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

• ClinicalTrials.gov Identifier: NCT01467882
• Recruitment Status: Completed
• First Posted: November 9, 2011
• Results First Posted: September 4, 2015
• Last Update Posted: July 28, 2017
• Sponsor: Debiopharm International SA
• Information provided by (Responsible Party): Debiopharm International SA

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Central Precocious Puberty	Drug: Triptorelin	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: April 2012
• Actual Primary Completion Date: August 2013
• Actual Study Completion Date: July 2014

Arms and Interventions

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 Name: Trelstar

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Percentage of Children With LH Suppression to Prepubertal Levels 30 Minutes After Leuprolide Stimulation at Months 1, 2, 3, 9 and 12 [ Time Frame: 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.
2. Percentage of Children Maintaining LH Suppression at Prepubertal Levels 30 Minutes After Leuprolide Stimulation From Month 6 to 12 [ Time Frame: 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.
3. Percentage of Children With LH Suppression (LH ≤ 4 IU/L)30 Minutes After Leuprolide Stimulation at Months 1, 2, 3, 6, 9 and 12 [ Time Frame: 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.
4. Percentage of Children Maintaining LH Suppression at </= 4 IU/L 30 Minutes After Leuprolide Stimulation From Month 6 to 12 [ Time Frame: 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.
5. Change From Baseline in Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) at Months 1, 2, 3, 6, 9, and 12 [ Time Frame: Baseline to Months 1, 2, 3, 6, 9, and 12 ]
6. Change From Baseline in Estradiol Levels at Months 1, 2, 3, 6, 9, and 12 [ Time Frame: Baseline to Months 1, 2, 3, 6, 9, and 12 ]
7. Change From Baseline in Testosterone Levels at Months 1, 2, 3, 6, 9, and 12 [ Time Frame: Baseline to Months 1, 2, 3, 6, 9, and 12 ]
8. Percentage of Children With Prepubertal Estradiol or Testosterone Levels at Months 1, 2, 3, 6, 9, and 12 [ Time Frame: at Months 1, 2, 3, 6, 9, and 12 ]
9. Percentage of Children Without Higher Basal LH and Estradiol or Testosterone [ Time Frame: at 2 days after second triptorelin injection (Day 171) ]
10. Change From Baseline in Height-for-age Z-score Per 2000 CDC Growth Charts at Months 6 and 12 [ Time Frame: Baseline to Months 6 and 12 ]
11. Change From Baseline in Height-for-age Percentile Per 2000 CDC Growth Charts at Months 6 and 12 [ Time Frame: Baseline to Months 6 and 12 ]
12. Change From Baseline in Growth Velocity at Months 6 and 12 [ Time Frame: Baseline to Months 6 and 12 ]
13. Percentage of Participants Without Bone Age / Chronological Age Ratio Increase From Baseline at Months 6 and 12 [ Time Frame: Baseline to Months 6 and 12 ]
14. Percentage of Children Achieving Stabilization of Sexual Maturation at Months 6 and 12 [ Time Frame: at Months 6 and 12 ]
15. Percentage of Girls With Regression of Uterine Length Compared to Baseline at Months 6 and 12 [ Time Frame: Baseline to Months 6 and 12 ]
16. Percentage of Boys With Absence of Progression of Testis Volumes Compared to Baseline at Months 6 and 12 [ Time Frame: Baseline to Months 6 and 12 ]

Eligibility Criteria

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

Criteria

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).

Contacts and Locations

Locations

United States, Arizona

Pediatric Endocrinology of Phoenix

Phoenix, Arizona, United States, 85053

United States, California

Children's National Medical Center

San Diego, California, United States

United States, District of Columbia

Children's National Medical Center

Washington, D.C., District of Columbia, United States

United States, Florida

Arnold Palmer Pediatric Endocrinology Practice

Orlando, Florida, United States

Nancy Wright MD P.A.

Tallahassee, Florida, United States, 32308

United States, Missouri

Washington University

Saint Louis, Missouri, United States

United States, New Jersey

Hackensack university medical center

Hackensack, New Jersey, United States

United States, New York

Women's & Children's Hospital of Buffalo

Buffalo, New York, United States

United States, Ohio

Cincinnati Children's Hospital

Cincinnati, Ohio, United States

United States, Oklahoma

Lynn health Science Institute

Oklahoma City, Oklahoma, United States, 73112

United States, Washington

Swedish Pediatric Specialist

Seattle, Washington, United States

Chile

IDIMI

Santiago, Chile

Mexico

Hospital Universitario de Monterrey

Monterrey, Mexico

Sponsors and Collaborators

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

More Information

Additional Information:

Study sponsor 

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. Review.

Martínez-Aguayo A, Hernández MI, Beas F, Iñiguez 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.

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.

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. Review.

• Responsible Party: Debiopharm International SA
• ClinicalTrials.gov Identifier: NCT01467882 History of Changes
• Other Study ID Numbers: Debio 8206-CPP-301
• First Posted: November 9, 2011
• Results First Posted: September 4, 2015
• Last Update Posted: July 28, 2017
• Last Verified: July 2017

Additional relevant MeSH terms:

Puberty, Precocious; Gonadal Disorders; Endocrine System Diseases; Triptorelin Pamoate; Luteolytic Agents; Contraceptive Agents, Female; Contraceptive Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents