Theophylline Treatment for Pseudohypoparathyroidism - Children 2-12 Years Old

Pseudohypoparathyroidism is a genetic disorder with limited treatment options, characterized by early-onset obesity, short stature and resistance to multiple hormones. This phase 2 clinical trial and open-label extension study will test the efficacy of theophylline, a phosphodiesterase inhibitor, in pseudohypoparathyroidism. We hypothesize that theophylline will cause weight loss, slow the rate of growth plate closure and decrease hormone resistance in children.

Pseudohypoparathyroidism (PHP) is a rare, genetic disorder caused by impaired stimulatory G protein (Gsα) signaling through downregulation of the gene, GNAS. The resultant hormone abnormalities can be treated with hormone replacement therapy, but other aspects of the disorder such as early-onset obesity and short stature are without effective treatment options. Gsα signaling is essential for the normal hormonal function of the pituitary, thyroid, gonads, renal proximal tubules and hypothalamus. While many of the resulting hormone deficiencies can be treated with hormone replacement therapy (HRT), HRT is not an effective therapy for the severe early-onset obesity and short stature which are major features of the PHP phenotype. Therefore, the goal of this clinical trial is to test the efficacy of upstream therapy aimed at correcting the function of Gsα-dependent receptors in children with PHP. Gsα-coupled receptor signaling cascade begins with an increase in cyclic adenosine monophosphate (cAMP) which is rapidly degraded by the enzyme phosphodiesterase (PDE). PDE inhibitors act by prolonging cAMP signaling by decreasing the rate of degradation. Given that patients with PHP have reduced, but not completely absent, cAMP production, the investigators seek to test the hypothesis that the PDE inhibitor theophylline will reduce body mass index (BMI), slow the rate of epiphyseal closure, and decrease hormone resistance in children with PHP through improved Gsα-coupled receptor signaling. The investigators will conduct a 52-week randomized, placebo-controlled clinical trial of theophylline in children with PHP. Theophylline is a non-selective PDE inhibitor that is generically available and has a long history of use in pediatric patients, making it an ideal drug for repurposing in youth with PHP. Furthermore, the pharmacokinetics of theophylline are well understood, and serum drug levels are easily measured. Our primary outcome is change in BMI. Secondary outcome measures include change in epiphyseal closure and HRT medication doses.

Theophylline capsules by mouth once daily or Theophylline elixir by mouth q6h (dose determined by serum drug levels)

Inclusion Criteria: Age 2 to 12 years old Clinical diagnosis of PHP (per the EuroPHP network classification guidelines5): Presence of PTH resistance and/or ectopic ossification OR brachydactyly type E plus 2 minor criteria (TSH resistance, other hormonal resistance, developmental delay, intrauterine or post-natal growth retardation, obesity/overweight, specific facial features) Obesity (BMI >95th percentile for age/gender and/or ≥30 kg/m2) Exclusion Criteria: Use of a PDE inhibitor in the past 30 days History of a seizure disorder unrelated to hypocalcemia History of a cardiac arrhythmia (not including bradycardia) Hepatic insufficiency including cirrhosis and acute hepatitis (AST or ALT >3x upper limit of normal) Congestive heart failure Current cigarette use or alcohol abuse Pregnancy or intention to become pregnant during the next year Untreated hypothyroidism (defined as free thyroxine below the lower limit of normal) Active peptic ulcer disease Current use of medications known to effect theophylline levels (see protection of human subjects) History of hypersensitivity to theophylline or other medication components History of Major Depressive Disorder in the past 2 years, lifetime history of suicide attempt, history of any suicidal behavior in the past month, history of other sever psychiatric disorders (e.g. schizophrenia, bipolar disorder) PHQ-9 score is ≥15 or suicidal ideation of type 4 or 5 (C-SSR) in the past month Untreated hypothyroidism or uncontrolled PTH resistance (PTH >2x upper limit of normal), or treatment of these disorders by medications other than calcitriol or levothyroxine (such as Cytomel or Armour thyroid) Unable to comply with study procedures in the opinion of the investigator

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