Efficacy, Metabolism and BMD of the 3-month TP Compared to the 1-month TP in ICPP

Official title

The Effects of the 3-month Formulation of Triptorelin (TP) Compared to the 1-month Formulation on the Efficacy, Glucose and Lipid Metabolism, and Bone Mineral Density(BMD) in Idiopathic Central Precocious Puberty(ICPP)

Overview

The primary objective of this study is to compare the efficacy of the 3-month formulation and 1-month formulation of triptorelin and to assess the short-term effects of the 3-month formulation of triptorelin on glucose and lipid metabolism, body composition, and bone density in Chinese ICPP patients.

Detailed description

Idiopathic central precocious puberty (CPP) is an important treatable disease causing pubertal growth disorders. Gonadotropin-releasing hormone analogs (GnRHa) are the first-line drugs for treating idiopathic central precocious puberty (ICPP). Currently, the 1-month formulation (3.75mg) is the most widely used in China. The development of long-acting formulations will reduce the number of injections and treatment costs for children, as well as reduce the clinical visit burden. The 3-month formulation of Triptorelin Pamoate (15mg) was approved for use in central precocious puberty in March 2023. At present, there is only one publicly reported small-sample, single-arm clinical study in China, and there are no large-sample, real-world, concurrent controlled clinical study data on the efficacy and safety of the 3-month and 1-month formulations of triptorelin in the treatment of central precocious puberty. In currently reported safety events both domestically and internationally, there are no reports on the effects of the 3-month formulation of triptorelin on patients' glucose and lipid metabolism, body composition, and bone density. Our research team previously observed in a small-sample retrospective study of female patients with ICPP that after 1 year of treatment with the 3-month formulation of GnRHa (11.25mg leuprorelin), it effectively inhibited the hypothalamic-pituitary-gonadal axis and bone age progression, improved predicted adult height, and had no serious safety events. Therefore, based on our previous work, we plan to conduct a large-sample, real-world, concurrent controlled study to evaluate the gonadal axis suppression and predicted adult height benefits of the 3-month formulation of triptorelin compared to the 1-month formulation in patients with central precocious puberty (CPP). Additionally, we will assess the short-term effects of the 3-month formulation of triptorelin on glucose and lipid metabolism, body composition, and bone density in ICPP patients. The study results are expected to provide clinical evidence for the application of the 3-month formulation in the treatment of central precocious puberty in China.

Interventions

• Drug Triptorelin pamoate（15mg）
  Triptorelin pamoate 15mg is administered via intramuscular injection once every three months.
• Drug Triptorelin acetate （3.75mg）
  Triptorelin acetate 3.75mg is administered via intramuscular injection once every four weeks.

Primary outcome measures

• The proportion of LH of ≤ 3 IU/L [Time frame: 3 months after injection of 3-month TP and 1-month TP]

Secondary outcome measures (11)

• Basal LH（ IU/L),Basal FSH（IU/L), Estradiol (female) (pg/mL)and testosterone (male)(pg/mL) [Time frame: Month 0, 3 ,6 and 12 after injection of triptorelin 3M and 1M]
• Tanner stage [Time frame: Month 0, 3 ,6 and 12 after injection of triptorelin 3M and 1M]
• Uterine length (female)（mL) and testicular volume (male)(mL) [Time frame: Month 0, 3 ,6 and 12 after injection of triptorelin 3M and 1M]
• Growth velocity (cm/y) [Time frame: Month 0, 3 ,6 and 12 after injection of triptorelin 3M and 1M]
• BA/CA [Time frame: Month 0, 6 and 12 after injection of triptorelin 3M and 1M]
• PAH(cm) [Time frame: Month 0, 6 and 12 after injection of triptorelin 3M and 1M]
• Body composition [Time frame: Month 0 and 12 after injection of triptorelin 3M and 1M]
• Bone Mineral Density [Time frame: Month 0 and 12 after injection of triptorelin 3M and 1M]
• BMISDS [Time frame: Month 0, 6 and 12 after injection of triptorelin 3M and 1M]
• glucose metabolism [Time frame: Month 0, 6 and 12 after injection of triptorelin 3M and 1M]
• lipid metabolism [Time frame: Month 0, 6 and 12 after injection of triptorelin 3M and 1M]

Eligibility criteria

Inclusion criteria

• Early appearance of secondary sexual characteristics, specifically breast development in girls before 8 years old or menarche before 10 years old, and testicular enlargement in boys before 9 years old.
• Gonadal enlargement: pelvic ultrasound shows that girls have at least one ovarian follicle with a diameter \>4mm, and breast development is at least at Tanner stage II; boys have a testicular volume ≥ 4 ml (measured with Prader orchidometer).
• GnRH stimulation test: LH peak value ≥ 5 IU/L (chemiluminescence method), with an LH peak/FSH peak ratio ≥ 0.6.
• Bone age (BA) exceeds chronological age (CA) by 1 year or more (based on bone age assessment during the screening period at this center).
• Accelerated linear growth, with an annual growth rate higher than that of healthy children of the same age.
• No prior treatment with gonadotropin-releasing hormone agonists.
• Body weight of at least 20 kg.

Exclusion criteria

1.Target Diseases:

• Secondary central precocious puberty: This includes central nervous system abnormalities (tumors or space-occupying lesions, acquired injuries, congenital developmental abnormalities, etc.) and other diseases (congenital adrenal hyperplasia, familial male-limited precocious puberty, McCune-Albright syndrome, etc.).
• Slow-progressing central precocious puberty: Some children show signs of sexual development before the defined age (7-8 years), but the progression of sexual development and bone age is slow, and linear growth remains within the corresponding percentiles.

2.Treatment History, Medical History, and Concomitant Medical Conditions:

• Known hypersensitivity to any investigational substance or related compounds.
• Any chronic disease or treatment deemed by the investigator to potentially interfere with growth or other study endpoints \[including but not limited to: long-term glucocorticoid use (excluding short-term topical use), renal failure, diabetes, moderate to severe scoliosis\].
• Girls with a bone age over 12.5 years or menarche ≥ 1 year; boys with a bone age over 14 years (based on bone age assessment during the screening period at this center).
• Congenital long QT syndrome/12-lead ECG at screening showing QTc ≥ 500 ms corrected by Bazett's formula, excluding other factors causing prolonged QT interval on ECG/12-lead ECG at screening showing QTc between 480 and 499 ms accompanied by unexplained syncope, with no other factors causing prolonged QT interval and no pathogenic mutations.
• BMI ≥ 95th percentile (same age and gender).

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

• Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University — Guangzhou

Publications

• Subspecialty Group of Endocrinologic, Hereditary and Metabolic Diseases, the Society of Pediatrics, Chinese Medical Association; Editorial Board, Chinese Journal of Pediatrics. [Expert consensus on the diagnosis and treatment of central precocious puberty(2022)]. Zhonghua Er Ke Za Zhi. 2023 Jan 2;61(1):16-22. doi: 10.3760/cma.j.cn112140-20220802-00693. Chinese. PMID 36594116
• Cheuiche AV, da Silveira LG, de Paula LCP, Lucena IRS, Silveiro SP. Diagnosis and management of precocious sexual maturation: an updated review. Eur J Pediatr. 2021 Oct;180(10):3073-3087. doi: 10.1007/s00431-021-04022-1. Epub 2021 Mar 21. PMID 33745030
• Luo X, Zhang C, Yang Y, Xu X, Cheng X, Wei H, Wang L, Huang F, Shi X, Cabri P. Efficacy and Safety of Triptorelin 3-Month Formulation in Chinese Children with Central Precocious Puberty: A Phase 3, Open-Label, Single-Arm Study. Adv Ther. 2023 Oct;40(10):4574-4588. doi: 10.1007/s12325-023-02617-8. Epub 2023 Aug 16. PMID 37584898
• Bangalore Krishna K, Fuqua JS, Rogol AD, Klein KO, Popovic J, Houk CP, Charmandari E, Lee PA, Freire AV, Ropelato MG, Yazid Jalaludin M, Mbogo J, Kanaka-Gantenbein C, Luo X, Eugster EA, Klein KO, Vogiatzi MG, Reifschneider K, Bamba V, Garcia Rudaz C, Kaplowitz P, Backeljauw P, Allen DB, Palmert MR, Harrington J, Guerra-Junior G, Stanley T, Torres Tamayo M, Miranda Lora AL, Bajpai A, Silverman LA, PMID 31319416
• Durand A, Tauber M, Patel B, Dutailly P. Meta-Analysis of Paediatric Patients with Central Precocious Puberty Treated with Intramuscular Triptorelin 11.25 mg 3-Month Prolonged-Release Formulation . Horm Res Paediatr. 2017;87(4):224-232. doi: 10.1159/000456545. Epub 2017 Mar 23. PMID 28334719
• Chung LY, Kang E, Nam HK, Rhie YJ, Lee KH. Efficacy of Triptorelin 3-Month Depot Compared to 1-Month Depot for the Treatment of Korean Girls with Central Precocious Puberty in Single Tertiary Center. J Korean Med Sci. 2021 Aug 30;36(34):e219. doi: 10.3346/jkms.2021.36.e219. PMID 34463062
• Carel JC, Blumberg J, Seymour C, Adamsbaum C, Lahlou N; Triptorelin 3-month CPP Study Group. Three-month sustained-release triptorelin (11.25 mg) in the treatment of central precocious puberty. Eur J Endocrinol. 2006 Jan;154(1):119-24. doi: 10.1530/eje.1.02056. PMID 16382000
• Huang S, Zhang L, Gao C, Ou H, Hou L, Liu Z, Wang D, Xu Y, Liang L, Meng Z. Efficacy and safety of leuprorelin 3-month depot (11.25 mg) for idiopathic central precocious puberty treatment of Chinese girls: a single-center retrospective study. J Pediatr Endocrinol Metab. 2023 Nov 20;37(1):15-20. doi: 10.1515/jpem-2023-0410. Print 2024 Jan 29. PMID 37975727

Identifiers

NCT: NCT06487143 · 3-month TP vs 1-month TP

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗