E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Central Precocious Puberty
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E.1.1.1 | Medical condition in easily understood language |
Central Precocious Puberty |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the safety and efficacy of a leuprolide acetate (LA) 45 mg 6- month depot formulation for the treatment of CPP in children who are either naïve to treatment with a GnRHa or who have been previously treated with a GnRHa. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the pharmacokinetic profile and pharmacodynamics of leuprolide following intramuscular administration of the LA 45 mg 6- month depot formulation in subjects with CPP. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Children with CPP who are naïve to treatment with a GnRHa (females 2–8 years of age, inclusive, or males 2 –9 years of age, inclusive) or who have been on standard GnRHa therapy for at least 6 months (females 2–10 years of age, inclusive, or males 2 –11 years of age, inclusive).
•Parent or legal guardian has voluntarily signed and dated an informed consent form, approved by an institutional review board (IRB), after the nature of the study has been explained and the subject and the subject's parent or legal guardian has had the opportunity to ask questions. The informed consent must be signed before any study-specific procedures are performed or before any concomitant medication is discontinued for the purpose of the study. Pediatric subjects will be included in all discussions in order to obtain verbal and/or written assent.
•Chronological age at the appearance of pubertal changes < 8 years in females and < 9 years in males at Day 1 of the study.
•Bone age advancement over chronological age at least 1 year at time of CPP diagnosis or first GnRHa therapy.
•Bone age < 13 years for females and < 14 years for males.
•In general good health with no uncontrolled, clinically significant disease that could interfere with bone maturation or mask the objectives of this protocol as assessed by the investigator.
•A negative serum pregnancy test for female subjects ≥10 years of age at Screening and negative urine pregnancy test on Day 1 prior to study drug administration. For female subjects < 10 years of age, pregnancy tests may be performed at Screening and on Day 1 at the discretion of the principal investigator.
•Willing and able to comply with procedures required in this protocol.
Additional Criteria for Subjects Naïve to GnRHa treatment •Pretreatment pubertal response to GnRHa stimulation test (LH ≥6 mIU/mL) at Screening. •Breast pubertal staging (modified Tanner) of at least 2 in females; testicular volume of at least 4 cc in males at Screening.
Additional Criteria for Subjects Previously Treated with a GnRHa •Must have been on GnRHa therapy for at least 6 months prior to Day 1. •Should have documented maintenance of LH suppression as evidenced by peak stimulated LH < 4 mIU/mL at Screening.
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E.4 | Principal exclusion criteria |
•Abnormal laboratory value that suggests a clinically significant underlying disease or condition that may prevent the subject from entering the study.
•Diagnosis of short stature, i.e., more than 2.25 SD below the mean height for age (growth chart assessment).
•Diagnosis of incomplete precocious puberty, peripheral precocious puberty; evidence of any abnormal pituitary, hypothalamic, adrenal, thyroid, and gonadal function other than premature secretion of gonadotropins not adequately controlled; no unstable intracranial tumors (unresponsive to treatment/expanding) except hamartoma.
•Has concomitant medical condition that, in the opinion of the investigator, may expose a subject to an unacceptable level of safety risk or that affects subject compliance.
•History of clinically significant medical conditions or any other reason that the investigator determines would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug.
•History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same class.
•Have not discontinued therapy with medroxyprogesterone acetate, growth hormone, insulin-like growth factor-1 (IGF-1), or estrogen or testosterone preparations at least 5 half-lives or 4 weeks prior to Screening, whichever is longer.
•have been treated with any investigational drug within 30 days or 5 half-lives of the drug (whichever is longer) prior to Screening or is currently enrolled in another clinical study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of subjects with suppression of GnRHa-stimulated luteinizing hormone (LH) (< 4 mIU/mL) at Week 24 after the first dose of study drug but before the Week 24 dose.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 24 after the first dose of study drug but before the Week 24 dose
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are: •Proportion of subjects with suppression of GnRHa-stimulated LH (< 4 mIU/mL) at Weeks 12, 20, 44, and 48. •Proportion of female subjects with suppression of basal estradiol to < 20 pg/mL at Weeks 12, 20, 24, 44, and 48. •Proportion of male subjects with suppression of testosterone to < 30 ng/dL at Weeks 12, 20, 24, 44, and 48. •Proportion of subjects with maintenance of suppression of GnRHa-stimulated LH (< 4 mIU/mL) at Weeks 72, 96, 120, and 144. •Proportion of female subjects with maintenance of suppression of basal estradiol to < 20 pg/mL at Weeks 72, 96, 120, and 144. •Proportion of male subjects with maintenance of suppression of testosterone to < 30 ng/dL at Weeks 72, 96, 120, and 144. •Proportion of subjects with suppression of the physical signs of puberty (breast development in females; testicular volume or genital development in males) at each scheduled assessment using modified Tanner staging. •Incremental growth rate (cm/year) at each scheduled assessment. •Ratio of change from Baseline in bone age/change from Baseline in chronological age at each scheduled assessment.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 12, 20, 24, 44, 48, 72, 96, 120, and 144
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Puerto Rico |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end-of-study is defined as the date of the last subject's last visit or the actual date of follow-up contact, whichever is later.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial days | 24 |