A Study of Leuprolide 11.25 mg and 30 mg Administered Every 3 Months to Treat Central Precocious Puberty

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 3, Randomized, Multi-Center, Open-Label Study to Evaluate the Efficacy and Safety of Leuprolide Acetate 11.25 and 30 mg Formulations in Children With Central Precocious Puberty

Conditions
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Puberty, Precocious

Intervention / Treatment
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* Drug: Leuprolide acetate 11.25 mg
* Drug: Leuprolide acetate 30 mg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Leuprolide acetate 11.25 mg<br>There are 2 arms that received leuprolide acetate 11.25 mg. Subjects who are treatment naive to leuprolide acetate are designated to be in Arm A and subjects who have previously been treated with leuprolide acetate are designated to be in Arm B. | Drug: Leuprolide acetate 11.25 mg<br>* Two intramuscular injections of leuprolide acetate for depot suspension 11.25 mg administered 3 mo apart.<br>* Other names: Lupron;|
| Experimental: Leuprolide acetate 30 mg<br>There are 2 arms that received leuprolide acetate 30 mg. Subjects who are treatment naive to leuprolide acetate are designated to be in Arm C and subjects who have previously been treated with leuprolide acetate are designated to be in Arm D. | Drug: Leuprolide acetate 30 mg<br>* Two intramuscular injections of leuprolide acetate for depot suspension 30 mg administered 3 mo apart.<br>* Other names: Lupron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Month 2 through 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Month 1, 2, 3 and 6 | 
| 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. | Month 1, 2, 3 and 6 | 
| Peak-stimulated Luteinizing Hormone Concentration by Visit | Observed data were used with no imputation for missing data. | Baseline, Month 1, 2, 3 and 6 | 
| 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. | Month 6 | 
| 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. | Month 6 | 
| 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. | Baseline and Month 6 | 
| 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. | Baseline to Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CPP, central precocious puberty, pediatrics, suppression of luteinizing hormone, Lupron, leuprolide acetate, depot formulation, GnRHa, GnRH agonist, GnRH analog, luteinizing hormone