Theophylline Treatment for Pseudohypoparathyroidism
Theophylline Treatment for Pseudohypoparathyroidism
Pseudohypoparathyroidism is a genetic disorder with limited treatment options. Patients have
 early-onset obesity, short stature and increased risk of type 2 diabetes. This phase 2
 clinical trial will test the efficacy of theophylline, a phosphodiesterase inhibitor, in
 pseudohypoparathyroidism. The investigators hypothesize that theophylline will cause weight
 loss, improve glucose tolerance and slow growth plate closure in children and young adults.
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 premature epiphyseal closure 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 proposal is to test the efficacy
 of upstream therapy aimed at correcting the function of two Gsα-dependent receptors
 responsible for the obesity (melanocortin-4 receptor, MC4R) and short stature (parathyroid
 hormone, PTH, receptor) phenotype 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 BMI, glucose intolerance, and hormone
 resistance in children and young adults with PHP through improved Gsα-coupled receptor
 signaling. The investigators will conduct a 52-week randomized, placebo controlled clinical
 trial of theophylline in children and young adults 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 re-purposing in youth with PHP. Furthermore, the
 pharmacokinetics of theophylline are well understood and serum drug levels are easily
 measured. The investigators primary outcome is change in body mass index. Secondary outcome
 measures include change in glucose tolerance and HRT dose. Anticipating a 10% dropout rate,
 the investigators will enroll 34 patients and expect that 30 patients will complete the
 study.
Inclusion Criteria:

 1. Age 13 years and above

 2. Clinical diagnosis of PHP (per the EuroPHP network classification guidelines1):
 Presence of PTH resistance or ectopic classification 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)

 3. Obesity (BMI >95th percentile for age/gender and/or ≥30 kg/m2)

 Exclusion Criteria:

 1. Use of a PDE inhibitor in the past 30 days

 2. History of a seizure disorder unrelated to hypocalcemia

 3. History of a cardiac arrhythmia (not including bradycardia)

 4. Hepatic insufficiency including cirrhosis and acute hepatitis (AST or ALT >3x upper
 limit of normal)

 5. Congestive heart failure

 6. Current cigarette use or alcohol abuse

 7. Pregnancy or intention to become pregnant during the next year

 8. Untreated hypothyroidism (defined as free thyroxine below the lower limit of normal)

 9. Active peptic ulcer disease

 10. Current use of medications known to effect theophylline levels

 11. History of hypersensitivity to theophylline or other medication components

 12. 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)

 13. PHQ-9 score is ≥15 or suicidal ideation of type 4 or 5 (C-SSR) in the past month

 14. Unable to comply with study procedures in the opinion of the investigator