Theophylline Treatment for Pseudohypoparathyroidism

April 23, 2026 updated by: Jaclyn Tamaroff, Vanderbilt University Medical Center

Phase 2 Study of Theophylline Treatment for Pseudohypoparathyroidism

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

29

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Tennessee
      • Nashville, Tennessee, United States, 37212
        • Jaclyn Tamaroff

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

13 years to 99 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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 Names:
  • Theo-24, Elixophyllin
Placebo Comparator: Placebos
Theophylline capsule by mouth once daily or Theophylline elixir by mouth q6h
Drug: Placebos
oral placebo
Other Names:
  • placebo

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University Medical Center

Collaborators

Harvard University

Investigators

  • Principal Investigator: Jaclyn Tamaroff, MD, Vanderbilt University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2018

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

January 18, 2017

First Submitted That Met QC Criteria

January 23, 2017

First Posted (Estimated)

January 24, 2017

Study Record Updates

Last Update Posted (Actual)

April 29, 2026

Last Update Submitted That Met QC Criteria

April 23, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IND 133103

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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