Study of Leuprolide Acetate Injectable Suspension in the Treatment of Central Precocious Puberty

An Open-label, Single Arm, Multicenter Study on the Efficacy, Safety, and Pharmacokinetics of Leuprolide Acetate 45 mg for Injectable Suspension Controlled Release in Subjects With Central (Gonadotropin-Dependent) Precocious Puberty

This study determines the effectiveness of leuprolide acetate 45 mg for injectable suspension for treatment of children with Central Precocious Puberty.

Study Overview

• Status: Completed
• Conditions: Precocious Puberty, Central
• Intervention / Treatment: Drug: Leuprolide Acetate 45 mg

Detailed Description

Leuprolide acetate is a GnRH agonist that inhibits pituitary gonadotropin secretion by binding to the GnRH receptors and blocking downstream hormone synthesis. The steady decrease in hormone synthesis (LH and FSH) leads to a suppression of testicular and ovarian steroidogenesis. In children with CPP, this steady decrease in hormone synthesis disrupts the progression of puberty.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425EFD
    • Hospital de Niños
• Canada
  • Quebec, Canada, G1V 4G2
    • CHU de Québec-Université Laval
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • University of Calgary, Alberta Children's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre
• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile, 8330074
      • Pontificia Universidad Catolica de Chile
    • Santiago, Metropolitana, Chile, 8360160
      • Instituto de Investigaciones Materno Infantil (IDIMI)
  • Second Region
    • Antofagasta, Second Region, Chile, 1270001
      • Hospital Regional de Antofagasta Leonardo Guzman
• Mexico
  • Durango, Mexico, 34000
    • Instituto de Investigaciones Aplicadas a la Neurociencia, A.C.
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64460
      • Hospital Unversitario "Dr. Jose Eleuterio Gonzalez"
• New Zealand
  • Auckland, New Zealand, 1023
    • The Liggins Institute, University of Auckland
• United States
  • California
    • San Diego, California, United States, 92123
      • University of California, San Diego
  • Florida
    • Hollywood, Florida, United States, 33021
      • Joe DiMaggio Children's Hospital
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children at Indiana University Health
  • Minnesota
    • Minneapolis, Minnesota, United States, 55414
      • University of Minnesota
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center, Endocrine
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74135
      • University of Oklahoma College of Medicine
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's
    • Tacoma, Washington, United States, 98405
      • MultiCare Institute for Research and Innovation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 9 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Females age 2 to 8 years (inclusive) or males age 2 to 9 years (inclusive)
• Confirmed diagnosis of CPP within 12 months of Baseline Visit (Day 0) but have not received prior GnRH agonist treatment for CPP
• Pubertal-type LH response following an abbreviated GnRHa stimulation test before treatment initiation
• Clinical evidence of puberty, defined as Tanner stage ≥ 2 for breast development in females or testicular volume ≥ 4 mL in males
• Difference between bone age (Greulich and Pyle method) and chronological age ≥ 1 year

Exclusion Criteria:

• Gonadotropin-independent (peripheral) precocious puberty
• Prior or current GnRH treatment for CPP
• Prior or current therapy with medroxyprogesterone acetate, growth hormone or insulin-like growth factor-1 (IGF-1)
• Diagnosis of short stature (ie, 2.25 standard deviations (SD) below the mean height for age)
• Known history of seizures, epilepsy, and/or central nervous system disorders that may be associated with seizures or convulsions
• Any other medical condition or serious intercurrent illness that, in the opinion of the Investigator, may make it undesirable for the subject to participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Assigned Intervention; Leuprolide acetate 45 mg will be administered as a subcutaneous injection at 6-month intervals for the 12 month study period.	Drug: Leuprolide Acetate 45 mg; Subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Suppression of Peak-Stimulated Luteinizing Hormone at 6 Months.	Luteinizing Hormone (LH) suppression is defined as peak-stimulated LH <4 IU/L. Peak stimulated LH refers to the maximum LH concentration measured 30 minutes after a gonadotropin-releasing hormone agonst (GnRHa) stimulation test.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects With Suppression of Luteinizing Hormone Measured by Blood Levels.	Percentage of subjects with suppressed serum LH concentrations(<4 IU/L) 30 minutes post GnRHa stimulation test at all assessed timepoints.	Week 12, Week 24, Week 36, and Week 48
Changes in Height Velocity (Growth Rate)	Changes in height velocity (growth rate) at all study timepoints after Screening to end of study. Growth velocity is defined for each visit as change from baseline / [(number of weeks since baseline)/52]. Week 48: Change from Week 24 growth velocity is defined as change from week 24 to week 48 / [(number of weeks since week 24)/52].	Week 4, Week 12, Week 20, Week 24, Week 36, Week 44, and Week 48
Bone Age Ratio to Chronological Age at Time of Measurement	Bone Age Ratio to Chronological Age at Time of Measurement is bone age/age at bone age assessment.	Week 24 and Week 48
Percent Change From Baseline in Height	The percent change from baseline in height at each available post-baseline measurement. Percent change is defined as (((change from Baseline)/(Baseline)) x 100).	Week 4, Week 12, Week 20, Week 24, Week 36, Week 44, and Week 48
Tanner Scores: Boys - Development of External Genitalia	Sexual development (physical signs) in puberty were assessed by Tanner staging, a system developed by Marshall and Tanner to categorize pubertal maturation. Tanner stages are commonly used to categorize pubertal maturation in terms of sequence, timing and tempo. Tanner Stages: the minimum is Stage 1 = pre-pubertal physical characteristics and the maximum is Stage 5 = fully matured (adult) physical characteristics.	Baseline, Week 12, Week 24, Week 36, and Week 48
Tanner Scores: Boys - Development of External Genitalia (Change From Baseline)	Sexual development (physical signs) in puberty were assessed by Tanner staging, a system developed by Marshall and Tanner to categorize pubertal maturation. Tanner stages are commonly used to categorize pubertal maturation in terms of sequence, timing and tempo. Tanner Stages: the minimum is Stage 1 = pre-pubertal physical characteristics and the maximum is Stage 5 = fully matured (adult) physical characteristics.	Week 12, Week 24, Week 36, and Week 48
Tanner Scores: Boys and Girls - Pubic Hair	Sexual development (physical signs) in puberty were assessed by Tanner staging, a system developed by Marshall and Tanner to categorize pubertal maturation. Tanner stages are commonly used to categorize pubertal maturation in terms of sequence, timing and tempo. Tanner Stages: the minimum is Stage 1 = pre-pubertal physical characteristics and the maximum is Stage 5 = fully matured (adult) physical characteristics.	Baseline, Week 12, Week 24, Week 36, and Week 48
Tanner Scores: Boys and Girls - Pubic Hair (Change From Baseline)	Sexual development (physical signs) in puberty were assessed by Tanner staging, a system developed by Marshall and Tanner to categorize pubertal maturation. Tanner stages are commonly used to categorize pubertal maturation in terms of sequence, timing and tempo. Tanner Stages: the minimum is Stage 1 = pre-pubertal physical characteristics and the maximum is Stage 5 = fully matured (adult) physical characteristics.	Week 12, Week 24, Week 36, and Week 48
Tanner Scores: Girls - Breast Development	Sexual development (physical signs) in puberty were assessed by Tanner staging, a system developed by Marshall and Tanner to categorize pubertal maturation. Tanner stages are commonly used to categorize pubertal maturation in terms of sequence, timing and tempo. Tanner Stages: the minimum is Stage 1 = pre-pubertal physical characteristics and the maximum is Stage 5 = fully matured (adult) physical characteristics.	Baseline, Week 12, Week 24, Week 36, and Week 48
Tanner Scores: Girls - Breast Development (Change From Baseline)	Sexual development (physical signs) in puberty were assessed by Tanner staging, a system developed by Marshall and Tanner to categorize pubertal maturation. Tanner stages are commonly used to categorize pubertal maturation in terms of sequence, timing and tempo. Tanner Stages: the minimum is Stage 1 = pre-pubertal physical characteristics and the maximum is Stage 5 = fully matured (adult) physical characteristics.	Week 12, Week 24, Week 36, and Week 48

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Height	Height at each available measurement point. Baseline is defined as the last non-missing height measurement collected prior to or on the date of first injection.	Screening, Baseline, Week 4, Week 12, Week 20, Week 24, Week 36, Week 44, and Week 48
Bone Age	Bone Age at each available measurement point.	Baseline, Week 24, and Week 48
Bone Age Progression	Bone age progression at each available post-baseline measurement point. Bone age progression is defined as (((change from baseline)/(baseline)) x 100), which is percent change from baseline.	Week 24 and Week 48
Bone Age Ratio to Chronological Age at Time of Measurement (Percent Change From Baseline)	Bone Age Ratio to Chronological Age at Time of Measurement is bone age/age at bone age assessment.	Week 24 and Week 48
Bone Age Ratio to Chronological Age at Start of Study (Percent Change From Baseline)	Bone age advancement was evaluated relative to chronological age at each given measurement point. Percent change from baseline is: 100 x (the change from baseline value at the post-baseline visit / baseline value).	Week 24 and Week 48
Bone Age Ratio to Chronological Age at Start of Study	Bone age advancement was evaluated relative to chronological age at each given measurement point. Bone Age Ratio to Chronological Age at Start of Study is bone age/age at first injection.	Baseline, Week 24, and Week 48
GnRH Antagonist Evaluation	GnRH Antagonist Evaluation occurred for the two week period following each treatment and at each visit to assess flare symptoms. The percent of subjects who affirm (or whose parent/guardian affirms) each symptom domain in the global interview.	Week 2, Week 4, Week 12, Week 20, Week 24, Week 26, Week 36, Week 44, and Week 48
Percentage of Subjects With Suppression of FSH, Estradiol, Oestradiol (HS), and Testosterone Measured by Blood Levels.	The percentage of subjects with FSH, estradiol and testosterone suppression to prepubertal levels (FSH < 2.5 mIU/mL, estradiol < 20 pg/mL and testosterone < 28.4 ng/dL) at each available time point.	Week 12, Week 24, Week 36, and Week 48
Changes in the Ratio of LH/FSH	Changes in ratio of LH/FSH at each time point from Screening to End of Study	Screening (Pre&Post GnRHa Stim Test), Baseline (0,1,4,6 hours Post-Injection), Week 4, Week 12 (Pre&Post GnRHa Stim Test), Week 20, Week 24 (Pre&Post GnRHa Stim Test), Week 36 (Pre&Post GnRHa Stim Test), Week 44, and Week 48 (Pre&Post GnRHa Stim Test)

Collaborators and Investigators

• Sponsor: Tolmar Inc.
• Investigators: Study Director: Peggy Schorr, orphan reach USA, LLC

Publications and helpful links

General Publications

• Klein KO, Freire A, Gryngarten MG, Kletter GB, Benson M, Miller BS, Dajani TS, Eugster EA, Mauras N. Phase 3 Trial of a Small-volume Subcutaneous 6-Month Duration Leuprolide Acetate Treatment for Central Precocious Puberty. J Clin Endocrinol Metab. 2020 Oct 1;105(10):e3660-71. doi: 10.1210/clinem/dgaa479. Erratum In: J Clin Endocrinol Metab. 2021 Jun 16;106(7):e2842.

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2015
• Primary Completion (Actual): September 5, 2018
• Study Completion (Actual): September 5, 2018

Study Registration Dates

• First Submitted: May 5, 2015
• First Submitted That Met QC Criteria: May 20, 2015
• First Posted (Estimate): May 25, 2015

Study Record Updates

• Last Update Posted (Actual): June 2, 2020
• Last Update Submitted That Met QC Criteria: May 19, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Gonadal Disorders; Puberty, Precocious; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Leuprolide
• Other Study ID Numbers: TOL2581A