Long-Term Continuous Suppression With Once-Yearly Histrelin Subcutaneous Implants for the Treatment of Central Precocious Puberty: A Final Report of a Phase 3 Multicenter Trial

Abstract

Context and objective: The histrelin implant has proven to be an effective method of delivering GnRH analog (GnRHa) therapy to children with central precocious puberty (CPP), yet there are limited data available regarding hormonal suppression and auxological changes during an extended course of therapy.

Design: This was a phase 3, prospective, open-label study.

Setting and participants: Thirty-six children with CPP who participated in a phase 3, open-label study and required further GnRHa therapy were eligible to continue treatment receiving a new implant upon removal of the prior 12-month histrelin implant during a long-term extension phase.

Outcome measures: Hormone levels and auxologic parameters were measured periodically for up to 6 years of treatment and up to 1 year of posttreatment follow-up.

Results: Hormonal suppression was maintained throughout the study in patients who had prior GnRHa therapy (n = 16) and in treatment-naive patients (n = 20). Bone age to chronological age ratio decreased from 1.417 (n = 20) at baseline to 1.18 (n = 8) at 48 months in treatment-naive children (P < .01). Predicted adult height in girls increased from 151.9 cm at baseline to 166.5 cm at month 60 (n = 6; P < .05), with a 10.7-cm height gain observed among treatment-naive children (n = 5). No adverse effect on growth or recovery of the hypothalamic-pituitary-gonadal axis was observed with hormonal suppression. The histrelin implant was generally well tolerated during long-term therapy.

Conclusions: Long-term histrelin implant therapy provided sustained gonadotropin suppression safely and effectively and improved predicted adult height in children with CPP.

Trial registration: ClinicalTrials.gov NCT00779103.

Figures

Figure 1.

Patient disposition throughout the extension treatment phases and posttreatment follow-up phase of the trial. Only patients for whom continued therapy was considered clinically appropriate entered each stage subsequent to the initial treatment phase. Most patients who discontinued after entering a subsequent stage did so because of age appropriateness for entry into puberty or parental decision. One patient did not continue due to weight gain, one patient died, and one patient was lost to follow-up due to study site closing.

Figure 2.

Peak stimulated serum LH and FSH levels. LH (A) and FSH (B) levels are mean ± SD. Dashed line represents predetermined pubertal response for peak LH (4 mIU/mL) or peak FSH (2.5 mIU/mL) levels. Patients' hormone levels had to be below this level to be considered suppressed. Histrelin treatment period (treatment) as well as posttreatment follow-up (6-month follow-up) is indicated. Pretreated and naive patients, as well as the two groups combined, are indicated. *, P ≤ .0001; †, P < .001; ‡, P < .01; §, P < .05 combined patient group vs baseline.

Figure 3.

Serum estradiol in girls. Data are mean ± SD. Dashed line represents predetermined suppression levels of 73.42 pmol/L. Patients' hormone levels had to be below these to be considered suppressed. Histrelin treatment period (treatment) as well as posttreatment follow-up (6- and 12-month follow-up) is indicated. Pretreated and naive patients, as well as the two groups combined, are indicated. Dotted lines represent the lower level of quantification (18.36 pmol/L) of the RIA. *, P < .01, combined patient group vs baseline.

Figure 4.

Bone age minus chronological age, bone age to chronological age ratio, and predicted adult height. A, Bone age minus chronological age measurements, and B, Bone age to chronological age ratio measurements. Data are mean ± SD. Pretreated patients, treatment-naive patients, and the two groups combined are indicated. *, P ≤ .0001; †, P < .001; ‡, P < .01; §, P < .05 vs baseline. Baseline bone age was missing for one patient. C, Predicted adult height for girls only. Data are mean ± SD. Histrelin treatment period (treatment) as well as posttreatment follow-up (6 months' follow-up) is indicated. Pretreated patients, treatment-naive patients, and the two groups combined are indicated. *, P < .001; ‡, P < .02; §, P < .05 combined patient group vs baseline. Baseline bone age was missing for one patient.

Figure 5.

A, Growth velocity SDSs from baseline up to 5 years. *, P ≤ .0001; ‡, P < .01; §, P < .05 vs baseline. Growth velocity SDSs were based on the Growth Calculator, version 2.01, from Children's Hospital in Boston. B and C, Mean height and BMI SDSs in the combined population adjusted for bone age (B) or chronological age (C). *, P ≤ .01; ‡, P < .02; §, P < .05 vs baseline.