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

Primary Purpose

Silver Russell Syndrome, Prader-Willi Syndrome

Status

Unknown status

Phase

Not Applicable

Locations

France

Study Type

Interventional

Intervention

Anastrozole

Placebo

About this trial

This is an interventional treatment trial for Silver Russell Syndrome focused on measuring SRS, PWS, pathological adrenarche, aromatase inhibitor, Children

Eligibility Criteria

5 Years - 12 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Explorations Fonctionnelles d'Endocrinologie - Centre de Référence des Maladies Endocriniennes Rares de la Croissance Hôpital Armand Trousseau

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Anastrozole

Placebo

Arm Description

stratification according to the rare disease. Oral administration of Anastrozole (1mg/day) for 18 months

stratification according to the rare disease. Oral administration of 1 placebo tablet /day for 18 months

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

metabolic impact (monitoring of body composition by bi photonic absorptiometry, lipid, glucose, HbA1c, insulin and HOMA-IR profiles, leptin).

impact on bone (X-ray of the dorsolumbar spine, bi photonic absorptiometry, blood-borne markers of bone remodeling).

impact on the gonadotropic axis

impact on the somatotropic axis (growth rate, IGF-1, IGFBP3).

Full Information

NCT ID

NCT01520467

First Posted

January 25, 2012

Last Updated

August 23, 2016

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT01520467

Brief Title

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

Acronym

ANASILPRA

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2016

Overall Recruitment Status

Unknown status

Study Start Date

April 2012 (undefined)

Primary Completion Date

July 2016 (Actual)

Study Completion Date

October 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Silver Russell Syndrome, Prader-Willi Syndrome

Keywords

SRS, PWS, pathological adrenarche, aromatase inhibitor, Children

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

27 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Anastrozole

Arm Type

Experimental

Arm Description

stratification according to the rare disease. Oral administration of Anastrozole (1mg/day) for 18 months

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

stratification according to the rare disease. Oral administration of 1 placebo tablet /day for 18 months

Intervention Type

Drug

Intervention Name(s)

Anastrozole

Intervention Description

Anastrozole (1mg/day), administered orally for 18 months

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

1 placebo tablet /day administered orally for 18 months.

Primary Outcome Measure Information:

Title

Description

Time Frame

18 months

Secondary Outcome Measure Information:

Title

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

Title

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

Title

impact on the gonadotropic axis

Time Frame

baseline, 6, 12 and 18 months

Title

impact on the somatotropic axis (growth rate, IGF-1, IGFBP3).

Time Frame

baseline, 6, 12 and 18 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

5 Years

Maximum Age & Unit of Time

12 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Irène Netchine, MD, PhD

Organizational Affiliation

Assistance Publique

Official's Role

Principal Investigator

Facility Information:

Facility Name

Explorations Fonctionnelles d'Endocrinologie - Centre de Référence des Maladies Endocriniennes Rares de la Croissance Hôpital Armand Trousseau

City

Paris

ZIP/Postal Code

75012

Country

France

12. IPD Sharing Statement

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

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