Efficacy and Safety of Leuprolide Acetate 6-Month Depot for the Treatment of Central Precocious Puberty: A Phase 3 Study

Abstract

Context: Treatment options for central precocious puberty (CPP) are important for individualization of therapy.

Objective: We evaluated the efficacy and safety of 6-month 45-mg leuprolide acetate (LA) depot with intramuscular administration.

Methods: LA depot was administered at weeks 0 and 24 to treatment-naïve (n = 27) or previously treated (n = 18) children with CPP in a phase 3, multicenter, single-arm, open-label study (NCT03695237). Week 24 peak-stimulated luteinizing hormone (LH) suppression (<4 mIU/mL) was the primary outcome. Secondary/other outcomes included basal sex hormone suppression (girls, estradiol <20 pg/mL; boys, testosterone <30 ng/dL), suppression of physical signs, height velocity, bone age, patient/parent-reported outcomes, and adverse events.

Results: All patients (age, 7.8 ± 1.27 years) received both scheduled study doses. At 24 weeks, 39/45 patients (86.7%) had LH suppressed. Six were counted as unsuppressed; 2 because of missing data, 3 with LH of 4.35-5.30 mIU/mL and 1 with LH of 21.07 mIU/mL. Through 48 weeks, LH, estradiol, and testosterone suppression was achieved in ≥86.7%, ≥97.4%, and 100%, respectively (as early as week 4 for LH and estradiol and week 12 for testosterone). Physical signs were suppressed at week 48 (girls, 90.2%; boys, 75.0%). Mean height velocity ranged 5.0 to 5.3 cm/year post-baseline in previously treated patients and declined from 10.1 to 6.5 cm/year at week 20 in treatment-naïve patients. Mean bone age advanced slower than chronological age. Patient/parent-reported outcomes remained stable. No new safety signals were identified. No adverse event led to treatment discontinuation.

Conclusion: Six-month intramuscular LA depot demonstrated 48-week efficacy with a safety profile consistent with other GnRH agonist formulations.

Keywords: central precocious puberty; gonadotropin-releasing hormone agonist; intramuscular depot; leuprolide acetate.

Figure 1.

Study design and key part 1 assessments. Week 0 indicates baseline assessment before the first dose (ie, day 1 of treatment). Baseline stimulation test, BA radiograph, and pubertal staging were conducted during the screening period. Hormonal flare was evaluated via questionnaire on the day of, 48 hours after, and 7 days after treatment administration. AOC biochemical response assessments were performed 1 week after the first dose (week 0) and 48 hours after the second dose (week 24). *The dose at week 48 marked the first dose in Part 2 of the study and was administered after the indicated Part 1 assessments. Abbreviations: AOC, acute-on-chronic; BA, bone age; E2, estradiol; FSH, follicle-stimulating hormone; IM, intramuscular; LA, leuprolide acetate; LH, luteinizing hormone; PedsQL, Pediatric Quality of Life Inventory; PROMIS, Patient Reported Outcomes Measurement Information System; q24w, every 24 weeks; T, testosterone.

Figure 2.

Suppression* of peak-stimulated LH (A) and mean concentrations^† of peak-stimulated LH (B) and basal LH (C) in previously treated (black) and treatment-naïve (gray) patients. Week 0 indicates baseline assessment prior to the first dose (ie, day 1 of treatment). *Error bars are lower 95% CIs. ^†Error bars are ± SEM.

Figure 3.

Suppression* (A) and mean concentration^† (B) of basal estradiol in previously treated (black) and treatment-naïve (gray) patients. Week 0 indicates baseline assessment prior to the first dose (ie, day 1 of treatment). *Error bars are lower 95% CIs. ^†Error bars are ± SEM.

Figure 4.

Mean height velocity (A) and BA/CA (B) in previously treated (black) and treatment-naïve (gray) patients. Week 0 indicates baseline assessment prior to the first dose (ie, day 1 of treatment). Error bars are ± SEM. BA/CA, bone age/chronological age ratio; HV, height velocity.