A Cohort Study on the Safety and Efficacy of XH-02 in Treating Hypoparathyroidism

Official title

An Expanded Cohort Study on the Safety and Efficacy of mRNA Nucleic Acid Drug XH-02 in Treating 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. Previous clinical studies have demonstrated the safety of subcutaneously administered XH-02 in several patients with hypoparathyroidism and have yielded clear efficacy results. This study aims to further validate the safety and efficacy of subcutaneously injected XH-02 in the treatment of hypoparathyroidism in a expanded cohort.

Interventions

• Drug Single subcutaneous injection
  Participants will receive a single dose of XH-02 through subcutaneous injection.
• Drug Multiple subcutaneous injection
  Participants will receive XH-02 via subcutaneous injection daily or every other day, for a total of 5 doses.

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 dosing) and 4, 8, 12, 18, 24, 30, 36, 48, 60, and 72 hours postdose. Multiple dose: Predose (within one hour 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 dosing) and 4, 8, 12, 18, 24, 30, 36, 48, 60, and 72 hours postdose.]
• Serum calcium (efficacy) [Time frame: Single dose: Predose (within one hour before dosing), and 4, 8, 12, 24, 36, 48, and 72 hours postdose. Multiple dose: Predose (within one hour 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 dosing) and 4, 8, 12, 24, 36, 48, and 72 hours postdose. Multiple dose: Predose (within one hour 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 dosing) and 4, 8, 12, 24, 36, 48, and 72 hours postdose. Multiple dose: Predose (within one hour 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 dosing) and 24, 48, and 72 hours postdose. Multiple dose: Predose (within one hour before the 1st, 3rd, and 5th dose) and 48 hours and 72 hours after the last dose.]
• 24-hour urine calcium (efficacy) [Time frame: Single dose: Predose (within 3 days before dosing), and 24, 48, and 72 hours postdose. Multiple dose: Predose (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 dosing) and 12, 24, 36, 48, and 72 hours postdose. Multiple dose: Predose (before each dose) and 24, 48, and 72 hours after the last dose.]

Eligibility criteria

Inclusion criteria

• Age ≥18 years, both males and females eligible;
• History of postoperative chronic HP or autoimmune, genetic, or idiopathic HP for at least 26 weeks. The diagnosis of HP is established based on the presence of inappropriately low serum PTH levels concurrent with hypocalcemia in the past.
• Poorly controlled or intolerant to conventional treatment (calcium and vitamin D) for hypoparathyroidism;
• BMI 17-40 kg/m² (inclusive) at screening;
• If age ≤25 years, radiographic evidence of epiphyseal closure based on X-ray results of the wrist and palm of the non-dominant hand.

Exclusion criteria

• Impaired PTH response (pseudohypoparathyroidism), characterized by PTH resistance and elevated PTH levels in the presence of hypocalcemia;
• Allergic constitution, or allergy to the investigational drug or polyethylene glycol (PEG)-based drugs;
• 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; parathyroid carcinoma occurring within 5 years prior to screening; acromegaly; or multiple endocrine neoplasia;
• Pregnant or breastfeeding women;
• Male partners with female partners planning to become pregnant, or partners of childbearing potential who are unwilling to use adequate contraceptive methods during the study period;
• Patients with high-risk thyroid cancer requiring TSH suppression to <0.2 mIU/L within 2 years, or those with a history of tumors;
• Use of loop diuretics, phosphate binders (except calcium supplements), digoxin, lithium, methotrexate, biotin >30 mcg/day, or systemic corticosteroids (except as replacement therapy);
• Use of PTH-like drugs (whether commercially available or obtained through participation in clinical trials), 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 receiving investigational drugs or devices within 8 weeks prior to screening, or still within 5.5 half-lives of the investigational drug from the trial in which they participated;
• Presence of uncontrolled hypertension at baseline, or a history of the following cardiovascular or cerebrovascular diseases, including: (1) unstable angina; (2) cardiac arrhythmias requiring medication or severe arrhythmias; (3) myocardial infarction; (4) heart failure class III or higher (NYHA classification), second-degree or higher atrioventricular block; (5) cerebral infarction (excluding lacunar infarction), cerebral hemorrhage, or other such diseases;
• Increased risk of osteosarcoma, such as having Paget's disease of bone or unexplained elevated alkaline phosphatase, having genetic disorders predisposing to osteosarcoma, or having a prior history of extensive external beam or implant radiation therapy involving bone;
• Disease processes that adversely affect gastrointestinal absorption, including but not limited to short bowel syndrome, significant small bowel resection, gastric bypass surgery, tropical sprue, active celiac disease, active ulcerative colitis, active Crohn's disease, gastroparesis, and autoimmune regulator gene mutations associated with malabsorption;
• Any medical or other condition that, in the investigator's judgment, may affect the conduct of the study, interfere with the study results, or increase the risk to the subject/study.

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

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking Union Medical College Hospital — Beijing

Publications

• Shoback DM, Bilezikian JP, Costa AG, Dempster D, Dralle H, Khan AA, Peacock M, Raffaelli M, Silva BC, Thakker RV, Vokes T, Bouillon R. Presentation of Hypoparathyroidism: Etiologies and Clinical Features. J Clin Endocrinol Metab. 2016 Jun;101(6):2300-12. doi: 10.1210/jc.2015-3909. Epub 2016 Mar 4. PMID 26943721
• Khan AA, Bilezikian JP, Brandi ML, Clarke BL, Gittoes NJ, Pasieka JL, Rejnmark L, Shoback DM, Potts JT, Guyatt GH, Mannstadt M. Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop. J Bone Miner Res. 2022 Dec;37(12):2568-2585. doi: 10.1002/jbmr.4691. Epub 2022 Nov 14. PMID 36054621
• Gosmanova EO, Houillier P, Rejnmark L, Marelli C, Bilezikian JP. Renal complications in patients with chronic hypoparathyroidism on conventional therapy: a systematic literature review : Renal disease in chronic hypoparathyroidism. Rev Endocr Metab Disord. 2021 Jun;22(2):297-316. doi: 10.1007/s11154-020-09613-1. Epub 2021 Feb 18. PMID 33599907
• 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
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT07540286 · K10348

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗