The primary purpose of this amendment was to include a lower dose of leuprolide acetate (11.25 mg) in addition to the 30 mg dose, both administered with a 3-month dosing interval; to increase the number of study subjects to approximately 80, approximately 40 naïve to GnRHa therapy (a minimum of 30) and a minimum of 40 subjects previously treated with GnRHa; to change the study design to a randomized open-label study utilizing an Interactive Voice-Response System/Interactive Web-Response System to randomize subjects. The option for entry into a separate open-label extension study for qualifying subjects who were adequately suppressed through Month 6 of this study, was included. The Posttreatment Follow-up Period was extended to 12 weeks (occurred 12 weeks following the subject's Month 6 visit) to better coincide with routine office visit schedule for standard of care treatment. Telephone calls were added to assess the occurrence of any potential hormonal flare responses to the 11.25 and 30 mg leuprolide acetate depot doses. Clarifications to the adverse event assessment section were made. Windows for retrospective diagnostic imaging (diagnostic brain imaging by magnetic resonance imaging (MRI)/computed tomography (CT) scan; screening pelvic, adrenal, and testicular ultrasounds) and laboratory test results (beta human chorionic gonadotropin [β-hCG] in male subjects, adrenal blood tests, GnRHa stimulation testing) were increased. Growth rate and bone age versus chronological age were changed from additional endpoints to secondary endpoints, and peak-stimulated luteinizing hormone concentration was added as a secondary endpoint. 14. Prior and concomitant use of insulin-like growth factor-1 (IGF-1) and use of estrogen preparations within 2 months of Day 1 were added as exclusionary criteria.

As a result of the transition of the Lupron program from TAP Pharmaceuticals to Abbott, the primary purpose of Amendment 2 was to document changes regarding Sponsor name and contact information and to provide a new fax number and a revised timeline for reporting serious adverse events to Abbott. Major changes included the following: -include convulsions as a rarely reported event -document that the commercially-available generic leuprolide acetate daily injection (Leuprolide Acetate Injection) will be used to conduct the GnRHa Stimulation test -clarify that a copy of the hand-wrist radiograph will be maintained at the study site in the subject's study file and include reference to (and a sample of) the Hand/Wrist Radiograph Transmittal Form that is submitted with the radiograph to Lifespan -clarify that screening baseline sex steroids are required even if a stimulation test in the treatment-naïve population was performed within the past 30 days -clarify that at the Month 6 and Early Discontinuation Visits, the blood collections for basal gonadotropin and sex steroids are relative to the Day 1 depot Injection -clarify that the congenital adrenal hyperplasia (CAH) panel was not required if an alternative cause of precocious puberty had been ruled-out, that testosterone levels were only performed on males, and that an adrenocorticotropic hormone (ACTH) stimulation test was required prior to randomization if the initial Screening CAH panel results were inconclusive -incorporate a longer study duration as a result of the enrollment period having been extended a few months -update criteria for withdrawal (accelerated progression of pubertal symptoms, excluding pubic hair, any time after the Month 2 study visit) -clarify premature discontinuation from trial, permitted/prohibited medications, adverse event and serious adverse event procedures