A Study to Assess the Efficacy and Safety of the Triptorelin 6-month Formulation in Paediatric Participants With Central Precocious Puberty.

• Triptorelin Pamoate (Drug): Triptorelin 6-month formulation for IM on day 1 and Month 6.

Primary outcomes

• Percentage of Participants With Luteinising Hormone (LH) Suppression [At Month 6]: LH response was defined as a peak LH <=5 international units per liter (IU/L) after intravenous (IV) gonadotropin-releasing hormone (GnRH) stimulation. The GnRH stimulation test was performed by using an IV injection of gonadorelin (synthetic GnRH) to stimulate gonadotrophin release and blood samples were collected after the gonadorelin injection for central assessment of serum LH levels. Percentage of response was calculated by number of participants in the specified category divided by number of participants in the analysis population multiplied by 100.

Secondary outcomes

• Percentage of Participants With LH Response to GnRH Test [At Months 3 and 12]: LH response was defined as a peak LH <=5 IU/L after IV GnRH stimulation. The GnRH stimulation test was performed by using an IV injection of gonadorelin (synthetic GnRH) to stimulate gonadotrophin release and blood samples were collected after the gonadorelin injection for central assessment of serum LH levels. Percentage of response was calculated by number of participants in the specified category divided by number of participants in the analysis population multiplied by 100.
• Change From Baseline in Basal Serum LH and Follicle-Stimulating Hormone (FSH) Levels [Baseline and at Months 3, 6, 9 and 12]: Basal LH and FSH serum concentrations were analyzed centrally. Change from baseline was defined as the values for LH and FSH at indicated timepoints minus the value at baseline. Baseline was defined as the last non-missing measurement taken prior to the first study treatment administered.
• Change From Baseline in Peak Serum LH and FSH Level After the GnRH Stimulation Test [Baseline and at Months 3, 6 and 12]: Peak LH and FSH serum concentrations were analyzed centrally. Change from baseline was defined as the values for LH and FSH at indicated timepoints minus the value at baseline. Baseline was defined as the last non-missing measurement taken prior to the first study treatment administered. Blood samples were collected prior to gonadorelin injection (timepoint T0) and at 30 minutes (T30), 60 minutes (T60) and 90 minutes (T90) after a single IV injection of gonadorelin. A suppressed LH response to GnRH stimulation test was defined as peak serum LH <=5 IU/L among the four timepoints (T0, T30, T60 and T90). The FSH response to GnRH stimulation was the peak serum FSH level among the four timepoints (T0, T30, T60 and T90).
• Percentage of Participants With LH Response (Peak LH <=5 IU/L) From Month 6 to Month 12 [Month 6 to Month 12]: Peak LH serum concentration was analyzed centrally. LH response was defined as a peak LH <=5 IU/L after IV GnRH stimulation. The GnRH stimulation test was performed by using an IV injection of gonadorelin (synthetic GnRH) to stimulate gonadotrophin release and blood samples were collected after the gonadorelin injection for central assessment of peak LH levels. Percentage of response was calculated by number of participants in the specified category divided by number of participants in the analysis population multiplied by 100.
• Percentage of Participants With Prepubertal Levels of Sex Steroids [At Months 3, 6, 9 and 12]: Prepubertal sex steroids assessment included estradiol in female participants and testosterone in male participants. Prepubertal sex steroids levels were defined as: estradiol <=20 picogram (pg)/ milliliter (mL) in female participants and testosterone <=30 nanogram (ng)/ deciliter (dL) in male participants. Percentage of response was calculated by number of participants in the specified category divided by number of participants in the analysis population multiplied by 100.
• Change From Baseline in Mean Height for Age (Z-Score) [Baseline and at Months 6 and 12]: Z-scores are calculated using Centers for Disease Control and Prevention (CDC) Growth Charts. Change from baseline was defined as the values for Z-score at indicated timepoints minus the value at baseline. Baseline was defined as the last non-missing measurement taken prior to study treatment administration. Negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean.
• Change From Baseline in Percentile for Height for Age [Baseline and at Months 6 and 12]: Z-scores were calculated using CDC growth charts, that contained Box-Cox transformation (L), the median (M) and the generalized coefficient of variation (S). Percentile was obtained using the following equation M (1 + LSZ) ** (1/L), where ** indicated an exponent, such that m (1+LSZ)** (1/L) meant raising (1+LSZ) to the (1/L)th power and then multiplying the M. Z was the Z-score that corresponds to the percentile. Negative Z-score indicates values lower than the mean while a positive Z-score indicates values higher than the mean. Change from baseline was defined as the values for percentile of Z-score at indicated timepoints minus the value at baseline. Baseline was defined as the last non-missing measurement taken prior to the first study treatment administered.
• Change From Baseline in Growth Velocity [Baseline and at Months 6 and 12]: Growth velocity analysis was part of auxological parameter. Change from baseline was defined as the value for each auxological parameter at indicated timepoints minus the value at baseline. Baseline was defined as the last non-missing measurement taken prior to the first study treatment administered.
• Percentage of Participants With Bone Age (BA)/Chronological Age (CA) Ratio Not Risen [At Months 6 and 12]: BA was determined using X-rays of the hand and wrist by Greulich and Pyle method. CA was calculated as (visit date -birth date + 1)/365.25. Percentage of response was calculated as n/N*100, where n was number of participants in the specified category and N was number of participants in the analysis population.
• Change From Baseline in BA:CA Ratio [Baseline, Months 6 and 12]: BA was determined using X-rays of the hand and wrist by Greulich and Pyle method. CA was calculated as (visit date -birth date + 1)/365.25. Change from baseline was defined as the values for BA:CA ratio at indicated timepoints minus the value at baseline. Baseline was defined as the last non-missing measurement taken prior to the first study treatment administered.
• Percentage of Participants With Stabilized Pubertal Stage [At Months 6 and 12]: Pubertal stage parameters were analyzed using Tanner method. Pubertal stage parameters included genital development stage (GDS) in male participants, breast development stage (BDS) in female participants and pubic hair development (PHD) stage in both sexes. Percentage of response was calculated by number of participants in the specified category divided by number of participants in the analysis population multiplied by 100.
• Percentage of Participants With Regression of Uterine Length [At Months 6 and 12]: Uterine length was determined by transabdominal ultrasound. Percentage of response was calculated by number of participants in the specified category divided by number of participants in the analysis population multiplied by 100.
• Percentage of Participants With Absence of Progression of Testis Volumes [At Months 6 and 12]: Testis volume was a clinical assessment with orchidometer. Percentage of response was calculated by number of participants in the specified category divided by number of participants in the analysis population multiplied by 100.
• Change From Baseline in Body Mass Index (BMI) [Baseline and at Months 6 and 12]: BMI analysis was part of auxological parameter assessment. Change from baseline was defined as the value for each auxological parameter at indicated timepoints minus the value at baseline. Baseline was defined as the last non-missing measurement taken prior to the first study treatment administered.
• Change From Baseline in Weight [Baseline and at Months 6 and 12]: Weight analysis was part of auxological parameter assessment. Change from baseline was defined as the value for each auxological parameter at indicated timepoints minus the value at baseline. Baseline was defined as the last non-missing measurement taken prior to the first study treatment administered.
• Plasma Concentrations of Triptorelin [Day 1, 4 hours post-injection; Month 3; Month 6, predose; Month 6, 4 hours post-injection; and Month 12]: Blood samples were collected at specified timepoints.

Sex: All, ages: any to 10 Years

Inclusion Criteria:

* Participant is less than 9 years old for girls and less than 10 years old for boys at initiation of triptorelin treatment or at the time of signing the informed consent.
* Participant must present evidence of CPP documented by:
* Onset of development of secondary sex characteristics (breast development in girls or testicular enlargement in boys according to the Tanner method: Stage II) before the age of 8 years in girls and 9 years in boys.
* Pubertal response of LH to GnRH stimulation test (stimulated peak LH ≥6 IU/L) in both sexes.
* Difference between bone age (BA) and CA >1 year.
* Girls with Tanner staging ≥2 for breast development and who have enlarged uterine length and/or ovarian volume and at last 2 follicles with diameter >4 mm in the ovary observed by pelvic type B ultrasound at the Screening visit; boys who have testicular volume ≥4 mL observed by testicular orchidometer at the Screening visit.
* Girls who have already had menophania/menarche must have a negative highly sensitive (urine) pregnancy test as required by local regulations within 24 hours before the first dose of study intervention and should not be at risk of pregnancy throughout the study period.

Exclusion Criteria:

* Gonadotropin-independent (peripheral) precocious puberty: extrapituitary secretion of gonadotropins or gonadotropin-independent gonadal or adrenal sex steroid secretion.
* Non-progressing isolated premature thelarche.
* Presence of an unstable intracranial tumour or an intracranial tumour requiring neurosurgery or cerebral irradiation. Participants with hamartomas not requiring surgery are eligible.
* Prior or current therapy with a GnRHa (Gonadotropin-releasing Hormone Agonist) , medroxyprogesterone acetate, growth hormone or insulin-like growth factor 1 (IGF 1).Use of anticoagulants (heparin and coumarin derivatives) within the 2 weeks prior to the Screening visit.

Participant flow

Outcome results

• Percentage of Participants With Luteinising Hormone (LH) Suppression (Primary), Number, percentage of participants: All Participants 100 (94.6 to 100.0)
• Percentage of Participants With LH Response to GnRH Test (Secondary), Number, percentage of participants: All Participants 97.0 (89.5 to 99.6)
• Change From Baseline in Basal Serum LH and Follicle-Stimulating Hormone (FSH) Levels (Secondary), Mean, IU/L: All Participants -1.6420 +/- 2.4287
• Change From Baseline in Peak Serum LH and FSH Level After the GnRH Stimulation Test (Secondary), Mean, IU/L: All Participants -26.0075 +/- 19.8863
• Percentage of Participants With LH Response (Peak LH <=5 IU/L) From Month 6 to Month 12 (Secondary), Number, percentage of participants: All Participants 98.5 (91.8 to 100.0)
• Percentage of Participants With Prepubertal Levels of Sex Steroids (Secondary), Number, percentage of participants: All Participants 97.0 (89.5 to 99.6)
• Change From Baseline in Mean Height for Age (Z-Score) (Secondary), Mean, Z-score: All Participants 0.0734 +/- 0.1433
• Change From Baseline in Percentile for Height for Age (Secondary), Mean, percentiles of Z-score: All Participants 1.4675 +/- 2.8638
• Change From Baseline in Growth Velocity (Secondary), Mean, centimeter (cm)/year: All Participants -3.938 +/- 6.075
• Percentage of Participants With Bone Age (BA)/Chronological Age (CA) Ratio Not Risen (Secondary), Number, percentage of participants: All Participants 95.5 (87.3 to 99.1)
• Change From Baseline in BA:CA Ratio (Secondary), Mean, ratio: All Participants -0.04 +/- 0.06
• Percentage of Participants With Stabilized Pubertal Stage (Secondary), Number, percentage of participants: All Participants 98.4 (91.3 to 100.0)
• Percentage of Participants With Regression of Uterine Length (Secondary), Number, percentage of participants: All Participants 64.5 (51.3 to 76.3)
• Percentage of Participants With Absence of Progression of Testis Volumes (Secondary), Number, percentage of participants: All Participants 75.0 (19.4 to 99.4)
• Change From Baseline in Body Mass Index (BMI) (Secondary), Mean, kilogram (kg)/meter square: All Participants 0.282 +/- 0.882
• Change From Baseline in Weight (Secondary), Mean, kg: All Participants 2.020 +/- 1.927
• Plasma Concentrations of Triptorelin (Secondary), Geometric mean, ng/mL: All Participants 41.8 +/- 56.9

Adverse events

Time frame: Treatment-emergent adverse events were reported from the first dose of study treatment (Day 1) up to a maximum of approximately 344 days.

Other adverse events by term

• Results publication: Yu X, Cheng X, Wei H, Xu X, Gong C, Li G, Yao H, Zhou L, Zhong Y, Yang Y, Luo F, Zhang Y, Huang F, Shi X, Cabri P, Luo X. A Phase 3, Open-Label, Single-Arm Trial of the Efficacy and Safety of Triptorelin 6-Month Formulation in Chinese Children with Central Precocious Puberty. Adv Ther. 2024 Dec;41(12):4537-4556. doi: 10.1007/s12325-024-02991-x. Epub 2024 Oct 16. PMID 39412628

• Study Protocol (PDF, 2022-04-29)
• Statistical Analysis Plan (PDF, 2023-04-19)

• Ipsen Medical Director, Study director, Ipsen