Theophylline Treatment for Pseudohypoparathyroidism

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ClinicalTrials.gov Identifier: NCT03029429

Recruitment Status : Recruiting

First Posted : January 24, 2017

Last Update Posted : August 6, 2021

See Contacts and Locations

Sponsor:

Collaborator:

Harvard University

Information provided by (Responsible Party):

Ashley Shoemaker, Vanderbilt University Medical Center

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Pseudohypoparathyroidism Albright Hereditary Osteodystrophy	Drug: Theophylline Drug: Placebos	Phase 2

Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	34 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Phase 2 Study of Theophylline Treatment for Pseudohypoparathyroidism
Actual Study Start Date :	September 1, 2018
Estimated Primary Completion Date :	July 1, 2023
Estimated Study Completion Date :	November 1, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Theophylline

Genetic and Rare Diseases Information Center resources: Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Albright's Hereditary Osteodystrophy Pseudohypoparathyroidism Type 1A

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Theophylline Theophylline capsules by mouth once daily or Theophylline elixir by mouth q6h (dose determined by serum drug levels)	Drug: Theophylline oral theophylline Other Name: Theo-24, Elixophyllin
Placebo Comparator: Placebos Theophylline capsule by mouth once daily or Theophylline elixir by mouth q6h	Drug: Placebos oral placebo Other Name: placebo

Outcome Measures

Primary Outcome Measures :

Change in body mass index [ Time Frame: baseline and 52 weeks ]
BMI will be expressed a percent of the 95th percentile

Secondary Outcome Measures :

Change in insulinogenic index [ Time Frame: baseline and 52 weeks ]
Insulinogenic index measured during a 75g oral glucose tolerance test
change in levothyroxine dose [ Time Frame: baseline and 52 weeks ]
levothyroxine dose (mcg/kg/day)
change in calcitriol dose [ Time Frame: baseline and 52 weeks ]
calcitriol dose (mcg/kg/day)

Other Outcome Measures:

Change in body mass index z-score [ Time Frame: baseline and 52 weeks ]
Change in BMI [ Time Frame: 52 weeks ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	13 Years to 99 Years (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03029429

Contacts

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Contact: Sarah Wright, RN	6153438116	sarah.e.wright@vumc.org
Contact: Ashley Shoemaker	6153438116	ashley.h.shoemaker@vumc.org

Locations

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United States, Tennessee
Ashley Shoemaker	Recruiting
Nashville, Tennessee, United States, 37212
Contact: Ashley Shoemaker, MD 615-343-8116 ashley.h.shoemaker@vanderbilt.edu
Principal Investigator: Ashley Shoemaker, MD, MSCI

Sponsors and Collaborators

Vanderbilt University Medical Center

Harvard University

Investigators

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Principal Investigator:	Ashley Shoemaker, MD	Vanderbilt University Medical Center

More Information

Additional Information:

Vanderbilt PHP Research Page This link exits the ClinicalTrials.gov site

Publications:

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

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.

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.

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.

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.

Perez KM, Lee EB, Kahanda S, Duis J, Reyes M, Jüppner 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.

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.

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, Jüppner 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.

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Responsible Party:	Ashley Shoemaker, Assistant Professor of Pediatrics, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier:	NCT03029429
Other Study ID Numbers:	IND 133103
First Posted:	January 24, 2017 Key Record Dates
Last Update Posted:	August 6, 2021
Last Verified:	August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Ashley Shoemaker, Vanderbilt University Medical Center:


pseudohypoparathyroidism AHO Albright Hereditary Osteodystrophy

Additional relevant MeSH terms:

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Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Bone Diseases, Metabolic Bone Diseases Musculoskeletal Diseases Metal Metabolism, Inborn Errors Metabolism, Inborn Errors Genetic Diseases, Inborn Metabolic Diseases Calcium Metabolism Disorders Theophylline Bronchodilator Agents Autonomic Agents	Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Asthmatic Agents Respiratory System Agents Phosphodiesterase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Vasodilator Agents Purinergic P1 Receptor Antagonists Purinergic Antagonists Purinergic Agents Neurotransmitter Agents

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