Theophylline Treatment for Pseudohypoparathyroidism

  • End date
    Nov 1, 2023
  • participants needed
  • sponsor
    Vanderbilt University Medical Center
Updated on 4 October 2022


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 (Gs) 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. Gs 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 Gs-dependent receptors responsible for the obesity (melanocortin-4 receptor, MC4R) and short stature (parathyroid hormone, PTH, receptor) phenotype in children with PHP. Gs-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 Gs-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.

Condition Pseudohypoparathyroidism, Albright Hereditary Osteodystrophy
Treatment placebos, Theophylline
Clinical Study IdentifierNCT03029429
SponsorVanderbilt University Medical Center
Last Modified on4 October 2022


Yes No Not Sure

Inclusion Criteria

Age 13 years and above
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)
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
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
Unable to comply with study procedures in the opinion of the investigator
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