Theophylline for Pseudohypoparathyroidism

Recruiting in Palo Alto (17 mi)

Overseen by Ashley Shoemaker, MD, MSCI

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Vanderbilt University Medical Center

Must not be taking: PDE inhibitors, Theophylline

Disqualifiers: Seizure disorder, Cardiac arrhythmia, Hepatic insufficiency, Congestive heart failure, others

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests theophylline, a medication that helps important body signals last longer, in children and young adults with pseudohypoparathyroidism (PHP). These patients often struggle with obesity and short stature, which current treatments do not effectively address. Theophylline aims to improve their hormone response, potentially reducing weight and improving growth.

Do I need to stop my current medications for the trial?

The trial requires you to stop using any medications that affect theophylline levels. If you're taking such medications, you may need to stop them to participate.

How does the drug Theophylline work for pseudohypoparathyroidism?

Theophylline is unique for pseudohypoparathyroidism because it acts as a phosphodiesterase inhibitor, which can increase the levels of cyclic AMP (a molecule that helps transmit signals inside cells) and enhance the body's response to parathyroid hormone, potentially improving phosphate and calcium balance in patients. ^{1 2 3 4 5}

Research Team

Ashley Shoemaker, MD, MSCI

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for individuals aged 13 and above with a clinical diagnosis of pseudohypoparathyroidism, who are significantly overweight. They must not have liver problems, heart arrhythmias (except slow heartbeat), untreated low thyroid hormone levels, active stomach ulcers, severe psychiatric disorders including recent major depression or suicidal behavior, heart failure, pregnancy plans within a year, or be using certain other medications.

Inclusion Criteria

I am considered obese based on my BMI.

I am 13 years old or older.

I have been diagnosed with PHP, showing specific symptoms like hormone resistance or unique hand features.

Exclusion Criteria

Pregnancy or intention to become pregnant during the next year

I have taken a PDE inhibitor medication in the last 30 days.

Your PHQ-9 score is 15 or higher, or you have had serious thoughts of harming yourself in the past month.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive theophylline or placebo for 52 weeks to test its efficacy in reducing BMI and improving glucose tolerance

52 weeks

Regular visits for monitoring and dose adjustments based on serum drug levels

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Theophylline (Phosphodiesterase Inhibitor)

Trial Overview The study is testing theophylline's effectiveness in treating pseudohypoparathyroidism by comparing it to a placebo. The goal is to see if theophylline can help with weight loss, improve blood sugar control and affect bone growth in children and young adults.

Participant Groups

Group I: Theophylline Experimental Treatment 1 Intervention

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

Group II: Placebos Placebo Group 1 Intervention

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

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Jeffrey R. Balser

Vanderbilt University Medical Center

Chief Executive Officer since 2009

MD and PhD from Vanderbilt University

Rick W. Wright

Vanderbilt University Medical Center

Chief Medical Officer since 2023

MD from University of Missouri-Columbia

Harvard University

Collaborator

Trials

237

Recruited

588,000+

Dr. Christopher Anzalone

Harvard University

Chief Executive Officer since 2007

PhD in Biology from UCLA

Dr. Perry

Harvard University

Chief Medical Officer since 2011

MD from Albert Einstein College of Medicine, MPH from Harvard University

Findings from Research

Bovine parathyroid hormone (bPTH) effectively stimulates the production of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) in kidney slices from vitamin D-deficient chicks, with optimal stimulation occurring at low concentrations (25 ng/ml) and showing a 65% increase.

The presence of theophylline enhances the effect of bPTH on 1,25-(OH)2D3 production, achieving a 170% increase at a lower bPTH concentration (2 ng/ml), indicating that theophylline can potentiate the action of PTH in vitamin D metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro stimulation of 25-hydroxycholecalciferol 1 alpha-hydroxylation by parathyroid hormone in chick kidney slices: evidence for a role for adenosine 3',5'-monophosphate. Rost, CR., Bikle, DD., Kaplan, RA.[2019]

In a study of a 25-year-old woman with pseudohypoparathyroidism (PHP) type Ia, her bone-derived osteoblast-like cells showed normal responsiveness to parathyroid hormone (PTH), indicating that the skeletal system can still respond to PTH despite the overall lack of response seen in PHP.

The normal response of these bone cells to PTH suggests that the adenylyl cyclase system is functional in the skeleton, which may help explain the patient's episodes of normal calcium levels (normocalcemia) despite her condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Normal parathyroid hormone responsiveness of bone-derived cells from a patient with pseudohypoparathyroidism. Ish-Shalom, S., Rao, LG., Levine, MA., et al.[2015]

In two young infants with transitory pseudohypoparathyroidism, high doses of vitamin D were ineffective, but treatment with 1.25-(OH)2-D3 (Rocaltrol) quickly corrected metabolic abnormalities like hypocalcemia and hyperphosphatemia.

Monitoring urinary cAMP excretion levels helped differentiate between transient and permanent forms of the disease, with specific values indicating when treatment could be safely stopped.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Transitory pseudohypoparathyroidism in the newborn infant]. Schaumberger, E., Hohenauer, L., Sommer, R.[2013]

Infusion of parathyroid hormone (PTH) or cAMP significantly enhances the production of 1alpha,25-dihydroxyvitamin D3 in vitamin D-deficient rats, indicating a strong stimulatory effect on vitamin D metabolism.

The study demonstrates that cAMP is a crucial mediator in the process, as both cAMP and PTH can restore vitamin D levels to those found in normal, sham-operated rats, highlighting its potential role in vitamin D regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo evidence for the intermediary role of 3',5'-cyclic AMP in parathyroid hormone-induced stimulation of 1alpha,25-dihydroxyvitamin D3 synthesis in rats. Horiuchi, N., Suda, T., Takahashi, H., et al.[2013]

The 58-year-old woman diagnosed with pseudohypoparathyroidism type II showed increased urinary phosphate and cAMP excretion after treatment with the phosphodiesterase inhibitor theophylline, indicating a potential therapeutic approach for this condition.

High doses of cAMP or long-term use of phosphodiesterase inhibitors can restore the responsiveness of urinary phosphate secretion, suggesting that cAMP signaling in the kidneys may be a key factor in managing PHP type II.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased urinary phosphate excretion in pseudohypoparathyroidism type II with long-term treatment with phosphodiesterase inhibitor. Mano, T., Uchimura, K., Hayashi, R., et al.[2015]

References

1. United States pubmed.ncbi.nlm.nih.gov

In vitro stimulation of 25-hydroxycholecalciferol 1 alpha-hydroxylation by parathyroid hormone in chick kidney slices: evidence for a role for adenosine 3',5'-monophosphate. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Normal parathyroid hormone responsiveness of bone-derived cells from a patient with pseudohypoparathyroidism. [2015]

3. Germany pubmed.ncbi.nlm.nih.gov

[Transitory pseudohypoparathyroidism in the newborn infant]. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

In vivo evidence for the intermediary role of 3',5'-cyclic AMP in parathyroid hormone-induced stimulation of 1alpha,25-dihydroxyvitamin D3 synthesis in rats. [2013]

5. Germany pubmed.ncbi.nlm.nih.gov

Increased urinary phosphate excretion in pseudohypoparathyroidism type II with long-term treatment with phosphodiesterase inhibitor. [2015]