Precocious Puberty Clinical Trial
Official title:
Effects of the Aromatase Inhibitor Letrozole on Pubertal Progression and Indices of Bone Turnover in Girls With Precocious Puberty and McCune-Albright Syndrome (MAS)
This study will test the safety and effectiveness of letrozole in treating precocious (early)
puberty in girls with McCune-Albright syndrome (MAS). The physical changes of puberty, such
as breast enlargement, menstruation and growth spurt, as well as the emotional changes of
this developmental stage, usually begin in girls between the ages of 8 and 14. Girls with
MAS, however, often begin puberty before age 7. In MAS, large ovarian cysts produce high
levels of estrogens (female hormones) that cause the changes of puberty. Children with MAS
also have polyostotic fibrous dysplasia (PFD), a disease of bones that, depending on what
parts of the skeleton are affected, can lead to broken bones or disfigurement of the head,
face, arms and legs, or can cause pressure on nerves and blood vessels. Many children with
MAS have cafe-au-lait spots (increased pigmentation) on areas of their skin as well.
Letrozole is an estrogen-lowering drug that has been approved for treating women with breast
and other cancers. Although the drug has not been tested or approved for use in children,
some pediatric specialists have given it to girls with precocious puberty and MAS and found
that it improves their condition without harmful side effects. This study will examine
whether letrozole can lower estrogen in girls with MAS and arrest puberty. It will also study
the drug's effects on substances involved in bone growth, including calcium, phosphate and
amino acids.
Girls 1 to 8 years old with MAS may be eligible for this study. Patients who were enrolled in
NIH protocol 98-D-0145 (Screening and Natural History of Patients with Polyostotic Fibrous
Dysplasia and the McCune-Albright syndrome) are also eligible. Participants will be admitted
to the hospital for 2 to 3 days every 3 months for 15 months, for a total of 6 visits. They
will undergo a complete history and physical examination and routine blood and urine tests
every visit, as well as evaluations of their general health, growth and bone development,
endocrine system (hormone-secreting glands) status and PFD status. A hand X-ray will be taken
at the first visit and every 6 months to measure bone age advance. The children will begin
taking letrozole at the second visit and continue the drug for 6 months. They will be
evaluated after 3 months and 6 months on the drug (visits 3 and 4), and again after 3 months
and 6 months after stopping treatment (visits 5 and 6).
Parents of children who weigh more than 18 kilograms (about 40 pounds) may be asked if extra
blood may be drawn after 3 months (visit 3) and 6 months (visit 4) of treatment to measure
letrozole levels. The blood will be drawn before the morning dose and at 0.5, 1, 1.5, 2, 3,
4, 6, 8, and 24 hours after the dose through an indwelling needle placed in the vein for 8 to
24 hours.
Parents will keep a record of all episodes of menstrual bleeding and any other symptoms or
complaints. Children who respond well to therapy (decreased menses, slowed breast
development, slowed growth and bone age advance) will be offered another 12 months of
letrozole treatment.
Girls ages 1 - 8 years with the McCune-Albright syndrome (MAS) and girls with other conditions characterized by precocious puberty due to estrogen hypersecretion from ovarian cysts will be eligible for this pilot study. Patients who have previously enrolled in Protocol 98-D-0145 (Screening and natural history of patients with polyostotic fibrous dysplasia and the McCune-Albright Syndrome) will also be eligible. Patients will be treated with letrozole, a potent, nonsteroidal aromatase inhibitor, to suppress their elevated serum estrogen levels. We will confirm the safety and efficacy of letrozole, and study its effectiveness in controlling the elevated sex steroid levels, and the advanced rates of linear growth, bone maturation, and pubertal progression in these patients. We will also study the effect of decreased estrogen levels on the status of their polyostotic fibrous dysplasia by measuring serum and urine values for bone biomarkers, including calcium, phosphate, organic amino acids, and vitamin D metabolites, which are known to be abnormal in many patients with MAS. Patients will act as their own controls. We will compare serum and urine parameters of pubertal progression and bone biomarkers before, during, and after discontinuation of letrozole. This trial will be carried out in parallel with in-vitro and in-vivo laboratory studies using an animal model of fibrous dysplasia. In this model, osteogenic precursor cells from patient bone biopsies will be cultured in a hydroxyapatite/tricalcium phosphate matrix and transplanted into immunocompromised mice. We anticipate that our laboratory findings will complement the care of our patients, resulting in more effective treatment for the precocious puberty and the bone disease in children with MAS. Because our initial studies have indicated that letrozole is effective in treating precocious puberty in MAS patients, this protocol also enrolls girls who have a related condition, gonadotropin-independent precocious puberty without the bone disease polyostotic fibrous dysplasia. We also believe that this study complements the recent FDA and NIH mandates that children be included in the evaluation of pharmaceutical products and in federally funded clinical research studies. ;
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