Theophylline Treatment for Pseudohypoparathyroidism

Pseudohypoparathyroidism Clinical Trial

Official title:

Phase 2 Study of Theophylline Treatment for Pseudohypoparathyroidism

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03029429
• Other study ID #: IND 133103
• Status: Recruiting
• Phase: Phase 2
• Start date: September 1, 2018
• Est. completion date: November 1, 2026

Study information

• Verified date: April 2024
• Source: Vanderbilt University Medical Center
• Contact: Jenny Leshko, RN
• Phone: 6153438116
• Email: jenny.leshko[@]vumc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 34
• Est. completion date: November 1, 2026
• Est. primary completion date: July 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Albright Hereditary Osteodystrophy
• Pseudohypoparathyroidism

Intervention

Drug:
• Theophylline
oral theophylline
• Placebos
oral placebo

Locations

Country	Name	City	State
United States	Ashley Shoemaker	Nashville	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center	Harvard University

Country where clinical trial is conducted

United States, 

References & Publications (8)

Curley KL, Kahanda S, Perez KM, Malow BA, Shoemaker AH. Obstructive Sleep Apnea and Otolaryngologic Manifestations in Children with Pseudohypoparathyroidism. Horm Res Paediatr. 2018;89(3):178-183. doi: 10.1159/000486715. Epub 2018 Feb 16. — View Citation

Hanna P, Grybek V, Perez de Nanclares G, Tran LC, de Sanctis L, Elli F, Errea J, Francou B, Kamenicky P, Linglart L, Pereda A, Rothenbuhler A, Tessaris D, Thiele S, Usardi A, Shoemaker AH, Kottler ML, Juppner H, Mantovani G, Linglart A. Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity. J Bone Miner Res. 2018 Aug;33(8):1480-1488. doi: 10.1002/jbmr.3450. Epub 2018 Jun 7. — View Citation

Landreth H, Malow BA, Shoemaker AH. Increased Prevalence of Sleep Apnea in Children with Pseudohypoparathyroidism Type 1a. Horm Res Paediatr. 2015;84(1):1-5. doi: 10.1159/000381452. Epub 2015 Apr 23. — View Citation

Mano T, Uchimura K, Hayashi R, Kobahashi T, Fujiwara K, Makino M, Kakizawa H, Nagata M, Nakai A, Wada M, Nagasaka A, Itoh M. Increased urinary phosphate excretion in pseudohypoparathyroidism type II with long-term treatment with phosphodiesterase inhibitor. Horm Metab Res. 1999 Nov;31(11):602-5. doi: 10.1055/s-2007-978804. — View Citation

Perez KM, Lee EB, Kahanda S, Duis J, Reyes M, Juppner H, Shoemaker AH. Cognitive and behavioral phenotype of children with pseudohypoparathyroidism type 1A. Am J Med Genet A. 2018 Feb;176(2):283-289. doi: 10.1002/ajmg.a.38534. Epub 2017 Nov 28. — View Citation

Shoemaker AH, Juppner H. Nonclassic features of pseudohypoparathyroidism type 1A. Curr Opin Endocrinol Diabetes Obes. 2017 Feb;24(1):33-38. doi: 10.1097/MED.0000000000000306. — View Citation

Shoemaker AH, Lomenick JP, Saville BR, Wang W, Buchowski MS, Cone RD. Energy expenditure in obese children with pseudohypoparathyroidism type 1a. Int J Obes (Lond). 2013 Aug;37(8):1147-53. doi: 10.1038/ijo.2012.200. Epub 2012 Dec 11. — View Citation

Wang L, Shoemaker AH. Eating behaviors in obese children with pseudohypoparathyroidism type 1a: a cross-sectional study. Int J Pediatr Endocrinol. 2014;2014(1):21. doi: 10.1186/1687-9856-2014-21. Epub 2014 Oct 15. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in body mass index z-score		baseline and 52 weeks
Other	Change in BMI		52 weeks
Primary	Change in body mass index	BMI will be expressed a percent of the 95th percentile	baseline and 52 weeks
Secondary	Change in insulinogenic index	Insulinogenic index measured during a 75g oral glucose tolerance test	baseline and 52 weeks
Secondary	change in levothyroxine dose	levothyroxine dose (mcg/kg/day)	baseline and 52 weeks
Secondary	change in calcitriol dose	calcitriol dose (mcg/kg/day)	baseline and 52 weeks

External Links

•   Vanderbilt PHP Research Page