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Theophylline Treatment for Pseudohypoparathyroidism - Children 2-12 Years Old

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: NCT04551170
Recruitment Status : Recruiting
First Posted : September 16, 2020
Last Update Posted : September 28, 2021
Information provided by (Responsible Party):
Ashley Shoemaker, Vanderbilt University Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Pseudohypoparathyroidism Albright Hereditary Osteodystrophy Pseudohypoparathyroidism Type 1a Drug: Theophylline Drug: Placebo 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 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.

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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 : July 13, 2020
Estimated Primary Completion Date : June 30, 2025
Estimated Study Completion Date : June 30, 2025

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

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

Secondary Outcome Measures :
  1. Change in levothyroxine dose [ Time Frame: baseline and 52 weeks ]
    levothyroxine dose (mcg/kg/day)

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

  3. Change in epiphyseal closure [ Time Frame: baseline and 52 weeks ]
    Bone age minus chronologic age

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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): NCT04551170

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Contact: Sarah Wright, RN 6153438116
Contact: Ashley Shoemaker, MD 6153438116

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United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37212
Contact: Ashley Shoemaker, M.D.    615-343-8116   
Principal Investigator: Ashley Shoemaker, M.D.         
Sponsors and Collaborators
Vanderbilt University Medical Center
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Principal Investigator: Ashley Shoemaker, MD Vanderbilt University Medical Center
Additional Information:

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Responsible Party: Ashley Shoemaker, Assistant Professor, Vanderbilt University Medical Center Identifier: NCT04551170    
Other Study ID Numbers: IND 133103 R01
First Posted: September 16, 2020    Key Record Dates
Last Update Posted: September 28, 2021
Last Verified: September 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:
Albright Hereditary Osteodystrophy
Additional relevant MeSH terms:
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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