Theophylline for Pseudohypoparathyroidism

Overseen By Jenny Leshko, RN

Age: Any Age

Sex: Any

Trial Phase: Phase 2

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 This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

34 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if theophylline, a drug typically used for breathing problems, can aid in treating pseudohypoparathyroidism—a genetic disorder causing issues like early obesity and short stature. Researchers hope theophylline will help participants lose weight, manage blood sugar more effectively, and slow bone growth issues. Individuals with pseudohypoparathyroidism who experience obesity and related challenges might be suitable for this study. Participants will receive either theophylline or a placebo to compare the effects. As a Phase 2 trial, this study focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that theophylline is likely to be safe for humans?

Research has shown that theophylline is generally safe and well-tolerated for people with pseudohypoparathyroidism. Some studies have found that patients using theophylline long-term have experienced improvements in their body mass index (BMI). These studies also report that most patients did not encounter serious side effects.

One study specifically highlighted theophylline's safety and tolerability for treating pseudohypoparathyroidism type 1a, suggesting it could be a good option for managing symptoms of this condition.

While all treatments can have side effects, the available evidence supports theophylline as a well-tolerated choice for pseudohypoparathyroidism. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pseudohypoparathyroidism?

Theophylline is unique because it offers a different approach to managing pseudohypoparathyroidism. Unlike standard treatments that typically focus on calcium and vitamin D supplementation, Theophylline works by increasing the levels of cyclic AMP, which can help improve the body's response to parathyroid hormone. Researchers are excited because this could potentially lead to more effective regulation of calcium levels in patients with this condition. Additionally, Theophylline's oral administration, in both capsule and elixir forms, provides flexibility in dosing based on individual needs.

What evidence suggests that theophylline might be an effective treatment for pseudohypoparathyroidism?

Research has shown that theophylline, a type of medication, might help treat pseudohypoparathyroidism. In this trial, participants will receive either theophylline or a placebo. Studies suggest that theophylline can aid in weight loss and improve sugar metabolism, which is crucial for people with this condition. It may also slow the closing of growth plates in children and young adults, potentially aiding in height increase. Additionally, theophylline appears to enhance the effect of certain hormones on vitamin D production, which might help manage hormone resistance often seen in these patients. While more research is needed, these findings offer a hopeful outlook for those considering this treatment. ^{1 6 7 8 9}

Who Is on the Research Team?

Ashley Shoemaker, MD, MSCI

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Theophylline

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.

How Is the Trial Designed?

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

Theophylline is already approved in United States, European Union for the following indications:

Approved in United States as Theophylline for:

• Asthma
• Bronchitis
• Emphysema
• Apnea of Prematurity

Approved in European Union as Theophylline for:

• Asthma
• Chronic obstructive pulmonary disease (COPD)

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Harvard University

Collaborator

Trials

237

Recruited

588,000+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03029429?term=THEO-24&viewType=Table&rank=2

Theophylline Treatment for Pseudohypoparathyroidism The investigators hypothesize that theophylline will cause weight loss, improve glucose tolerance and slow growth plate closure in children and young adults. ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04551170

Study Details | NCT04551170 | Theophylline Treatment for ... ... efficacy of theophylline, a phosphodiesterase inhibitor, in pseudohypoparathyroidism. We hypothesize that theophylline will cause weight loss, slow the rate ...

3. ctv.veeva.com ctv.veeva.com/study/theophylline-treatment-for-pseudohypoparathyroidism-children-2-12-years-old

Theophylline Treatment for Pseudohypoparathyroidism We hypothesize that theophylline will cause weight loss, slow the rate of growth plate closure and decrease hormone resistance in children.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10553654/

FRI596 Randomized Clinical Trial Of Theophylline For ... The primary outcome is change in BMI, expressed as % of the 95th %ile (BMI95), to account for age and gender.

5. withpower.com withpower.com/trial/phase-3-pseudopseudohypoparathyroidism-8-2018-c96fa

Theophylline for Pseudohypoparathyroidism 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), ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10555958/

FRI597 Impact Of Theophylline On BMI In ... Conclusion: Most patients with PHP1A in a long term, OLE study of theophylline demonstrated an improvement in BMI95. Theophylline was safe and well tolerated.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04551170

Theophylline Treatment for Pseudohypoparathyroidism We hypothesize that theophylline will cause weight loss, slow the rate of growth plate closure and decrease hormone resistance in children. Detailed Description.

8. researchgate.net researchgate.net/publication/374502029_FRI596_Randomized_Clinical_Trial_Of_Theophylline_For_Treatment_Of_Pseudohypoparathyroidism_Type_1a

FRI596 Randomized Clinical Trial Of Theophylline For ... FRI596 Randomized Clinical Trial Of Theophylline For Treatment Of Pseudohypoparathyroidism Type 1a ... Theophylline was safe and well tolerated. 1.

9. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT04240821/

Trial | NCT04240821 1. The primary objective of this study is to evaluate the long-term safety of theophylline in patients with PHP. 2. The secondary objectives of this study are ...