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Theophylline Treatment for Pseudohypoparathyroidism - Children 2-12 Years Old

NCT ID: NCT04551170

Last Updated: 2025-11-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE2

Total Enrollment

34 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-07-13

Study Completion Date

2026-12-31

Brief Summary

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Pseudohypoparathyroidism is a genetic disorder with limited treatment options, characterized by early-onset obesity, short stature and resistance to multiple hormones. This phase 2 clinical trial and open-label extension study will test the efficacy of theophylline, a phosphodiesterase inhibitor, in pseudohypoparathyroidism. We hypothesize that theophylline will cause weight loss, slow the rate of growth plate closure and decrease hormone resistance in children.

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 short stature 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 clinical trial is to test the efficacy of upstream therapy aimed at correcting the function of Gsα-dependent receptors 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 body mass index (BMI), slow the rate of epiphyseal closure, and decrease hormone resistance in children with PHP through improved Gsα-coupled receptor signaling. The investigators will conduct a 52-week randomized, placebo-controlled clinical trial of theophylline in children 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 repurposing in youth with PHP. Furthermore, the pharmacokinetics of theophylline are well understood, and serum drug levels are easily measured. Our primary outcome is change in BMI. Secondary outcome measures include change in epiphyseal closure and HRT medication doses.

Conditions

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Pseudohypoparathyroidism Albright Hereditary Osteodystrophy Pseudohypoparathyroidism Type 1a

Keywords

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Pseudohypoparathyroidism PHP AHO Albright Hereditary Osteodystrophy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Theophylline

Theophylline capsules by mouth once daily or Theophylline elixir by mouth q6h (dose determined by serum drug levels)

Group Type EXPERIMENTAL

Theophylline

Intervention Type DRUG

oral theophylline

Placebo

Placebo capsule by mouth once daily or Placebo elixir by mouth q6h

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Placebo capsule or elixir

Interventions

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Theophylline

oral theophylline

Intervention Type DRUG

Placebo

Placebo capsule or elixir

Intervention Type DRUG

Other Intervention Names

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Theo-24 Elixophyllin

Eligibility Criteria

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Inclusion Criteria

* Age 2 to 12 years old
* Clinical diagnosis of PHP (per the EuroPHP network classification guidelines5): Presence of PTH resistance and/or ectopic ossification 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

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 (see protection of human subjects)
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. Untreated hypothyroidism or uncontrolled PTH resistance (PTH \>2x upper limit of normal), or treatment of these disorders by medications other than calcitriol or levothyroxine (such as Cytomel or Armour thyroid)
15. Unable to comply with study procedures in the opinion of the investigator
Minimum Eligible Age

2 Years

Maximum Eligible Age

12 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Vanderbilt University Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Ashley Shoemaker

Assistant Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Ashley Shoemaker, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

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Vanderbilt University Medical Center

Nashville, Tennessee, United States

Site Status

Countries

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United States

References

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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.

Reference Type BACKGROUND
PMID: 29193623 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 29455209 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 27875418 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25337124 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 10598827 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25925491 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 29693731 (View on PubMed)

Related Links

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http://www.facebook.com/pseudohypoparathyroidism

Vanderbilt PHP Research Page

Other Identifiers

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IND 133103 R01

Identifier Type: -

Identifier Source: org_study_id