Efficacy, Safety, and Pharmacokinetics (PK) of Triptorelin 6-month Formulation in Patients With Central Precocious Puberty

An Open-label, Non-comparative, Multicenter Study on the Efficacy, Safety, and Pharmacokinetics of Triptorelin Pamoate (Embonate) 22.5 mg 6-month Formulation in Patients Suffering From Central (Gonadotropin-dependent) Precocious Puberty

The study will investigate the efficacy, safety and pharmacokinetics of triptorelin 22.5 mg 6-month formulation in 44 patients suffering from central precocious puberty. The total study duration per patient will be 12 months (48 weeks).

Study Overview

• Status: Completed
• Conditions: Central Precocious Puberty
• Intervention / Treatment: Drug: Triptorelin

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 3

Contacts and Locations

Study Locations

• Chile
  • Santiago, Chile
    • IDIMI
• Mexico
  • Monterrey, Mexico
    • Hospital Universitario de Monterrey
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85053
      • Pediatric Endocrinology of Phoenix
  • California
    • San Diego, California, United States
      • Children's National Medical Center
  • District of Columbia
    • Washington, D.C., District of Columbia, United States
      • Children's National Medical Center
  • Florida
    • Orlando, Florida, United States
      • Arnold Palmer Pediatric Endocrinology Practice
    • Tallahassee, Florida, United States, 32308
      • Nancy Wright MD P.A.
  • Missouri
    • Saint Louis, Missouri, United States
      • Washington University
  • New Jersey
    • Hackensack, New Jersey, United States
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States
      • Women's & Children's Hospital of Buffalo
  • Ohio
    • Cincinnati, Ohio, United States
      • Cincinnati Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Lynn Health Science Institute
  • Washington
    • Seattle, Washington, United States
      • Swedish Pediatric Specialist

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:

1. Onset of development of sex characteristics before 8 and 9 years in girls and boys, respectively (breast development in girls or testicular enlargement in boys according to the Tanner method), and candidate to receive at least 12 months of GnRH agonist therapy after study entry.
2. Aged 2-8 years inclusive (i.e. < 9 years) for girls and 2-9 years inclusive (i.e. < 10 years) for boys at initiation of triptorelin treatment.
3. Initiation of triptorelin treatment at the latest 18 months after onset of the first signs of precocious puberty.
4. Difference (Δ) bone age (Greulich and Pyle method) - chronological age ≥ 1 year.
5. Pubertal-type LH response 30 minutes following a GnRH agonist stimulation test before treatment initiation (leuprolide acetate 20 μg/kg SC) ≥ 6 IU/L.
6. Clinical evidence of puberty, defined as Tanner Staging ≥ 2 for breast development for girls and testicular volume ≥ 4 mL (cc) for boys.
7. Informed consent signed by one parent or both parents (as per local requirements), by the liable parent or by the legal guardian (when applicable); assent signed by the child if ≥ 7 years.

Non-inclusion criteria:

1. Gonadotropin-independent (peripheral) precocious puberty: extra pituitary secretion of gonadotropins or gonadotropin-independent gonadal or adrenal sex steroid secretion.
2. Non-progressing isolated premature thelarche.
3. Presence of an unstable intracranial tumour or an intracranial tumour requiring neurosurgery or cerebral irradiation. Patients with hamartomas not requiring surgery are eligible.
4. Evidence of renal (creatinine > 2 x ULN) or hepatic impairment (bilirubin or ASAT > 3 x ULN).
5. Any other condition or chronic illness or treatment possibly interfering with growth or other study endpoints (e.g. chronic steroid use [except mild topical steroids], renal failure, diabetes, moderate to severe scoliosis, previously treated intracranial tumour).
6. Prior or current therapy with a GnRH agonist, medroxyprogesterone acetate, growth hormone or insulin-like growth factor-1 (IGF 1).
7. Major medical or psychiatric illness that could interfere with study visits.
8. Diagnosis of short stature, i.e. > 2.25 SD below the mean height for age.
9. Positive pregnancy test.
10. Known hypersensibility to any of the test materials or related compounds.
11. Use of anticoagulants (heparin and coumarin derivatives).

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: Triptorelin; Triptorelin 22.5 mg, intramuscular (IM), at Day 1 and Day 169	Drug: Triptorelin; Powder and solution for solution for injection; Other Names: Trelstar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Children With Luteinizing Hormone (LH) Suppression to Prepubertal Levels 30 Minutes After Leuprolide Stimulation at Month 6	This is a lab test to see what percentage of participants were returned to normal before-puberty levels at Month 6.	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Children With LH Suppression to Prepubertal Levels 30 Minutes After Leuprolide Stimulation at Months 1, 2, 3, 9 and 12	This is a lab test to see what percentage of children were returned to normal before-puberty levels by the drug at each time point.	at Months 1, 2, 3, 9 and 12
Percentage of Children Maintaining LH Suppression at Prepubertal Levels 30 Minutes After Leuprolide Stimulation From Month 6 to 12	This is a lab test to see what percentage of children stayed at the normal before-puberty level from month 6 to month 12.	from Month 6 to 12
Percentage of Children With LH Suppression (LH ≤ 4 IU/L)30 Minutes After Leuprolide Stimulation at Months 1, 2, 3, 6, 9 and 12	This is a lab test to see what percentage of children were returned to lower than normal before-puberty levels by the drug at each time point.	at Months 1, 2, 3, 6, 9 and 12
Percentage of Children Maintaining LH Suppression at </= 4 IU/L 30 Minutes After Leuprolide Stimulation From Month 6 to 12	This is a lab test to see what percentage of children stayed at the lower than normal before-puberty level from month 6 to month 12.	from Month 6 to 12
Change From Baseline in Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) at Months 1, 2, 3, 6, 9, and 12		Baseline to Months 1, 2, 3, 6, 9, and 12
Change From Baseline in Estradiol Levels at Months 1, 2, 3, 6, 9, and 12		Baseline to Months 1, 2, 3, 6, 9, and 12
Change From Baseline in Testosterone Levels at Months 1, 2, 3, 6, 9, and 12		Baseline to Months 1, 2, 3, 6, 9, and 12
Percentage of Children With Prepubertal Estradiol or Testosterone Levels at Months 1, 2, 3, 6, 9, and 12		at Months 1, 2, 3, 6, 9, and 12
Percentage of Children Without Higher Basal LH and Estradiol or Testosterone		at 2 days after second triptorelin injection (Day 171)
Change From Baseline in Height-for-age Z-score Per 2000 CDC Growth Charts at Months 6 and 12		Baseline to Months 6 and 12
Change From Baseline in Height-for-age Percentile Per 2000 CDC Growth Charts at Months 6 and 12		Baseline to Months 6 and 12
Change From Baseline in Growth Velocity at Months 6 and 12		Baseline to Months 6 and 12
Percentage of Participants Without Bone Age / Chronological Age Ratio Increase From Baseline at Months 6 and 12		Baseline to Months 6 and 12
Percentage of Children Achieving Stabilization of Sexual Maturation at Months 6 and 12		at Months 6 and 12
Percentage of Girls With Regression of Uterine Length Compared to Baseline at Months 6 and 12		Baseline to Months 6 and 12
Percentage of Boys With Absence of Progression of Testis Volumes Compared to Baseline at Months 6 and 12		Baseline to Months 6 and 12

Collaborators and Investigators

• Sponsor: Debiopharm International SA
• Investigators: Principal Investigator: Tala Dajani, MD, Pediatric Endocrinology of Phoenix, Arizona; Principal Investigator: Barry Reiner, MD, Barry J. Reiner, MD, LLC, Baltimore, Maryland; Principal Investigator: Galal Salem, MD, SRCR, Inc, Bell Gardens, California; Principal Investigator: Heidi Shea, MD, Endocrine Associates of Dallas, Plano, Texas; Principal Investigator: Mark Rappaport, MD, Pediatric Endocrine Associates, Atlanta, Georgia; Principal Investigator: Opada Alzohaili, MD, Alzohaili Medical Consultants, Dearborn, Michigan; Principal Investigator: Quentin Van Meter, MD, Van Meter Pediatric Endocrinology, Peachtree City, Georgia; Principal Investigator: David Domek, MD, Lynn health Science Institute, Oklahoma City; Principal Investigator: Kathleen Bethin, MD, Women's & Children's Hospital of Buffalo, New York; Principal Investigator: Paul Kaplowitz, MD, Children's National Medical Center, Washington; Principal Investigator: Karen Klein, MD, Children's National Medical Center, San Diego, California; Principal Investigator: Diane Merritt, MD, Washington University, St. Louis, Missouri; Principal Investigator: Susan Rose, MD, Cincinnati Children's Hospital, Ohio; Principal Investigator: Gad Kletter, MD, Swedish Pediatric Specialist, Seattle, Washington; Principal Investigator: Javier Aisenberg, MD, Hackensack university medical center, New Jersey; Principal Investigator: Dennis Brenner, MD, St. Barnabas Medical Center, Livingston, New Jersey; Principal Investigator: Douglas Rogers, MD, Cleveland Clinic, Ohio; Principal Investigator: Lawrence Silverman, MD, Goryeb Children's Hospital, Morristown, New Jersey; Principal Investigator: Peter Lee, MD, Penn State Hershey Children's Hospital, Pennsylvania; Principal Investigator: Ricardo Gomez, MD, Children's Hospital, New Orleans, Louisiana; Principal Investigator: Fernando Cassorla, MD, IDIMI, Santiago, Chile; Principal Investigator: Joshua Yang, MD, Arnold Palmer Pediatric Endocrinology Practice, Orlando, Florida; Principal Investigator: Erica Eugster, MD, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana; Principal Investigator: Oscar Flores, MD, Hospital Universitario de Monterrey, Mexico; Principal Investigator: Nancy Wright, MD, Nancy Wright MD P.A., Tallahasse, Florida

Publications and helpful links

General Publications

• Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR; ESPE-LWPES GnRH Analogs Consensus Conference Group, Antoniazzi F, Berenbaum S, Bourguignon JP, Chrousos GP, Coste J, Deal S, de Vries L, Foster C, Heger S, Holland J, Jahnukainen K, Juul A, Kaplowitz P, Lahlou N, Lee MM, Lee P, Merke DP, Neely EK, Oostdijk W, Phillip M, Rosenfield RL, Shulman D, Styne D, Tauber M, Wit JM. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009 Apr;123(4):e752-62. doi: 10.1542/peds.2008-1783. Epub 2009 Mar 30.
• Martinez-Aguayo A, Hernandez MI, Beas F, Iniguez G, Avila A, Sovino H, Bravo E, Cassorla F. Treatment of central precocious puberty with triptorelin 11.25 mg depot formulation. J Pediatr Endocrinol Metab. 2006 Aug;19(8):963-70. doi: 10.1515/jpem.2006.19.8.963.
• Houk CP, Kunselman AR, Lee PA. The diagnostic value of a brief GnRH analogue stimulation test in girls with central precocious puberty: a single 30-minute post-stimulation LH sample is adequate. J Pediatr Endocrinol Metab. 2008 Dec;21(12):1113-8. doi: 10.1515/jpem.2008.21.12.1113.
• Lahlou N, Carel JC, Chaussain JL, Roger M. Pharmacokinetics and pharmacodynamics of GnRH agonists: clinical implications in pediatrics. J Pediatr Endocrinol Metab. 2000 Jul;13 Suppl 1:723-37. doi: 10.1515/jpem.2000.13.s1.723.

Helpful Links

• Study sponsor

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: November 7, 2011
• First Submitted That Met QC Criteria: November 8, 2011
• First Posted (Estimate): November 9, 2011

Study Record Updates

• Last Update Posted (Actual): July 28, 2017
• Last Update Submitted That Met QC Criteria: July 27, 2017
• Last Verified: July 1, 2017

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; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Luteolytic Agents; Triptorelin Pamoate
• Other Study ID Numbers: Debio 8206-CPP-301