Table 2.
Biochemical and clinical pubertal suppression from pivotal trials of CPP therapies (approved in US).
| LUPRON DEPOT PED (22–24) | TRIPTODUR (26) | FENSOLVI (27) | SUPPRELIN (28) | |||
|---|---|---|---|---|---|---|
| Duration of action (months) | 1 | 3 (11.25 mg) |
3 (30 mg) |
6 | 6 | 12 |
| LH suppression* | ||||||
| Primary outcome: % below peak-stimulated LH threshold (% of patients) | LH <1.75 IU/L: 91a |
LH <4 IU/L: 78b |
LH <4 IU/L: 95b |
LH ≤ 5 IU/L: 93c |
LH <4 IU/L: 87a |
LH <4 IU/L: 100d |
| Mean peak-stimulated LH (IU/L) | 0.8a | ≤ 2.5e | ≤ 2.5e | 2.0–4.2d | 3.0a | 0.8f |
| Mean random LH (IU/L) | NR | NR | NR | 0.4–0.7d | 0.6a | 0.4f |
| GnRH receptor stimulating agent | Factrel 100 mcg IV | SQ leuprolide acetate 20 mcg/kg | SQ leuprolide acetate 20 mcg/kg | SQ leuprolide acetate 20 mcg/kg | SQ leuprolide acetate 20 mcg/kg or 500 mcg aqueous leuprolide acetate | Leuprolide acetate 20 mcg/kg IV |
| IU version | 1 | 4 | 4 | 5 | 5 | ND |
| LH assay | DELFIATM assay | Immuno-chemiluminometric assay | Immuno-chemiluminometric assay | Fluoro-immunometric assays with auto DELFIATM TRFIA reagents | ECLIA assay | Immuno-chemiluminescent assay |
| Assay LLOD (IU/L) | 0.15 | 0.02 | 0.02 | 0.01 | 0.10 | 0.02 |
| Estradiol (E2) suppression** | ||||||
| Prepubertal E2 definition (pg/mL) | NR | <20 | <20 | <20 | <20 | <20 |
| Mean E2 (pg/mL) | 5.0g | 1.8h | 2.8h | NR | 10.6i | 5.6j |
| E2 <20 pg/mL (% patients) | 99.2k | 100l | 100l | 79.5–92.3d | 97i | 79m |
| E2 <10 pg/mL (% patients) | 99.2k | NR | NR | NR | 98n | 79m |
| Proportion not achieving E2 <20 pg/mL % (n) | NR | 0% (0 of 39)l |
0% (0 of 37)l |
7.7–20.5% (3–8 of 39)d |
3% (2 of 60)i |
21%o |
| E2 assay | Radio- immunoassay | HPLC with tandem mass spectrometry | HPLC with tandem mass spectrometry | Radio-immunoassay | LC-MS/MS | Radio-immunoassay and LC-MS/MS |
| E2 Assay LLOD (pg/mL) | 5.0 | 1.0 | 1.0 | 0.9 | 10.0 | 5.0 |
| Testosterone (T) suppression | ||||||
| Prepubertal T definition (ng/dL) | <10 | <30 | <30 | <30 | <28.4 | <30 |
| Mean T (ng/dL) | 17.8p | 11.5h | 14.4h | NR | 15.9a | NR |
| T <30 ng/dL (% Patients) | NR | 67l | 100l | 80–100d | 50–100d | 100d |
| Proportion not achieving T <30 ng/dL % (n) | NR | 33% (1 of 3)l |
0% (0 of 5)l |
0–20% (0–1 of 5)d |
0–50% (0–1 of 2)d |
0% (0 of 3)d |
| T assay | Radio -immunoassay | HPLC with tandem mass spectrometry | HPLC with tandem mass spectrometry | LC-MS/MS | Chemi -luminescent microparticle immunoassay | Radio -immunoassay |
| T Assay LLOD (ng/dL) | 10.0 | 3.0 | 3.0 | 1.4 | 11.5 | 3.0 |
| Number of boys | 6 | 3 | 5 | 5 | 2 | 3 |
| Clinical pubertal suppression | ||||||
| Baseline BA/CA | 1.5 | NR | NR | 1.4 | NR | 1.4 |
| BA/CA | 0.7q | NR | NR | 1.3r | NR | 1.2s |
| Growth (cm/yr) | 5.0–6.0t | 5.9u | 6.7u | 6.8v | 6.0w | NR |
| Pubertal staging | Stabilized or regressedx | Stabilized or regressedy | Stabilized or regressedz | Stabilized or regressedaa | Stabilized or regressedab | Minimal maturationac |
Suppression of luteinizing hormone to prepubertal concentrations is the primary efficacy endpoint for CPP therapies. These data are similar across CPP therapies. Ninety-seven percentage or more girls achieved E2 suppression to prepubertal levels (<20 pg/mL) in pivotal trials for IM LA, SQ LA, and SQ histrelin implant. In pivotal trials that reported mean T data, all boys achieved suppression to prepubertal levels (<30 ng/dL). Stabilization or regression of pubertal progression was observed in all pivotal trials.
CPP, Central Precocious Puberty; LH, Luteinizing hormone; NR, Not reported; ND, Not determined; IU, International unit; IU Version, which reference preparation the definition of “1 IU” was based on, as the WHO regularly updates the definition when the reference preparation is depleted; LLOD, Lower limit of detection; ECLIA, Electrochemiluminescence immunoassay; E2, Estradiol; HPLC, High-Performance liquid chromatography; LC-MS/MS, Liquid chromatography with tandem mass spectrometry; T, Testosterone.
aAt week 24; bMonth 2–6; cAt month 6; dMonth 1–12; ePreviously treated children, at all timepoints; fMonth 1–48; gAll patients, at week 4, E2 <18.36 pmol/L; hTreatment-naïve, at month 6; iAll patients, at Week 24; jAll patients, at month 60; kAll timepoints post-baseline; lAt month 1; mFrom Month 1 through Month 72; nAt month 48; oNot reported for all of these n number (E2 ≤ 5 pg/mL); pAll patients, at week 4; qAfter the first year of treatment; rAt Month 12; sTreatment-naïve, at month 48; tAll patients, during the first 72 weeks; uTreatment-naïve, within 6 months of treatment; vAll patients, at month 6; wAll patients, at week 48; xBreast Tanner stage stabilized or regressed in 81.8% of females at week 4; yBreast development stabilized or regressed in 91% of girls at month 6; zBreast development stabilized or regressed in 82% of girls at month 6; aaTanner stage stable or reduced in 90.9%/88.6% of patients between baseline and month 6/12; abClinical signs of puberty stabilized or regressed in almost all girls (55/57) at week 48; acTanner breast stage at month 60 is similar to baseline in treatment-naive female patients but lower in previously treated female patients.
It should be noted that International Units (IU) used to express serum concentrations of LH are calibrated based on guidance from the WHO Expert Committee on Biological Standardization. This committee provides a reference preparation of LH, sets the number of IUs contained in that preparation, and specifies a procedure to compare other preparations of the same agent to this preparation. When the supply of reference preparation is depleted, a new version is prepared, sent out, and assays are revalidated. The first LH international standard was issued in 1988, and there have been four subsequent updates. For example, 1 IU of LH was ~0.2 μg LH in version 3 and ~0.3 μg LH in version 5 (29, 30). Therefore, the variability of the definition of one IU over time makes comparisons of results across clinical trials difficult and likely invalid, as efficacy endpoints derived from the use of older versions would need to be validated or recalibrated to match newer versions (29, 30).
Assay type and lower limit of detection (LLOD) are listed for each trial, but efficacy data are limited by the sensitivity of the assays. For example, Klein et al. found that E2 levels were considerably lower when measured by a research ultra-sensitive bioassay (LLOD = 0.02 pg/mL) in comparison to a radioimmunoassay (31), indicating that ultra-sensitive assays should be used to monitor treatment efficacy in children with CPP. The most sensitive commercially available E2 assays to date are LC-MS/MS.