Puberty, Precocious
Conditions
Keywords
CPP, central precocious puberty, pediatrics, suppression of luteinizing hormone, Lupron, leuprolide acetate, depot formulation, GnRHa, GnRH agonist, GnRH analog, luteinizing hormone
Brief summary
The purpose of this study is to determine if 11.25 and 30 mg formulations of leuprolide are effective in treating children with Central Precocious Puberty (CPP).
Detailed description
Study Design: A total of 80 children with confirmed CPP were planned to be enrolled and randomized in a 1:1 ratio to receive 2 injections of either leuprolide acetate 11.25 mg or 30 mg depot formulation, each injection administered 3 mo apart (6 mo of treatment): This study includes a 4-week Screening Period, two 3-mo treatment cycles, and a posttreatment follow-up period (12 weeks following the Mo 6 visit). Study visits will occur at Screening, Day 1, Week 2 (only for subjects participating in the pharmacokinetic subset), Mo 1, 2, 3, Mo 6/Early Termination, and 12 weeks later, for the Posttreatment Follow-up Visit. This study was conducted at 18 sites in the United States and 4 sites in Puerto Rico.
Interventions
DRUGLeuprolide acetate 11.25 mg
Two intramuscular injections of leuprolide acetate for depot suspension 11.25 mg administered 3 mo apart.
DRUGLeuprolide acetate 30 mg
Two intramuscular injections of leuprolide acetate for depot suspension 30 mg administered 3 mo apart.
Sponsors
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Subject has a clinical diagnosis of CPP. * Eligible to receive at least 6 mo of therapy to treat CPP after study entry. * Bone age advanced at least 1 year beyond the chronological age at time of diagnosis or first treatment. * In general good health with no uncontrolled, clinically significant disease which would interfere with bone maturation or mask the objectives of this protocol as assessed by the investigator. Additional criteria for subjects who have not had previous treatment: * Girls 2-8 years inclusive or Boys 2-9 years inclusive at Day 1. * Has pretreatment pubertal response to leuprolide acetate stimulation (luteinizing hormone ≥8 mIU/mL) at Screening. * Breast pubertal staging of at least 2 in girls; testicular volume of at least 4 cc or testicular length greater than 2.5 cm in boys at Screening. Additional criteria for subjects previously treated: * Girls 2-10 years inclusive or boys 2-11 years inclusive at Day 1. * Must have been on standard gonadotropin releasing hormone analog therapy for at least the 6 mo prior to Day 1. * Has documented maintenance of luteinizing hormone suppression as evidenced by peak stimulated level \<4 mIU/mL at Screening.
Exclusion criteria
* Incomplete precocious puberty (premature thelarche, premature adrenarche). * Peripheral precocious puberty: gonadal or adrenal tumors, congenital adrenal hyperplasia, testotoxicosis in boys, human chorionic gonadotropin secreting tumor or McCune-Albright syndrome in girls. * Evidence of any abnormal pituitary, hypothalamic, adrenal, thyroid and gonadal function other than premature secretion of gonadotropins not adequately controlled. * Unstable intracranial tumors (unresponsive to treatment/expanding) except hamartoma. * Previous treatment with GnRHa therapy requiring leuprolide acetate for depot suspension \>15 mg monthly. * Bone age \>13 years for girls and \>14 years for boys. * Any other condition interfering with growth, ie, skeletal dysplasia, cerebral palsy. * Chronic illness requiring treatment that may interfere with growth, ie, chronic steroid use, renal failure, moderate to severe scoliosis. * Diagnosis of short stature, ie more than 2.25 standard deviations below the mean height for age (growth chart measurement). * Prior or current therapy with medroxyprogesterone acetate or growth hormone. * Has an abnormal laboratory value suggesting a clinically significant underlying disease . * Creatinine \>1.5 mg/dL, alanine aminotransferase and/or aspartate aminotransferase \>2.0 x upper limit of normal, or total bilirubin \>2.0 mg/dL with aspartate aminotransferase/alanine aminotransferase elevated above normal limits. * Positive pregnancy test. * Known hypersensitivity to study medication or its excipients. * Participation in another drug research within 3 mo of enrollment into this study. * Prior or current therapy with insulin-like growth factor-1. * Use of an estrogen preparation within 2 mo prior to Day 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (<4 mIU/mL) From Month 2 Through Month 6 | Month 2 through 6 | Percentage of participants with suppression of peak stimulated luteinizing hormone that was measured after a gonadotropin-releasing hormone agonist (GnRHa) stimulation test at Month (Mo) 2, 3, and 6. The analysis was performed according to a life table method. Subjects who withdrew without peak-stimulated luteinizing hormone \>= 4 mIU/mL were censored at their last measurement of peak-stimulated luteinizing hormone. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak-stimulated Luteinizing Hormone Concentration by Visit | Baseline, Month 1, 2, 3 and 6 | Observed data were used with no imputation for missing data. |
| Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Month 1, 2, 3 and 6 | Percentage of participants with suppression of estradiol, out of the number of girls with at least 1 estradiol measurement at each visit (n/N%). Only girls are analyzed in this outcome measure. Observed data were used with no imputation for missing data. |
| Percentage of Participants With Suppression of the Physical Signs of Puberty (Breast Development) at Month 6 | Month 6 | Percentage of participants with suppression of breast development, out of the number of girls with pubertal staging of breast development (n/N%). Only girls are analyzed in this outcome measure. Breast development was rated from Stage 1 (early development) through Stage 5 (full development) according to a Tanner Staging pictogram. Girls entering the study with fully developed breasts (Stage 5) were excluded from this analysis. Observed data were used with no imputation for missing data. |
| Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Month 1, 2, 3 and 6 | Percentage of participants with suppression of testosterone, out of the number of boys with at least 1 testosterone measurement at each visit (n/N%). Only boys are analyzed in this outcome measure. Observed data were used with no imputation for missing data. |
| Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6 | Baseline and Month 6 | The growth rate at baseline was the growth rate during the last year before the start of treatment and was calculated with the measurement closest to Day -336 (before Day -30) and the measurement up to Day 1. Growth rate at Month 6 was defined as the ratio of the change in height from Day 1 to the change in chronological age, with an approximate 6-month interval between the 2 height measurements. Observed data were used with no imputation for missing data. |
| Ratio of Change From Baseline in Bone Age/Change From Baseline in Chronological Age at Month 6 | Baseline to Month 6 | The ratio at Month 6 was calculated as (bone age at Month 6 - bone age at baseline)/(chronological age at Month 6 - chronological age at baseline). Observed data were used with no imputation for missing data. Baseline bone-age radiograph was performed at or within 3 months of the Screening Visit. |
| Percentage of Participants With Suppression of the Physical Signs of Puberty (Testicular Volume and Genital Development) at Month 6 | Month 6 | Percentage of participants with suppression of genital development and testicular volume, out of the number of boys with pubertal staging of genital development or testicular volume (n/N%). Only boys are analyzed in this outcome measure. External genital development (testes and penis) was rated from Stage 1 (early development) through Stage 5 (full development) according to a Tanner Staging pictogram. Boys entering the study with fully developed genitals (Stage 5) were excluded from this analysis. Observed data were used with no imputation for missing data. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Eighteen sites in the US and 4 sites in Puerto Rico enrolled subjects into the study. The first subject was randomized 17 June 2008 and the last subject was randomized 12 Aug 2009.
Pre-assignment details
Subjects were randomized in a 1:1 ratio to 1 of the 2 treatment arms. To ensure balanced randomization, the study drug assignment was stratified on the basis of whether subjects were treatment-naive or had been treated with GnRHa previously.
Participants by arm
| Arm | Count |
|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive Subjects who received at least 1 dose of study drug. | 21 |
| Leuprolide Acetate 11.25 mg - Previous Treatment Subjects who received at least 1 dose of study drug. | 21 |
| Leuprolide Acetate 30 mg - Treatment Naive Subjects who received at least 1 dose of study drug. | 21 |
| Leuprolide Acetate 30 mg - Previous Treatment Subjects who received at least 1 dose of study drug. | 21 |
| Total | 84 |
Baseline characteristics
| Characteristic | Leuprolide Acetate 11.25 mg - Previous Treatment | Leuprolide Acetate 30 mg - Treatment Naive | Leuprolide Acetate 11.25 mg - Treatment Naive | Leuprolide Acetate 30 mg - Previous Treatment | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 21 Participants | 21 Participants | 21 Participants | 21 Participants | 84 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 8.1 Years STANDARD_DEVIATION 1.83 | 7.3 Years STANDARD_DEVIATION 1.74 | 7.4 Years STANDARD_DEVIATION 1.47 | 8.4 Years STANDARD_DEVIATION 1.75 | 7.8 Years STANDARD_DEVIATION 1.73 |
| Region of Enrollment North America | 21 Participants | 21 Participants | 21 Participants | 21 Participants | 84 Participants |
| Sex: Female, Male Female | 20 Participants | 19 Participants | 19 Participants | 18 Participants | 76 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 21 | 18 / 21 | 15 / 21 | 17 / 21 |
| serious Total, serious adverse events | 1 / 21 | 0 / 21 | 0 / 21 | 1 / 21 |
Outcome results
Primary
Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (<4 mIU/mL) From Month 2 Through Month 6
Percentage of participants with suppression of peak stimulated luteinizing hormone that was measured after a gonadotropin-releasing hormone agonist (GnRHa) stimulation test at Month (Mo) 2, 3, and 6. The analysis was performed according to a life table method. Subjects who withdrew without peak-stimulated luteinizing hormone \>= 4 mIU/mL were censored at their last measurement of peak-stimulated luteinizing hormone.
Time frame: Month 2 through 6
Population: Subjects must have received at least 1 dose of study drug and had at least 1 postbaseline measurement of peak stimulated luteinizing hormone at Mo 2 or afterward defined as the intent-to-treat population.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (<4 mIU/mL) From Month 2 Through Month 6 | 76.2 Percentage of Participants | 95% Confidence Interval 9.29 |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (<4 mIU/mL) From Month 2 Through Month 6 | 80.7 Percentage of Participants | 95% Confidence Interval 8.69 |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (<4 mIU/mL) From Month 2 Through Month 6 | 90.5 Percentage of Participants | 95% Confidence Interval 6.41 |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (<4 mIU/mL) From Month 2 Through Month 6 | 100 Percentage of Participants | 95% Confidence Interval 0 |
Secondary
Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6
The growth rate at baseline was the growth rate during the last year before the start of treatment and was calculated with the measurement closest to Day -336 (before Day -30) and the measurement up to Day 1. Growth rate at Month 6 was defined as the ratio of the change in height from Day 1 to the change in chronological age, with an approximate 6-month interval between the 2 height measurements. Observed data were used with no imputation for missing data.
Time frame: Baseline and Month 6
Population: Subjects must have received at least 1 dose of study drug and had at least 1 postbaseline measurement defined as the intent-to-treat population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6 | Baseline (Arm A N=20, B N=21, C N=21, D N=21) | 7.25 cm/year | Standard Deviation 5.3 |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6 | Mo 6 (Arm A N=14, B N=19, C N=19, D N=21) | -2.51 cm/year | Standard Deviation 5.29 |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6 | Mo 6 (Arm A N=14, B N=19, C N=19, D N=21) | -0.98 cm/year | Standard Deviation 2.24 |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6 | Baseline (Arm A N=20, B N=21, C N=21, D N=21) | 6.58 cm/year | Standard Deviation 2.39 |
| Leuprolide Acetate 30 mg - Treatment Naive | Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6 | Baseline (Arm A N=20, B N=21, C N=21, D N=21) | 7.83 cm/year | Standard Deviation 5.96 |
| Leuprolide Acetate 30 mg - Treatment Naive | Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6 | Mo 6 (Arm A N=14, B N=19, C N=19, D N=21) | -2.34 cm/year | Standard Deviation 4.22 |
| Leuprolide Acetate 30 mg - Previous Treatment | Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6 | Baseline (Arm A N=20, B N=21, C N=21, D N=21) | 6.05 cm/year | Standard Deviation 1.55 |
| Leuprolide Acetate 30 mg - Previous Treatment | Change From Baseline in Incremental Growth Rate (cm/Year) at Month 6 | Mo 6 (Arm A N=14, B N=19, C N=19, D N=21) | -0.91 cm/year | Standard Deviation 2.45 |
Comparison: Summary statistics were calculated and tests of significance of the change versus no change were performed.p-value: 0.099t-test, 2 sided
Comparison: Summary statistics were calculated and tests of significance of the change versus no change were performed.p-value: 0.074t-test, 2 sided
Comparison: Summary statistics were calculated and tests of significance of the change versus no change were performed.p-value: 0.026t-test, 2 sided
Comparison: Summary statistics were calculated and tests of significance of the change versus no change were performed.p-value: 0.102t-test, 2 sided
Secondary
Peak-stimulated Luteinizing Hormone Concentration by Visit
Observed data were used with no imputation for missing data.
Time frame: Baseline, Month 1, 2, 3 and 6
Population: Subjects must have received at least 1 dose of study drug and had at least 1 postbaseline measurement defined as the intent-to-treat population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 1 (Arm A N=21, B N=21, C N=21, D N=21) | 4.4 mIU/mL | Standard Deviation 7.29 |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 6 (Arm A N=15, B N=18, C N=18, D N=21) | 2.0 mIU/mL | Standard Deviation 0.85 |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 2 (Arm A N=21, B N=20, C N=21, D N=20) | 4.5 mIU/mL | Standard Deviation 7.2 |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 3 (Arm A N=16, B N=20, C N=20, D N=21) | 2.3 mIU/mL | Standard Deviation 1.23 |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Baseline (Arm A N=21, B N=21, C N=21, D N=21) | 45.9 mIU/mL | Standard Deviation 42.38 |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 2 (Arm A N=21, B N=20, C N=21, D N=20) | 2.0 mIU/mL | Standard Deviation 1.48 |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Baseline (Arm A N=21, B N=21, C N=21, D N=21) | 1.8 mIU/mL | Standard Deviation 1.78 |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 1 (Arm A N=21, B N=21, C N=21, D N=21) | 1.7 mIU/mL | Standard Deviation 1.36 |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 3 (Arm A N=16, B N=20, C N=20, D N=21) | 1.8 mIU/mL | Standard Deviation 1.1 |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 6 (Arm A N=15, B N=18, C N=18, D N=21) | 2.5 mIU/mL | Standard Deviation 2.43 |
| Leuprolide Acetate 30 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 1 (Arm A N=21, B N=21, C N=21, D N=21) | 1.9 mIU/mL | Standard Deviation 1.74 |
| Leuprolide Acetate 30 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 2 (Arm A N=21, B N=20, C N=21, D N=20) | 2.0 mIU/mL | Standard Deviation 2.25 |
| Leuprolide Acetate 30 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Baseline (Arm A N=21, B N=21, C N=21, D N=21) | 23.5 mIU/mL | Standard Deviation 16.76 |
| Leuprolide Acetate 30 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 6 (Arm A N=15, B N=18, C N=18, D N=21) | 1.6 mIU/mL | Standard Deviation 0.95 |
| Leuprolide Acetate 30 mg - Treatment Naive | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 3 (Arm A N=16, B N=20, C N=20, D N=21) | 1.4 mIU/mL | Standard Deviation 0.78 |
| Leuprolide Acetate 30 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Baseline (Arm A N=21, B N=21, C N=21, D N=21) | 1.7 mIU/mL | Standard Deviation 1.09 |
| Leuprolide Acetate 30 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 3 (Arm A N=16, B N=20, C N=20, D N=21) | 1.5 mIU/mL | Standard Deviation 0.61 |
| Leuprolide Acetate 30 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 2 (Arm A N=21, B N=20, C N=21, D N=20) | 1.5 mIU/mL | Standard Deviation 0.73 |
| Leuprolide Acetate 30 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 6 (Arm A N=15, B N=18, C N=18, D N=21) | 1.5 mIU/mL | Standard Deviation 0.89 |
| Leuprolide Acetate 30 mg - Previous Treatment | Peak-stimulated Luteinizing Hormone Concentration by Visit | Mo 1 (Arm A N=21, B N=21, C N=21, D N=21) | 1.4 mIU/mL | Standard Deviation 0.76 |
Secondary
Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit
Percentage of participants with suppression of estradiol, out of the number of girls with at least 1 estradiol measurement at each visit (n/N%). Only girls are analyzed in this outcome measure. Observed data were used with no imputation for missing data.
Time frame: Month 1, 2, 3 and 6
Population: Subjects must have received at least 1 dose of study drug and had at least 1 postbaseline measurement defined as the intent-to-treat population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 1 (Arm A N=17, B N=18, C N=19, D N=16) | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 2 (Arm A N=19, B N=14, C N=19, D N=14) | 94.7 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 3 (Arm A N=15, B N=18, C N=17, D N=18) | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 6 (Arm A N=12, B N=16, C N=15, D N=17) | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 2 (Arm A N=19, B N=14, C N=19, D N=14) | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 3 (Arm A N=15, B N=18, C N=17, D N=18) | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 6 (Arm A N=12, B N=16, C N=15, D N=17) | 93.8 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 1 (Arm A N=17, B N=18, C N=19, D N=16) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 3 (Arm A N=15, B N=18, C N=17, D N=18) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 2 (Arm A N=19, B N=14, C N=19, D N=14) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 6 (Arm A N=12, B N=16, C N=15, D N=17) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 1 (Arm A N=17, B N=18, C N=19, D N=16) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 6 (Arm A N=12, B N=16, C N=15, D N=17) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 2 (Arm A N=19, B N=14, C N=19, D N=14) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 1 (Arm A N=17, B N=18, C N=19, D N=16) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Basal Estradiol <20 pg/mL by Visit | Mo 3 (Arm A N=15, B N=18, C N=17, D N=18) | 100 Percentage of Participants |
Secondary
Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit
Percentage of participants with suppression of testosterone, out of the number of boys with at least 1 testosterone measurement at each visit (n/N%). Only boys are analyzed in this outcome measure. Observed data were used with no imputation for missing data.
Time frame: Month 1, 2, 3 and 6
Population: Subjects must have received at least 1 dose of study drug and had at least 1 postbaseline measurement defined as the intent-to-treat population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 1 (Arm A N=2, B N=1, C N=2, D N=3) | 50.0 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 3 (Arm A N=2, B N=1, C N=2, D N=3) | 50.0 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 2 (Arm A N=2, B N=1, C N=2, D N=3) | 50.0 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 6 (Arm A N=1, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 3 (Arm A N=2, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 6 (Arm A N=1, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 2 (Arm A N=2, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 1 (Arm A N=2, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 2 (Arm A N=2, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 3 (Arm A N=2, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 1 (Arm A N=2, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 6 (Arm A N=1, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 6 (Arm A N=1, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 1 (Arm A N=2, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 3 (Arm A N=2, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Testosterone in <30 ng/dL by Visit | Mo 2 (Arm A N=2, B N=1, C N=2, D N=3) | 100 Percentage of Participants |
Secondary
Percentage of Participants With Suppression of the Physical Signs of Puberty (Breast Development) at Month 6
Percentage of participants with suppression of breast development, out of the number of girls with pubertal staging of breast development (n/N%). Only girls are analyzed in this outcome measure. Breast development was rated from Stage 1 (early development) through Stage 5 (full development) according to a Tanner Staging pictogram. Girls entering the study with fully developed breasts (Stage 5) were excluded from this analysis. Observed data were used with no imputation for missing data.
Time frame: Month 6
Population: Subjects must have received at least 1 dose of study drug and had at least 1 postbaseline measurement defined as the intent-to-treat population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of the Physical Signs of Puberty (Breast Development) at Month 6 | 92.9 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of the Physical Signs of Puberty (Breast Development) at Month 6 | 88.9 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of the Physical Signs of Puberty (Breast Development) at Month 6 | 82.4 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of the Physical Signs of Puberty (Breast Development) at Month 6 | 82.4 Percentage of Participants |
Secondary
Percentage of Participants With Suppression of the Physical Signs of Puberty (Testicular Volume and Genital Development) at Month 6
Percentage of participants with suppression of genital development and testicular volume, out of the number of boys with pubertal staging of genital development or testicular volume (n/N%). Only boys are analyzed in this outcome measure. External genital development (testes and penis) was rated from Stage 1 (early development) through Stage 5 (full development) according to a Tanner Staging pictogram. Boys entering the study with fully developed genitals (Stage 5) were excluded from this analysis. Observed data were used with no imputation for missing data.
Time frame: Month 6
Population: Subjects must have received at least 1 dose of study drug and had at least 1 postbaseline measurement defined as the intent-to-treat population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of the Physical Signs of Puberty (Testicular Volume and Genital Development) at Month 6 | 100 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of the Physical Signs of Puberty (Testicular Volume and Genital Development) at Month 6 | 0 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of the Physical Signs of Puberty (Testicular Volume and Genital Development) at Month 6 | 50 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of the Physical Signs of Puberty (Testicular Volume and Genital Development) at Month 6 | 33.3 Percentage of Participants |
Secondary
Ratio of Change From Baseline in Bone Age/Change From Baseline in Chronological Age at Month 6
The ratio at Month 6 was calculated as (bone age at Month 6 - bone age at baseline)/(chronological age at Month 6 - chronological age at baseline). Observed data were used with no imputation for missing data. Baseline bone-age radiograph was performed at or within 3 months of the Screening Visit.
Time frame: Baseline to Month 6
Population: Participants must have received at least 1 dose of study drug and had at least 1 postbaseline measurement defined as the intent-to-treat population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Ratio of Change From Baseline in Bone Age/Change From Baseline in Chronological Age at Month 6 | 0.59 Ratio | Standard Deviation 0.59 |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Ratio of Change From Baseline in Bone Age/Change From Baseline in Chronological Age at Month 6 | 0.50 Ratio | Standard Deviation 0.57 |
| Leuprolide Acetate 30 mg - Treatment Naive | Ratio of Change From Baseline in Bone Age/Change From Baseline in Chronological Age at Month 6 | 1.00 Ratio | Standard Deviation 0.74 |
| Leuprolide Acetate 30 mg - Previous Treatment | Ratio of Change From Baseline in Bone Age/Change From Baseline in Chronological Age at Month 6 | 1.07 Ratio | Standard Deviation 1.6 |
Comparison: Summary statistics were calculated and tests of significance of the ratio versus 1 were performed. All analyses and summaries were conducted separately for the 2 treatment groups (subjects who received leuprolide acetate depot 11.25 mg and 30 mg).p-value: 0.008Wilcoxon (Mann-Whitney)
Comparison: Summary statistics were calculated and tests of significance of the ratio versus 1 were performed. All analyses and summaries were conducted separately for the 2 treatment groups (subjects who received leuprolide acetate depot 11.25 mg and 30 mg).p-value: 0.002Wilcoxon (Mann-Whitney)
Comparison: Summary statistics were calculated and tests of significance of the ratio versus 1 were performed. All analyses and summaries were conducted separately for the 2 treatment groups (subjects who received leuprolide acetate depot 11.25 mg and 30 mg).p-value: 0.347Wilcoxon (Mann-Whitney)
Comparison: Summary statistics were calculated and tests of significance of the ratio versus 1 were performed. All analyses and summaries were conducted separately for the 2 treatment groups (subjects who received leuprolide acetate depot 11.25 mg and 30 mg).p-value: 0.15Wilcoxon (Mann-Whitney)
Post Hoc
Percentage of Participants With a Decrease From Baseline in the Ratio of Bone Age to Chronological Age at Month 6 Compared to Baseline
The ratio at baseline or Month 6 was calculated as bone age at baseline or Month 6/chronological age at baseline or Month 6. The percentage of participants with a decrease in the ratio was calculated as a simple percentage for each dose group. Observed data were used with no imputation for missing data. The baseline time frame was increased from the secondary outcome in this analysis to include all participants with a bone age radiograph at screening. This analysis was performed after the clinical study report was completed & is included to match the FDA package insert.
Time frame: Baseline to Month 6
Population: The baseline time frame was increased from the secondary outcome to this analysis to include all participants with a bone age radiograph at screening. This analysis was performed post hoc to match the FDA package insert.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With a Decrease From Baseline in the Ratio of Bone Age to Chronological Age at Month 6 Compared to Baseline | 87.9 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With a Decrease From Baseline in the Ratio of Bone Age to Chronological Age at Month 6 Compared to Baseline | 75.0 Percentage of Participants |
Post Hoc
Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (< 4 mIU/mL) From Month 2 Through Month 6 (Simple Percentage With Binomial Exact Confidence Intervals)
Percentage of participants with suppression of peak stimulated luteinizing hormone that was measured after a GnRHa stimulation test at Mo 2, 3, and 6. A simple percentage and binomial exact confidence intervals were used in this analysis. Participants who withdrew with luteinizing hormone that remained suppressed were counted as a success. This analysis was performed after the clinical study report was completed and is included to match the FDA package insert.
Time frame: Month 2 through 6
Population: Subjects must have received at least 1 dose of study drug and had at least 1 postbaseline measurement of peak stimulated luteinizing hormone at Mo 2 or afterward defined as the intent-to-treat population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Leuprolide Acetate 11.25 mg - Treatment Naive | Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (< 4 mIU/mL) From Month 2 Through Month 6 (Simple Percentage With Binomial Exact Confidence Intervals) | 76.2 Percentage of Participants |
| Leuprolide Acetate 11.25 mg - Previous Treatment | Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (< 4 mIU/mL) From Month 2 Through Month 6 (Simple Percentage With Binomial Exact Confidence Intervals) | 81.0 Percentage of Participants |
| Leuprolide Acetate 30 mg - Treatment Naive | Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (< 4 mIU/mL) From Month 2 Through Month 6 (Simple Percentage With Binomial Exact Confidence Intervals) | 90.5 Percentage of Participants |
| Leuprolide Acetate 30 mg - Previous Treatment | Percentage of Participants With Suppression of Peak Stimulated Luteinizing Hormone (< 4 mIU/mL) From Month 2 Through Month 6 (Simple Percentage With Binomial Exact Confidence Intervals) | 100.0 Percentage of Participants |