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

• ClinicalTrials.gov Identifier: NCT01520467
• Recruitment Status: Unknown
• First Posted: January 30, 2012
• Last Update Posted: August 24, 2016
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

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.

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.

Study Design

• 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

Arms and Interventions

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.

Outcome Measures

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 ]

Eligibility Criteria

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

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.

Contacts and Locations

Locations

France

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

Investigators

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

More Information

• 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
• Last Update Posted: August 24, 2016
• Last Verified: August 2016

Keywords provided by Assistance Publique - Hôpitaux de Paris:

SRS; PWS; pathological adrenarche; aromatase inhibitor; Children

Additional relevant MeSH terms:

Silver-Russell Syndrome; Prader-Willi Syndrome; Syndrome; Disease; Pathologic Processes; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Obesity; Overweight; Overnutrition; Nutrition Disorders; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Musculoskeletal Diseases; Dwarfism; Anastrozole; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists