Central Precocious Puberty
Conditions
Keywords
puberty, precocious puberty, early puberty, early onset puberty, histrelin, histrelin subcutaneous implant, implant therapy
Brief summary
The purpose of this study is to follow and collect additional medical and developmental information on children after histrelin subcutaneous implant therapy is discontinued.
Detailed description
Thirty-two (32) patients will receive a histrelin subdermal implant under the anesthesia deemed appropriate by the administering physician. Ten-twelve (10-12) sites will enroll 2-3 patients per site. It is anticipated that half the patients will be receiving GnRH analog treatment and the other half will be treatment naïve. All patients will undergo selective PK sampling post-implantation to assess histrelin profile. At 12 months, provided that the patient continues to meet the safety and efficacy parameters, the original implant will be removed and the patient can receive a new implant. At 13 months, patients who receive new implants will be evaluated at the study site and administratively transferred to the initial extension study. At Month 24), the implants inserted at Month 12 will be removed. At this time, patients who have completed the initial extension study and who wish to continue therapy with the histrelin implant will be eligible to receive a new (ie, third) implant and to enter an additional 12-month extended access phase at the discretion of the investigator. At Month 36, the implants inserted at Month 24 for the Extended Access Phase will be removed. At this time, patients who have completed the Extended Access Phase and who wish to continue therapy with the histrelin implant will be eligible to receive a new (ie, fourth) implant and to enter the Long Term Extended Access Phase (referred to as the Implant Treatment Phase) at the discretion of the investigator. The purpose of this phase is to provide patients with the opportunity to continue to receive a new implant at the end of each 12-month period until the patient no longer requires hormone suppression. Once implant therapy is discontinued, all patients are eligible to enter the Long Term Follow Up Phase (Post Implant Phase) of the study.
Interventions
DRUGHistrelin Subcutaneous Implant
histrelin subcutaneous 50 mg implant
Sponsors
Endo Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 10 Years
Healthy volunteers
No
Inclusion criteria
* Pre-treated or treatment naive patients with gonadotropin-dependent precocious puberty * Pre-treatment pubertal type response of LH to a stndard GnRH stimulation test before initiation of treatment
Exclusion criteria
* Children who are less than 2 years of age at enrollment * Children whose chronological age is greater than 8 years (naive) and 10 years (pre-treated) for girls or 9 years (naive) and 11 years (pre-treated) for boys at the onset of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Luteinizing Hormone (LH) | Baseline - 6 Months Post Last Implant | The suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment.(LH suppression is defined as a peak LH \< 4 mIU/mL following stimulation with the GnRH analog). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Testosterone | Baseline - 12 Months Post Last Implant | Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Testosterone suppression is defined as serum testosterone \< 30.0 ng/dL (0.8 nmol/L) in boys following the induction of suppression. One black female participant age 8.9 years old had a testosterone value of 11ng/dL at visit 4 (month 6). |
| DHEA Sulfate | Baseline - 36 Months Post Last Implant | DHEA=Dehydroepiandrosterone |
| Estradiol (MS) | Month 36 - 36 Months Post Last Implant | Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Estradiol suppression is defined as serum estradiol in the assay specific range \< 20 pg/mL (73 pmol/L) in girls following the induction of suppression. |
| Follicle Stimulating Hormone (FSH) | Baseline - 6 Month Post Last Implant | The suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment.(LH suppression is defined as a peak LH \< 4 mIU/mL following stimulation with the GnRH analog). |
| Average Number of Implants Received | 12 months | There were 2 implants received that were not removed during the study and were excluded from this analysis due to unknown duration of treatment. |
| Average Mean Implant Duration by Subject | 12 Months | There were 2 implants received that were not removed during the study and were excluded from this analysis due to unknown duration of treatment. |
| Summary of EN3326 Implantation and Explantations | Day 1 - Month 60 | Once the female participants reached 11 years of age and the male participants reached 12 years of age or the investigator determined that subjects no longer required hormone suppression, participants underwent final explantation and were eligible to continue into an optional Long Term Follow Up Phase (Post Implant Treatment Phase) for up to 5 years. The purpose of the optional Long Term Follow Up Phase was to collect additional medical and developmental information, such as onset of menses and final adult height after hormone suppression was discontinued. |
| Estradiol (RIA) | Baseline - Month 24 | Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Estradiol suppression is defined as serum estradiol in the assay specific range \< 20 pg/mL (73 pmol/L) in girls following the induction of suppression. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Histrelin Subcutaneous Implant (50 mg) Subcutaneous implant designed to deliver histrelin continously for 12 months.
Histrelin Subcutaneous Implant: histrelin subcutaneous 50 mg implant
Extension Safety Population (Second & Third Implant) | 31 |
| Total | 31 |
Baseline characteristics
| Characteristic | Histrelin Subcutaneous Implant (50 mg) |
|---|---|
| Age, Continuous | 7.7 years STANDARD_DEVIATION 1.54 |
| Body Mass Index (BMI) | 20.66 kg/m^2 STANDARD_DEVIATION 3.541 |
| Height | 134.18 cm STANDARD_DEVIATION 12.947 |
| Pretreatment with Prior GnRH Therapy Naïve | 18 Participants |
| Pretreatment with Prior GnRH Therapy Pretreated | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 2 Participants |
| Weight | 38.12 kg STANDARD_DEVIATION 11.835 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 31 |
| other Total, other adverse events | 31 / 31 |
| serious Total, serious adverse events | 3 / 31 |
Outcome results
Primary
Luteinizing Hormone (LH)
The suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment.(LH suppression is defined as a peak LH \< 4 mIU/mL following stimulation with the GnRH analog).
Time frame: Baseline - 6 Months Post Last Implant
Population: Extension Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Observed Value | Luteinizing Hormone (LH) | Month 36, Visit 13 | 0.19 MIU/ML | Standard Deviation 0.126 |
| Observed Value | Luteinizing Hormone (LH) | Month 3, Visit 3 | 0.39 MIU/ML | Standard Deviation 0.247 |
| Observed Value | Luteinizing Hormone (LH) | Month 42, Visit 14 | 0.14 MIU/ML | Standard Deviation 0.119 |
| Observed Value | Luteinizing Hormone (LH) | Month 12, Visit 6 | 0.38 MIU/ML | Standard Deviation 0.247 |
| Observed Value | Luteinizing Hormone (LH) | Month 48, Visit 15 | 0.25 MIU/ML | Standard Deviation 0.232 |
| Observed Value | Luteinizing Hormone (LH) | Month 1, Visit 2 | 0.50 MIU/ML | Standard Deviation 0.302 |
| Observed Value | Luteinizing Hormone (LH) | Month 54, Visit 16 | 0.24 MIU/ML | Standard Deviation 0.272 |
| Observed Value | Luteinizing Hormone (LH) | Month 13, Visit 7 | 0.35 MIU/ML | Standard Deviation 0.216 |
| Observed Value | Luteinizing Hormone (LH) | Month 60, Visit 17 | 0.27 MIU/ML | Standard Deviation 0.336 |
| Observed Value | Luteinizing Hormone (LH) | Month 6, Visit 4 | 0.37 MIU/ML | Standard Deviation 0.225 |
| Observed Value | Luteinizing Hormone (LH) | Month 66, Visit 18 | 0.18 MIU/ML | Standard Deviation 0.02 |
| Observed Value | Luteinizing Hormone (LH) | Month 18, Visit 9 | 0.24 MIU/ML | Standard Deviation 0.118 |
| Observed Value | Luteinizing Hormone (LH) | Month 72, Visit 19 | 0.36 MIU/ML | Standard Deviation 0.357 |
| Observed Value | Luteinizing Hormone (LH) | Day 1, Visit 1 | 0.53 MIU/ML | — |
| Observed Value | Luteinizing Hormone (LH) | 1 Month Post Last Implant | 0.81 MIU/ML | Standard Deviation 0.952 |
| Observed Value | Luteinizing Hormone (LH) | Month 24, Visit 11 | 0.22 MIU/ML | Standard Deviation 0.124 |
| Observed Value | Luteinizing Hormone (LH) | 6 Month Post Last Implant | 3.66 MIU/ML | Standard Deviation 2.463 |
| Observed Value | Luteinizing Hormone (LH) | Baseline | 0.88 MIU/ML | Standard Deviation 1.244 |
| Observed Value | Luteinizing Hormone (LH) | Month 9, Visit 5 | 0.38 MIU/ML | Standard Deviation 0.266 |
| Change From Baseline | Luteinizing Hormone (LH) | 6 Month Post Last Implant | 3.38 MIU/ML | Standard Deviation 2.41 |
| Change From Baseline | Luteinizing Hormone (LH) | Day 1, Visit 1 | 0.07 MIU/ML | — |
| Change From Baseline | Luteinizing Hormone (LH) | Month 1, Visit 2 | -0.37 MIU/ML | Standard Deviation 1.111 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 3, Visit 3 | -0.50 MIU/ML | Standard Deviation 1.173 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 6, Visit 4 | -0.53 MIU/ML | Standard Deviation 1.227 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 9, Visit 5 | -0.51 MIU/ML | Standard Deviation 1.17 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 12, Visit 6 | -0.50 MIU/ML | Standard Deviation 1.108 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 13, Visit 7 | -0.58 MIU/ML | Standard Deviation 1.217 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 18, Visit 9 | -0.68 MIU/ML | Standard Deviation 1.233 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 24, Visit 11 | -0.66 MIU/ML | Standard Deviation 1.228 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 36, Visit 13 | -0.42 MIU/ML | Standard Deviation 0.734 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 42, Visit 14 | -0.53 MIU/ML | Standard Deviation 0.842 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 48, Visit 15 | -0.36 MIU/ML | Standard Deviation 0.871 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 54, Visit 16 | -0.47 MIU/ML | Standard Deviation 1.402 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 60, Visit 17 | -0.24 MIU/ML | Standard Deviation 0.937 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 66, Visit 18 | 0.07 MIU/ML | Standard Deviation 0.1 |
| Change From Baseline | Luteinizing Hormone (LH) | Month 72, Visit 19 | 0.26 MIU/ML | Standard Deviation 0.237 |
| Change From Baseline | Luteinizing Hormone (LH) | 1 Month Post Last Implant | 0.53 MIU/ML | Standard Deviation 0.958 |
Secondary
Average Mean Implant Duration by Subject
There were 2 implants received that were not removed during the study and were excluded from this analysis due to unknown duration of treatment.
Time frame: 12 Months
Population: Extension Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Observed Value | Average Mean Implant Duration by Subject | 12.62 Months | Standard Deviation 0.469 |
Secondary
Average Number of Implants Received
There were 2 implants received that were not removed during the study and were excluded from this analysis due to unknown duration of treatment.
Time frame: 12 months
Population: Extension Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Observed Value | Average Number of Implants Received | 3.5 Implants | Standard Deviation 1.36 |
Secondary
DHEA Sulfate
DHEA=Dehydroepiandrosterone
Time frame: Baseline - 36 Months Post Last Implant
Population: Extension Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Observed Value | DHEA Sulfate | Month 48, Visit 15 | 80.00 UG/DL | Standard Deviation 50.292 |
| Observed Value | DHEA Sulfate | Month 9, Visit 5 | 71.22 UG/DL | Standard Deviation 45.057 |
| Observed Value | DHEA Sulfate | Month 54, Visit 16 | 60.60 UG/DL | Standard Deviation 43.952 |
| Observed Value | DHEA Sulfate | Month 18, Visit 9 | 83.25 UG/DL | Standard Deviation 47.973 |
| Observed Value | DHEA Sulfate | Month 60, Visit 17 | 89.44 UG/DL | Standard Deviation 34.667 |
| Observed Value | DHEA Sulfate | Month 6, Visit 4 | 66.92 UG/DL | Standard Deviation 36.739 |
| Observed Value | DHEA Sulfate | Month 66, Visit 18 | 57.50 UG/DL | Standard Deviation 3.536 |
| Observed Value | DHEA Sulfate | Month 24, Visit 11 | 87.31 UG/DL | Standard Deviation 47.283 |
| Observed Value | DHEA Sulfate | Month 72, Visit 19 | 41.00 UG/DL | Standard Deviation 4.243 |
| Observed Value | DHEA Sulfate | Month 12, Visit 6 | 80.34 UG/DL | Standard Deviation 48.207 |
| Observed Value | DHEA Sulfate | 6 Months Post Last Implant | 114.25 UG/DL | Standard Deviation 50.692 |
| Observed Value | DHEA Sulfate | Month 36, Visit 13 | 78.50 UG/DL | Standard Deviation 72.809 |
| Observed Value | DHEA Sulfate | 12 Months Post Last Implant | 131.88 UG/DL | Standard Deviation 69.907 |
| Observed Value | DHEA Sulfate | Month 3, Visit 3 | 70.88 UG/DL | Standard Deviation 46.802 |
| Observed Value | DHEA Sulfate | 24 Months Post Last Implant | 195.00 UG/DL | Standard Deviation 98.995 |
| Observed Value | DHEA Sulfate | Month 42, Visit 14 | 49.00 UG/DL | Standard Deviation 39.443 |
| Observed Value | DHEA Sulfate | 36 Months Post Last Implant | 184.00 UG/DL | — |
| Observed Value | DHEA Sulfate | Baseline | 61.69 UG/DL | Standard Deviation 36.526 |
| Observed Value | DHEA Sulfate | Month 13, Visit 7 | 81.00 UG/DL | Standard Deviation 43.624 |
| Change From Baseline | DHEA Sulfate | 36 Months Post Last Implant | 119.00 UG/DL | — |
| Change From Baseline | DHEA Sulfate | Month 3, Visit 3 | 11.67 UG/DL | Standard Deviation 15.281 |
| Change From Baseline | DHEA Sulfate | Month 6, Visit 4 | 6.08 UG/DL | Standard Deviation 14.961 |
| Change From Baseline | DHEA Sulfate | Month 9, Visit 5 | 12.16 UG/DL | Standard Deviation 15.085 |
| Change From Baseline | DHEA Sulfate | Month 12, Visit 6 | 25.77 UG/DL | Standard Deviation 28.256 |
| Change From Baseline | DHEA Sulfate | Month 13, Visit 7 | 23.42 UG/DL | Standard Deviation 23.178 |
| Change From Baseline | DHEA Sulfate | Month 18, Visit 9 | 27.79 UG/DL | Standard Deviation 20.381 |
| Change From Baseline | DHEA Sulfate | Month 24, Visit 11 | 32.08 UG/DL | Standard Deviation 34.599 |
| Change From Baseline | DHEA Sulfate | Month 36, Visit 13 | 37.45 UG/DL | Standard Deviation 50.794 |
| Change From Baseline | DHEA Sulfate | Month 42, Visit 14 | 14.00 UG/DL | Standard Deviation 28.537 |
| Change From Baseline | DHEA Sulfate | Month 48, Visit 15 | 36.56 UG/DL | Standard Deviation 39.313 |
| Change From Baseline | DHEA Sulfate | Month 54, Visit 16 | 31.67 UG/DL | Standard Deviation 22.723 |
| Change From Baseline | DHEA Sulfate | Month 60, Visit 17 | 53.14 UG/DL | Standard Deviation 25.635 |
| Change From Baseline | DHEA Sulfate | Month 66, Visit 18 | 40.00 UG/DL | — |
| Change From Baseline | DHEA Sulfate | Month 72, Visit 19 | 23.00 UG/DL | — |
| Change From Baseline | DHEA Sulfate | 6 Months Post Last Implant | 61.43 UG/DL | Standard Deviation 28.148 |
| Change From Baseline | DHEA Sulfate | 12 Months Post Last Implant | 71.00 UG/DL | Standard Deviation 53.492 |
| Change From Baseline | DHEA Sulfate | 24 Months Post Last Implant | 140.50 UG/DL | Standard Deviation 84.146 |
Secondary
Estradiol (MS)
Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Estradiol suppression is defined as serum estradiol in the assay specific range \< 20 pg/mL (73 pmol/L) in girls following the induction of suppression.
Time frame: Month 36 - 36 Months Post Last Implant
Population: Extension Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Observed Value | Estradiol (MS) | Month 36, Visit 13 | 0.46 NG/DL | Standard Deviation 0.277 |
| Observed Value | Estradiol (MS) | Month 42, Visit 14 | 0.38 NG/DL | Standard Deviation 0.307 |
| Observed Value | Estradiol (MS) | Month 48, Visit 15 | 0.52 NG/DL | Standard Deviation 0.319 |
| Observed Value | Estradiol (MS) | Month 54, Visit 16 | 0.47 NG/DL | Standard Deviation 0.289 |
| Observed Value | Estradiol (MS) | Month 60, Visit 17 | 0.50 NG/DL | Standard Deviation 0.201 |
| Observed Value | Estradiol (MS) | Month 66, Visit 18 | 0.21 NG/DL | Standard Deviation 0.106 |
| Observed Value | Estradiol (MS) | Month 72, Visit 19 | 0.34 NG/DL | Standard Deviation 0.205 |
| Observed Value | Estradiol (MS) | 6 Months Post Last Implant | 2.38 NG/DL | Standard Deviation 0.909 |
| Observed Value | Estradiol (MS) | 12 Months Post Last Implant | 4.00 NG/DL | Standard Deviation 2.81 |
| Observed Value | Estradiol (MS) | 24 Months Post Last Implant | 2.70 NG/DL | Standard Deviation 0.424 |
| Observed Value | Estradiol (MS) | 36 Months Post Last Implant | 3.10 NG/DL | — |
Secondary
Estradiol (RIA)
Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Estradiol suppression is defined as serum estradiol in the assay specific range \< 20 pg/mL (73 pmol/L) in girls following the induction of suppression.
Time frame: Baseline - Month 24
Population: Extension Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Observed Value | Estradiol (RIA) | Baseline | 1.58 NG/DL | Standard Deviation 1.754 |
| Observed Value | Estradiol (RIA) | Day 1, Visit 1 | 0.50 NG/DL | — |
| Observed Value | Estradiol (RIA) | Month 1, Visit 2 | 0.58 NG/DL | Standard Deviation 0.199 |
| Observed Value | Estradiol (RIA) | Month 3, Visit 3 | 0.55 NG/DL | Standard Deviation 0.16 |
| Observed Value | Estradiol (RIA) | Month 6, Visit 4 | 0.52 NG/DL | Standard Deviation 0.061 |
| Observed Value | Estradiol (RIA) | Month 9, Visit 5 | 0.55 NG/DL | Standard Deviation 0.114 |
| Observed Value | Estradiol (RIA) | Month 12, Visit 6 | 0.72 NG/DL | Standard Deviation 0.526 |
| Observed Value | Estradiol (RIA) | Month 13, Visit 7 | 0.57 NG/DL | Standard Deviation 0.184 |
| Observed Value | Estradiol (RIA) | Month 18, Visit 9 | 0.61 NG/DL | Standard Deviation 0.154 |
| Observed Value | Estradiol (RIA) | Month 24, Visit 11 | 0.61 NG/DL | Standard Deviation 0.136 |
| Change From Baseline | Estradiol (RIA) | Month 9, Visit 5 | -1.06 NG/DL | Standard Deviation 1.794 |
| Change From Baseline | Estradiol (RIA) | Day 1, Visit 1 | 0.00 NG/DL | — |
| Change From Baseline | Estradiol (RIA) | Month 24, Visit 11 | -0.48 NG/DL | Standard Deviation 1.119 |
| Change From Baseline | Estradiol (RIA) | Month 1, Visit 2 | -1.00 NG/DL | Standard Deviation 1.775 |
| Change From Baseline | Estradiol (RIA) | Month 12, Visit 6 | -0.62 NG/DL | Standard Deviation 1.599 |
| Change From Baseline | Estradiol (RIA) | Month 3, Visit 3 | -1.03 NG/DL | Standard Deviation 1.765 |
| Change From Baseline | Estradiol (RIA) | Month 18, Visit 9 | -0.69 NG/DL | Standard Deviation 1.67 |
| Change From Baseline | Estradiol (RIA) | Month 6, Visit 4 | -1.10 NG/DL | Standard Deviation 1.742 |
| Change From Baseline | Estradiol (RIA) | Month 13, Visit 7 | -1.05 NG/DL | Standard Deviation 1.806 |
Secondary
Follicle Stimulating Hormone (FSH)
The suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment.(LH suppression is defined as a peak LH \< 4 mIU/mL following stimulation with the GnRH analog).
Time frame: Baseline - 6 Month Post Last Implant
Population: Extension Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 36, Visit 13 | 1.91 MIU/ML | Standard Deviation 1.146 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 3, Visit 3 | 1.36 MIU/ML | Standard Deviation 0.814 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 42, Visit 14 | 1.63 MIU/ML | Standard Deviation 1.119 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 12, Visit 6 | 2.16 MIU/ML | Standard Deviation 1.712 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 48, Visit 15 | 1.55 MIU/ML | Standard Deviation 1.199 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 1, Visit 2 | 1.08 MIU/ML | Standard Deviation 0.611 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 54, Visit 16 | 1.43 MIU/ML | Standard Deviation 0.752 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 13, Visit 7 | 1.68 MIU/ML | Standard Deviation 1.048 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 60, Visit 17 | 1.50 MIU/ML | Standard Deviation 0.741 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 6, Visit 4 | 1.43 MIU/ML | Standard Deviation 0.787 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 66, Visit 18 | 0.76 MIU/ML | Standard Deviation 0.049 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 18, Visit 9 | 1.81 MIU/ML | Standard Deviation 1.142 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 72, Visit 19 | 1.24 MIU/ML | Standard Deviation 0.369 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Day 1, Visit 1 | 1.60 MIU/ML | — |
| Observed Value | Follicle Stimulating Hormone (FSH) | 1 Month Post Last Implant | 3.04 MIU/ML | Standard Deviation 2.125 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 24, Visit 11 | 1.89 MIU/ML | Standard Deviation 0.855 |
| Observed Value | Follicle Stimulating Hormone (FSH) | 6 Month Post Last Implant | 4.96 MIU/ML | Standard Deviation 1.411 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Baseline | 2.26 MIU/ML | Standard Deviation 1.656 |
| Observed Value | Follicle Stimulating Hormone (FSH) | Month 9, Visit 5 | 1.77 MIU/ML | Standard Deviation 0.939 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | 6 Month Post Last Implant | 3.46 MIU/ML | Standard Deviation 1.04 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Day 1, Visit 1 | -0.20 MIU/ML | — |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 1, Visit 2 | -1.18 MIU/ML | Standard Deviation 1.566 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 3, Visit 3 | -0.90 MIU/ML | Standard Deviation 1.464 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 6, Visit 4 | -0.86 MIU/ML | Standard Deviation 1.674 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 9, Visit 5 | -0.52 MIU/ML | Standard Deviation 1.776 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 12, Visit 6 | -0.10 MIU/ML | Standard Deviation 1.868 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 13, Visit 7 | -0.65 MIU/ML | Standard Deviation 1.394 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 18, Visit 9 | -0.50 MIU/ML | Standard Deviation 1.668 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 24, Visit 11 | -0.37 MIU/ML | Standard Deviation 1.486 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 36, Visit 13 | -0.01 MIU/ML | Standard Deviation 1.027 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 42, Visit 14 | -0.62 MIU/ML | Standard Deviation 1.457 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 48, Visit 15 | -0.48 MIU/ML | Standard Deviation 1.619 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 54, Visit 16 | -0.73 MIU/ML | Standard Deviation 2.288 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 60, Visit 17 | -0.57 MIU/ML | Standard Deviation 1.573 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 66, Visit 18 | -0.89 MIU/ML | Standard Deviation 1.578 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | Month 72, Visit 19 | -0.41 MIU/ML | Standard Deviation 1.257 |
| Change From Baseline | Follicle Stimulating Hormone (FSH) | 1 Month Post Last Implant | 1.80 MIU/ML | Standard Deviation 1.792 |
Secondary
Summary of EN3326 Implantation and Explantations
Once the female participants reached 11 years of age and the male participants reached 12 years of age or the investigator determined that subjects no longer required hormone suppression, participants underwent final explantation and were eligible to continue into an optional Long Term Follow Up Phase (Post Implant Treatment Phase) for up to 5 years. The purpose of the optional Long Term Follow Up Phase was to collect additional medical and developmental information, such as onset of menses and final adult height after hormone suppression was discontinued.
Time frame: Day 1 - Month 60
Population: Extension Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Observed Value | Summary of EN3326 Implantation and Explantations | First Implant (Day 1, Visit 1) | 31 Participants |
| Observed Value | Summary of EN3326 Implantation and Explantations | Second Implant (Month 12, Visit 6) | 31 Participants |
| Observed Value | Summary of EN3326 Implantation and Explantations | Third Implant (Month 24, Visit 11) | 22 Participants |
| Observed Value | Summary of EN3326 Implantation and Explantations | Fourth Implant (Month 36, Visit 13) | 13 Participants |
| Observed Value | Summary of EN3326 Implantation and Explantations | Fifth Implant (Month 48, Visit 15) | 11 Participants |
| Observed Value | Summary of EN3326 Implantation and Explantations | Sixth Implant (Month 60, Visit 17) | 2 Participants |
| Change From Baseline | Summary of EN3326 Implantation and Explantations | Fifth Implant (Month 48, Visit 15) | 9 Participants |
| Change From Baseline | Summary of EN3326 Implantation and Explantations | First Implant (Day 1, Visit 1) | 31 Participants |
| Change From Baseline | Summary of EN3326 Implantation and Explantations | Fourth Implant (Month 36, Visit 13) | 13 Participants |
| Change From Baseline | Summary of EN3326 Implantation and Explantations | Second Implant (Month 12, Visit 6) | 31 Participants |
| Change From Baseline | Summary of EN3326 Implantation and Explantations | Sixth Implant (Month 60, Visit 17) | 2 Participants |
| Change From Baseline | Summary of EN3326 Implantation and Explantations | Third Implant (Month 24, Visit 11) | 22 Participants |
Secondary
Testosterone
Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Testosterone suppression is defined as serum testosterone \< 30.0 ng/dL (0.8 nmol/L) in boys following the induction of suppression. One black female participant age 8.9 years old had a testosterone value of 11ng/dL at visit 4 (month 6).
Time frame: Baseline - 12 Months Post Last Implant
Population: Extension Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Observed Value | Testosterone | Month 13, Visit 7 | 14.00 NG/DL | — |
| Observed Value | Testosterone | Month 3, Visit 3 | 8.25 NG/DL | Standard Deviation 2.475 |
| Observed Value | Testosterone | Month 36, Visit 13 | 6.90 NG/DL | — |
| Observed Value | Testosterone | Month 18, Visit 9 | 9.80 NG/DL | Standard Deviation 0 |
| Observed Value | Testosterone | Month 42, Visit 14 | 8.10 NG/DL | — |
| Observed Value | Testosterone | Month 6, Visit 4 | 12.67 NG/DL | Standard Deviation 2.082 |
| Observed Value | Testosterone | Month 48, Visit 15 | 7.30 NG/DL | — |
| Observed Value | Testosterone | Baseline | 10.95 NG/DL | Standard Deviation 1.485 |
| Observed Value | Testosterone | Month 54, Visit 16 | 4.10 NG/DL | — |
| Observed Value | Testosterone | Month 9, Visit 5 | 8.15 NG/DL | Standard Deviation 2.616 |
| Observed Value | Testosterone | Month 60, Visit 17 | 7.00 NG/DL | — |
| Observed Value | Testosterone | Month 1, Visit 2 | 6.50 NG/DL | Standard Deviation 2.687 |
| Observed Value | Testosterone | 6 Months Post Last Implant | 17.00 NG/DL | — |
| Observed Value | Testosterone | Month 12, Visit 6 | 8.00 NG/DL | Standard Deviation 4.243 |
| Observed Value | Testosterone | 12 Months Post Last Implant | 130.00 NG/DL | — |
| Observed Value | Testosterone | Month 24, Visit 11 | 9.90 NG/DL | Standard Deviation 4.384 |
| Change From Baseline | Testosterone | Month 12, Visit 6 | -2.95 NG/DL | Standard Deviation 2.758 |
| Change From Baseline | Testosterone | Month 24, Visit 11 | -1.05 NG/DL | Standard Deviation 2.899 |
| Change From Baseline | Testosterone | 12 Months Post Last Implant | 120.10 NG/DL | — |
| Change From Baseline | Testosterone | Month 1, Visit 2 | -4.45 NG/DL | Standard Deviation 1.202 |
| Change From Baseline | Testosterone | Month 3, Visit 3 | -2.70 NG/DL | Standard Deviation 0.99 |
| Change From Baseline | Testosterone | Month 6, Visit 4 | 2.55 NG/DL | Standard Deviation 3.606 |
| Change From Baseline | Testosterone | Month 9, Visit 5 | -2.80 NG/DL | Standard Deviation 1.131 |
| Change From Baseline | Testosterone | Month 18, Visit 9 | -1.15 NG/DL | Standard Deviation 1.485 |
| Change From Baseline | Testosterone | Month 13, Visit 7 | 2.00 NG/DL | — |
| Change From Baseline | Testosterone | Month 36, Visit 13 | -3.00 NG/DL | — |
| Change From Baseline | Testosterone | Month 42, Visit 14 | -1.80 NG/DL | — |
| Change From Baseline | Testosterone | Month 48, Visit 15 | -2.60 NG/DL | — |
| Change From Baseline | Testosterone | Month 54, Visit 16 | -5.80 NG/DL | — |
| Change From Baseline | Testosterone | Month 60, Visit 17 | -2.90 NG/DL | — |
| Change From Baseline | Testosterone | 6 Months Post Last Implant | 7.10 NG/DL | — |