FRI596 Randomized Clinical Trial Of Theophylline For Treatment Of Pseudohypoparathyroidism Type 1a

Disclosure: A.H. Shoemaker: None. J. Tamaroff: None. H. Jueppner: None. Background: Pseudohypoparathyroidism type 1A (PHP1A) is a rare, genetic disorder caused by heterozygous inactivating mutations involving the maternal GNAS allele, the gene that encodes the stimulatory G protein (Gsα). Due to tissue specific reduced paternal Gsα expression, several tissues, particularly proximal renal tubules and thyroid, show decreased Gsα-coupled receptor function. Resultant hormone resistances can be treated, but other aspects of PHP1A such as early-onset obesity and short stature are without effective treatment options. Gsα-coupled receptor signaling cascade begins with agonist-stimulated increase in cAMP, the second messenger which is rapidly degraded by phosphodiesterase (PDE). Given that PHP1A patients have reduced, but not completely absent, cAMP production, this clinical trial will test the hypothesis that the non-selective PDE inhibitor theophylline will improve Gsα-coupled receptor signaling. We describe the study design and baseline characteristics of PHP1A patients enrolled in a double-blind, randomized, placebo-controlled clinical trial of theophylline. Methods: A single center will enroll 34 patients. Inclusion criteria: age >=2 years old, diagnosis of PHP1A and obesity. Exclusion criteria include seizure disorder, uncontrolled hormone resistance, pregnancy, and other significant medical problems. Enrollment starts with the oldest age group (>=13 years) and safety/efficacy is reviewed by the DSMB after each block of 6 patients before opening to the next age block (7-12 and 2-6 years). Patients are randomized to theophylline vs. placebo using a permuted-block randomization (2:1) stratified by age and gender. Theophylline levels guide dosing with a goal level of 10-19 mcg/mL. Unblinded study staff review theophylline levels and the dosing protocol includes sham placebo dose adjustments. The primary outcome is change in BMI, expressed as % of the 95(th) %ile (BMI95), to account for age and gender. Secondary endpoints include changes in glucose tolerance and insulin secretion (insulinogenic index), rate of epiphyseal closure and hormone replacement doses. Results: To date we have screened 27 and enrolled 24 patients. Enrollment in the youngest age block (2-6 years) opened in December 2022. Enrolled patients range from 4 to 55 years old (mean 16.0 ± 10.4 years, 18 pediatric patients), 92% are female, 100% are white and 13% are Hispanic. All patients were obese with a mean BMI95 130.8 ± 23.8%. Three adult patients withdrew due to headaches, nausea/difficulty swallowing pills or travel difficulties. The most common adverse event related to study drug was transient nausea/vomiting. Conclusion: This randomized clinical trial designed to test safety and efficacy of theophylline for PHP1A is ongoing. Thus far the study drug and procedures have been safe and well tolerated. Presentation: Friday, June 16, 2023