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

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ClinicalTrials.gov Identifier: NCT01520467
Recruitment Status : Unknown
Verified August 2016 by Assistance Publique - Hôpitaux de Paris.
Recruitment status was:  Active, not recruiting
First Posted : January 30, 2012
Last Update Posted : August 24, 2016
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.

Condition or disease Intervention/treatment Phase
Silver Russell Syndrome Prader-Willi Syndrome Drug: Anastrozole Drug: Placebo Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : April 2012
Actual Primary Completion Date : July 2016
Estimated Study Completion Date : October 2016

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.

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. impact on the gonadotropic axis [ Time Frame: baseline, 6, 12 and 18 months ]
  4. impact on the somatotropic axis (growth rate, IGF-1, IGFBP3). [ Time Frame: baseline, 6, 12 and 18 months ]

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Ages Eligible for Study:   5 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01520467

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Explorations Fonctionnelles d'Endocrinologie - Centre de Référence des Maladies Endocriniennes Rares de la Croissance Hôpital Armand Trousseau
Paris, France, 75012
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
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Principal Investigator: Irène Netchine, MD, PhD Assistance Publique
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01520467    
Other Study ID Numbers: P 100129
AOM 10093 ( Other Identifier: Assistance Publique )
First Posted: January 30, 2012    Key Record Dates
Last Update Posted: August 24, 2016
Last Verified: August 2016
Keywords provided by Assistance Publique - Hôpitaux de Paris:
pathological adrenarche
aromatase inhibitor
Additional relevant MeSH terms:
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Silver-Russell Syndrome
Prader-Willi Syndrome
Pathologic Processes
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Nutrition Disorders
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists