Aromatase Inhibitors, Alone And In Combination With Growth Hormone In Adolescent Boys With Idiopathic Short Stature (ThrasherAI)

A Randomized Controlled Trial Of The Use Of Aromatase Inhibitors, Alone And In Combination With Growth Hormone In Adolescent Boys With Idiopathic Short Stature

When treating very short children in puberty we are time-limited, as sex hormones cause the growth plates to fuse and growth to end. Growth Hormone (GH), plus drugs that stop puberty, increase height potential, but leave children sexually infantile at a critical time in development. Human and animal data show that estrogen, in females and males, is a principal regulator of the fusion of the growth plate in puberty. Using aromatase inhibitors (AIs), which block testosterone to estrogen conversion, in boys with different growth disorders, we have shown that AIs may have beneficial effects enhancing height potential in growth-retarded males, without affecting their puberty. However, no direct comparison of the effect of AIs alone vs. conventional GH treatment has been done to date. This study will assess the effect of AIs alone, GH alone and combination treatment in enhancing height potential in adolescent boys with idiopathic short stature.

Study Overview

• Status: Completed
• Conditions: Idiopathic Short Stature
• Intervention / Treatment: Drug: Aromatase Inhibitor; Drug: Growth Hormone; Drug: Aromatase Inhibitor and Growth Hormone

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 3

Contacts and Locations

Study Locations

• Chile
  • Santiago, Chile
    • Veronica Mericq, MD
• United States
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Orlando, Florida, United States, 32801
      • Nemours Children's Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Nemours Children's Clinic- Jefferson

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Males: Ages: 12 - less than 18 years.
• Bone age less than 14 ½ years at study initiation.
• Presence of puberty.
• Idiopathic short stature will be defined as a short child equal or less than -2SD for height, with normal GH responses to stimuli (> or = 5ng/ml to at least 2 secretagogues) or a normal IGF-I and BP-3, normal body proportions and no other identifiable growth pathology.
• Accurate growth data for at least 6 months at baseline is available.

Exclusion Criteria:

• Chronic illnesses.
• Chronic use of glucocorticosteroids.
• Previous use of hormonal treatment with AIs, sex steroids or GH in the preceding 6 months.
• Birth weight small for gestational age (SGA).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aromatase Inhibitor; Anastrozole 1mg or Letrozole 2.5mg daily orally for 2 to 3 years	Drug: Aromatase Inhibitor; Other Names: Arimidex (Anastrozole); Femara (Letrozole)
Active Comparator: Growth Hormone; Somatropin 0.3mg/kg/week divided daily subcutaneously for 2 to 3 years	Drug: Growth Hormone; Other Names: Nutropin (Somatropin); Genotropin (Somatropin)
Active Comparator: Aromatase Inhibitor and Growth Hormone; Anastrozole 1mg or Letrozole 2.5mg orally daily for 2 to 3 years and Somatropin 0.3mg/kg/week divided daily subcutaneously for 2 to 3 years	Drug: Aromatase Inhibitor; Other Names: Arimidex (Anastrozole); Femara (Letrozole); Drug: Growth Hormone; Other Names: Nutropin (Somatropin); Genotropin (Somatropin); Drug: Aromatase Inhibitor and Growth Hormone; Other Names: Arimidex (Anastrozole); Femara (Letrozole); Nutropin (Somatropin); Genotropin (Somatropin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Height	Differences in height gains	0 to 24 months
Change in Predicted Height	Primary efficacy end point: change in predicted height (cm) from baseline at 24 months based on change in bone age (years)	0 to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Bone Density z Score Adjusted for Height		0 to 24 months
Change in Lean Body Mass		0 to 24 months
Change in Body Mass Index		0 to 24 months
Change in IGF-I Concentrations		0 to 24 months
Change in Testosterone		0 to 24 months
Change in Estradiol	Those taking AI alone or AI/GH combined were grouped by type, either anastrozole or letrozole.	0 to 24 months
Change in Estrone		0 to 24 months

Collaborators and Investigators

• Sponsor: Nemours Children's Clinic
• Collaborators: Novartis; Pfizer; AstraZeneca; Genentech, Inc.; Thrasher Research Fund
• Investigators: Principal Investigator: Nelly Mauras, MD, Nemours Children's Clinic Jacksonville

Publications and helpful links

General Publications

• Mauras N, Ross JL, Gagliardi P, Yu YM, Hossain J, Permuy J, Damaso L, Merinbaum D, Singh RJ, Gaete X, Mericq V. Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature. J Clin Endocrinol Metab. 2016 Dec;101(12):4984-4993. doi: 10.1210/jc.2016-2891. Epub 2016 Oct 6.

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: November 2, 2010
• First Submitted That Met QC Criteria: November 23, 2010
• First Posted (Estimate): November 25, 2010

Study Record Updates

• Last Update Posted (Actual): August 7, 2018
• Last Update Submitted That Met QC Criteria: July 9, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Aromatase; Children; Growth; Puberty; GH; Letrozole; Anastrozole
• Additional Relevant MeSH Terms: Endocrine System Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Developmental; Dwarfism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole; Hormones; Anastrozole; Aromatase Inhibitors
• Other Study ID Numbers: 180984