Phase 3 Trial of a Small-volume Subcutaneous 6-Month Duration Leuprolide Acetate Treatment for Central Precocious Puberty

Abstract

Context: Gonadotropin-releasing hormone agonists (GnRHas) are standard of care for central precocious puberty (CPP). A 6-month subcutaneous injection has recently been approved by the Food and Drug Administration.

Objective: Determine efficacy, pharmacokinetics, and safety of 6-month 45-mg subcutaneous leuprolide acetate for CPP.

Design: Phase 3 multicenter, open-label, single-arm study.

Setting: 25 sites in 6 countries.

Subjects: 64 GnRHa-naïve children with CPP (age: 7.5 ± 0.1 years) received study drug: 59 completed the study.

Intervention(s): 2 doses of 45-mg subcutaneous leuprolide acetate (0.375 mL) at 0 and 24 weeks; children were followed for 48 weeks.

Main outcome measure(s): Percentage of children with serum luteinizing hormone (LH) <4 IU/L 30 minutes following GnRHa stimulation at week 24.

Results: 54/62 (87%) children achieved poststimulation LH <4 IU/L at week 24; 49/56 (88%) girls and 1/2 boys maintained peak LH <4 IU/L at week 48. Mean growth velocity decreased from 8.9 cm/year at week 4 to 6.0 cm/year at week 48. Mean bone age was advanced 3.0 years beyond chronological age at screening and 2.7 years at week 48. Breast pubertal stage regressed or was stable in 97% of girls and external genitalia development regressed in both boys. Adverse events were mild and did not cause treatment discontinuation.

Conclusions: A small volume of 45-mg subcutaneous leuprolide acetate administered at a 6-month interval effectively suppressed pubertal hormones and stopped or caused regression of pubertal progression. This long-acting GnRHa preparation of leuprolide acetate is a new, effective, and well-tolerated therapy for children with CPP.

Trial registration: ClinicalTrials.gov NCT02452931.

Keywords: central precocious puberty; gonadotropin releasing hormone agonists; leuprolide acetate.

Figure 1.

Study recruitment. ¹Up to 28 days of screening. ²Other conditions, chronic illnesses or treatments that, in the opinion of the investigator, may have interfered with growth or other study endpoints. ³Removed from study on day 169 after having been found to have a history of seizure (exclusion criteria #14). ⁴Completed treatment and was included in the safety population, but was removed from the efficacy analyses due to ineligibility for study (inclusion criteria #6: bone age was less than 1 year greater than chronological age at screening). ⁵Changes in child’s condition that, in the judgment of the investigator, rendered the child unacceptable for further treatment with the study drug. ⁶Post-GnRHa stimulation test LH was 48.1 IU/L at week 14 when discontinued treatment.

Figure 2.

(A) Mean (±SE) peak LH level and proportion of children who achieved peak LH < 4 IU/L (ITT population). (B) Mean (±SE) random LH (IU/L) (ITT population). ¹Screening random (pre-GnRHa stimulation test) LH data.

Figure 3.

Mean (±SE) growth velocity over time (ITT population). ¹Baseline defined as the last nonmissing assessment done prior to or on the date of first injection.

Figure 4.

Mean (±SE) serum concentration of leuprolide over 48 weeks (ITT population).