Aromatase Inhibitor in Bone Maturation, Children With Silver Russell or Prader-Willi Syndrome (ANASILPRA)

August 23, 2016 updated by: Assistance Publique - Hôpitaux de Paris

Efficacy and Tolerance of Treatment With an Aromatase Inhibitor (Anastrozole) to Limit the Progression of Bone Maturation Related to Pathological Adrenarche in Children With Silver-Russell or Prader-Willi Syndrome

There is currently no drug with pediatric marketing authorization capable of limiting the advance in bone maturation of children with aggressive adrenarche. Estrogens are the principal actors involved in bone maturation and premature epiphyseal fusion. Aromatase inhibitors, used for the treatment of hormone-dependent cancers, block the transformation of androgens into estrogens. Third generation inhibitors, of which Anastrozole is one, appear to be well tolerated in children and are sometimes used within the framework of clinical trials to limit bone maturation and improve prognosis with respect to final size, notably in children treated with growth hormone (GH) due to a GH deficit. Nevertheless, the data reported are based on small sample sizes and do not include children with pathological adrenarche.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Silver-Russell syndrome (SRS), which occurs secondary to an imprinting disorder due to the anomalous methylation of chromosome 11 or due to a uniparental disomy of chromosome 7, is a rare syndrome (ORPHA813, OMIM 180860) characterized by growth retardation with an intrauterine onset, a normal head circumference, small postnatal size and major feeding difficulties. Starting at a very young age, the rapid aging of bone can occur even in the absence of central puberty, in association with the production of androgens by the adrenal glands (adrenarche). This advanced bone maturation can compromise final size, even when the child receives growth hormone (GH) treatment for several years.

Prader-Willi syndrome (PWS) is also a rare disease (ORPHA739, OMIM 176270), occurring secondary to an imprinting disorder due to an anomaly in chromosome 15 (paternal deletion or maternal disomy). These children also present feeding difficulties during the first few years of life, as well as small size. They are frequently treated with GH, and their bone age can increase during the course of adrenarche, as in certain patients with SRS.

Study Type

Interventional

Enrollment (Actual)

27

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75012
        • Explorations Fonctionnelles d'Endocrinologie - Centre de Référence des Maladies Endocriniennes Rares de la Croissance Hôpital Armand Trousseau

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 10 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with genetically proven SRS or PWS, under treatment with GH in the usual context of the disease, presenting with adrenarche (defined either by DHEAS levels as a function of age or by the appearance of pubic hair) associated with a bone age at least 6 months greater than chronological age and in the absence of the onset of central puberty (LH peak ≤ LH peak in prepubertal patients, according to the standards of the laboratory performing the GnRH stimulation test for LH and FSH, and dating back to less than 3 months).
  • Patients with medical coverage.
  • The lower age limit for inclusion is 5 years and the upper age limit is 10 complete years for girls and 12 complete years for boys.
  • The maximum body-mass index (BMI) Z-score for inclusion is +4
  • Patients should be capable of swallowing pills of the same size as the experimental drug.

Exclusion Criteria:

  • Renal insufficiency (creatinine clearance, calculated according to the Schwartz formula, lower than 70ml/min/l, 73 m²),
  • Hepatic insufficiency (prothrombin ratio < 50% and factor V < 50%),
  • Hepatic cytolysis (liver transaminases levels greater than twice the normal level for age), cholestasis (gamma-glutamyl transferase (GGT) levels greater than twice the normal level for age),
  • Contraindication to one of the components of Anastrozole or the placebo.
  • Patients with scoliosis requiring surgery.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Anastrozole
stratification according to the rare disease. Oral administration of Anastrozole (1mg/day) for 18 months
Drug: Anastrozole
Anastrozole (1mg/day), administered orally for 18 months
Placebo Comparator: Placebo
stratification according to the rare disease. Oral administration of 1 placebo tablet /day for 18 months
Drug: Placebo
1 placebo tablet /day administered orally for 18 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The rate of success in each of the two groups, evaluated using an X-ray of the left hand and wrist. Success is defined as a difference in the rate of progression of bone maturation of at least 9 months after 18 months of treatment.
Time Frame: 18 months

Principal objective: To evaluate the efficacy of Anastrozole compared to placebo in slowing bone maturation during pathological adrenarche in children with SRS or PWS.

Principal criterion of evaluation: The rate of success in each of the two groups, evaluated using an X-ray of the left hand and wrist. Success is defined as a difference in the rate of progression of bone maturation of at least 9 months after 18 months of treatment.
18 months

Secondary Outcome Measures

Outcome Measure
Time Frame
metabolic impact (monitoring of body composition by bi photonic absorptiometry, lipid, glucose, HbA1c, insulin and HOMA-IR profiles, leptin).
Time Frame: baseline, 6, 12 and 18 months
baseline, 6, 12 and 18 months
impact on bone (X-ray of the dorsolumbar spine, bi photonic absorptiometry, blood-borne markers of bone remodeling).
Time Frame: 18 months, and earlier in case of bone pain
18 months, and earlier in case of bone pain
impact on the gonadotropic axis
Time Frame: baseline, 6, 12 and 18 months
baseline, 6, 12 and 18 months
impact on the somatotropic axis (growth rate, IGF-1, IGFBP3).
Time Frame: baseline, 6, 12 and 18 months
baseline, 6, 12 and 18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Investigators

  • Principal Investigator: Irène Netchine, MD, PhD, Assistance Publique

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2012

Primary Completion (Actual)

July 1, 2016

Study Completion (Anticipated)

October 1, 2016

Study Registration Dates

First Submitted

January 25, 2012

First Submitted That Met QC Criteria

January 27, 2012

First Posted (Estimate)

January 30, 2012

Study Record Updates

Last Update Posted (Estimate)

August 24, 2016

Last Update Submitted That Met QC Criteria

August 23, 2016

Last Verified

August 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P 100129
  • AOM 10093 (Other Identifier: Assistance Publique)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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