Try the modernized beta website. Learn more about the modernization effort.
Working… Menu

Theophylline Treatment for Pseudohypoparathyroidism

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03029429
Recruitment Status : Recruiting
First Posted : January 24, 2017
Last Update Posted : August 6, 2021
Harvard University
Information provided by (Responsible Party):
Ashley Shoemaker, Vanderbilt University Medical Center

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.

Layout table for study information
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

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

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

Secondary Outcome Measures :
  1. Change in insulinogenic index [ Time Frame: baseline and 52 weeks ]
    Insulinogenic index measured during a 75g oral glucose tolerance test

  2. change in levothyroxine dose [ Time Frame: baseline and 52 weeks ]
    levothyroxine dose (mcg/kg/day)

  3. change in calcitriol dose [ Time Frame: baseline and 52 weeks ]
    calcitriol dose (mcg/kg/day)

Other Outcome Measures:
  1. Change in body mass index z-score [ Time Frame: baseline and 52 weeks ]
  2. Change in BMI [ Time Frame: 52 weeks ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

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

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 identifier (NCT number): NCT03029429

Layout table for location contacts
Contact: Sarah Wright, RN 6153438116
Contact: Ashley Shoemaker 6153438116

Layout table for location information
United States, Tennessee
Ashley Shoemaker Recruiting
Nashville, Tennessee, United States, 37212
Contact: Ashley Shoemaker, MD    615-343-8116   
Principal Investigator: Ashley Shoemaker, MD, MSCI         
Sponsors and Collaborators
Vanderbilt University Medical Center
Harvard University
Layout table for investigator information
Principal Investigator: Ashley Shoemaker, MD Vanderbilt University Medical Center
Additional Information:

Layout table for additonal information
Responsible Party: Ashley Shoemaker, Assistant Professor of Pediatrics, Vanderbilt University Medical Center 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

Layout table for additional information
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:
Albright Hereditary Osteodystrophy
Additional relevant MeSH terms:
Layout table for MeSH terms
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Calcium Metabolism Disorders
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