ukena J, Sibley CT, Shu AD, Rejnmark L. Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial. J Bone Miner Res. 2023 Jan;38(1):14-25. doi: 10.1002 PMID 36271471
• Karpf DB, Pihl S, Mourya S, Mortensen E, Kovoor E, Markova D, Leff JA. A Randomized Double-Blind Placebo-Controlled First-In-Human Phase 1 Trial of TransCon PTH in Healthy Adults. J Bone Miner Res. 2020 Aug;35(8):1430-1440. doi: 10.1002/jbmr.4016. Epub 2020 Apr 16. PMID 32212275
• Gosmanova EO, Ayodele O, Chen K, Cook EE, Mu F, Young JA, Rejnmark L. Association of Calcium and Phosphate Levels with Incident Chronic Kidney Disease in Patients with Hypoparathyroidism: A Retrospective Case-Control Study. Int J Endocrinol. 2022 Nov 2;2022:6078881. doi: 10.1155/2022/6078881. eCollection 2022. PMID 36389126
• Gosmanova EO, Chen K, Rejnmark L, Mu F, Swallow E, Briggs A, Ayodele O, Sherry N, Ketteler M. Risk of Chronic Kidney Disease and Estimated Glomerular Filtration Rate Decline in Patients with Chronic Hypoparathyroidism: A Retrospective Cohort Study. Adv Ther. 2021 Apr;38(4):1876-1888. doi: 10.1007/s12325-021-01658-1. Epub 2021 Mar 9. PMID 33687651

Identifiers

NCT: NCT07530705 · K9040

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗