Theophylline Treatment for Pseudohypoparathyroidism

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase 2 Study of Theophylline Treatment for Pseudohypoparathyroidism

Conditions
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Pseudohypoparathyroidism, Albright Hereditary Osteodystrophy

Intervention / Treatment
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* Drug: Theophylline
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Theophylline<br>Theophylline capsules by mouth once daily or Theophylline elixir by mouth q6h (dose determined by serum drug levels) | Drug: Theophylline<br>* oral theophylline<br>* Other names: Theo-24, Elixophyllin;|
| Placebo Comparator: Placebos<br>Theophylline capsule by mouth once daily or Theophylline elixir by mouth q6h | Drug: Placebos<br>* oral placebo<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in body mass index | BMI will be expressed a percent of the 95th percentile | baseline and 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulinogenic index | Insulinogenic index measured during a 75g oral glucose tolerance test | baseline and 52 weeks | 
| change in levothyroxine dose | levothyroxine dose (mcg/kg/day) | baseline and 52 weeks | 
| change in calcitriol dose | calcitriol dose (mcg/kg/day) | baseline and 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pseudohypoparathyroidism, AHO, Albright Hereditary Osteodystrophy