FRI597 Impact Of Theophylline On BMI In Pseudohypoparathyroidism Type 1a - Results Of An Open Label Extension Trial
Bibliographic record
Abstract
Abstract Disclosure: A.H. Shoemaker: None. J. Tamaroff: None. H. Jueppner: None. Background: Pseudohypoparathyroidism type 1a (PHP1A) is a rare genetic disorder characterized by early onset obesity, short stature and multi hormone resistance. The underlying causes are maternally inherited, heterozygous inactivating mutations in GNAS, which encodes the α-subunit of stimulatory G protein (Gsα). Due to tissue specific silencing of paternal Gsα expression, maternal GNAS mutations lead to impaired Gsα-protein coupled receptor (GPCR) function and multihormone resistance. The GPCR signaling cascade begins with increased cAMP which is rapidly degraded by phosphodiesterase (PDE). We hypothesized that paternal Gsα expression is reduced, but not absent, and therefore the nonselective PDE inhibitor theophylline may potentiate the cAMP/PKA-dependent cellular events down-stream of GPCRs. We hypothesized that theophylline would reduce BMI in PHP1A patients while being safe and well tolerated. Methods: Children and adults with PHP1A who completed the randomized, placebo controlled, double-blind clinical trials (RCT) NCT03029429 and NCT04551170 were eligible for enrollment in an open-label extension (OLE) study of theophylline treatment (NCT04240821). As the RCT is ongoing and treatment assignment is blinded, we compared baseline enrollment data (prior to any exposure to theophylline or placebo) with the last study visit in the OLE study. The RCTs are 1 year long and then patients in the OLE study are followed for up to 2 additional years. The primary outcome is change in BMI, expressed as % of the 95th %ile (BMI95) to account for differences in gender and age. Results: To date, 23 patients have enrolled in, and 16 patients have completed the RCTs. Two patients completed RCTs before the OLE was available. One patient was ineligible due to study drug noncompliance. One patient was Canadian and unable to participate due to COVID-19 travel restrictions. The remaining 12 completers enrolled in the OLE. One withdrew prior to OLE visit 2 due to difficulty with travel and is not included in the analysis. Patients were 17.2 ± 12.9 years old (range 9-55 years) and 10 of 11 were female. All participants were white, one patient was Hispanic. Patients were followed for an average of 30 months. Baseline BMI95 was 133.5 ± 19.9% and at the last OLE visit, BMI95 had decreased to 124.7 ± 18.6% (p= 0.06 by paired t-test). A decrease in BMI95 was seen in 73% of patients and 36% had a decrease in BMI95 >20%. Review of the 3 patients without improvement in BMI95 showed one had an increasing BMI95 during the RCT, followed by decreasing BMI95 during the OLE, and another patient had persistently sub-therapeutic theophylline levels. The most common adverse event attributed to the drug was transient nausea/vomiting. There were no OLE withdrawals due to adverse events. Conclusion: Most patients with PHP1A in a long term, OLE study of theophylline demonstrated an improvement in BMI95. Theophylline was safe and well tolerated. Presentation: Friday, June 16, 2023
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.009 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".