Theophylline for Pseudohypoparathyroidism

Overseen By Jenny Leshko, RN

Age: < 18

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called theophylline to determine its effectiveness for children with pseudohypoparathyroidism, a genetic disorder that often causes obesity, short stature, and hormone resistance. Researchers believe theophylline might aid in weight loss, slow growth plate closure, and improve hormone sensitivity. The trial includes two groups: one receiving theophylline and the other a placebo (a pill with no active medicine). Children aged 2 to 12 with this condition, particularly those struggling with obesity, might be suitable candidates. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant findings.

Will I have to stop taking my current medications?

The trial requires that you stop using any PDE inhibitors 30 days before starting. Also, you cannot use medications that affect theophylline levels during the trial.

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. Some studies have found it can improve body mass index (BMI) in individuals with pseudohypoparathyroidism, potentially aiding weight management. In other trials, both adults and teenagers using theophylline encountered no major safety issues. Most participants responded well to the treatment, with few reports of serious side effects. Overall, evidence suggests that theophylline is a safe option for those with this condition. ^{1 2 3 4 5}

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

Theophylline is unique because it offers a potential new approach for treating pseudohypoparathyroidism by utilizing its ability to enhance cyclic AMP (cAMP) signaling. Unlike current treatments, which primarily focus on supplementing calcium and vitamin D to manage symptoms, Theophylline may address an underlying molecular pathway involved in the condition. Researchers are excited about this treatment because it could provide a more targeted way to manage pseudohypoparathyroidism, potentially improving patient outcomes and reducing reliance on supplements.

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

This trial will compare theophylline with a placebo to manage pseudohypoparathyroidism. Research has shown that theophylline, a type of medication, might assist with weight loss and slow the closing of growth plates in children, potentially benefiting those with short stature. Theophylline may also reduce hormone resistance, a common issue in this condition. Although more research is needed, these early findings offer promise for those dealing with this genetic disorder. ^{6 7 8 9 10}

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 children aged 2-12 with pseudohypoparathyroidism, characterized by obesity and hormone resistance. They must meet specific criteria including a BMI >95th percentile or ≥30 kg/m2 and have certain symptoms of the disorder. Kids can't join if they have untreated thyroid issues, liver problems, heart failure, are pregnant or planning to be, have had severe psychiatric disorders including depression in the last 2 years, smoke cigarettes or abuse alcohol.

Inclusion Criteria

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

I am considered obese based on my BMI.

I am between 2 and 12 years old.

Exclusion Criteria

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

My thyroid condition is untreated or not well-controlled, and I am not on calcitriol or levothyroxine.

Pregnancy or intention to become pregnant during the next year

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, slowing epiphyseal closure, and decreasing hormone resistance

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of theophylline treatment long-term

What Are the Treatments Tested in This Trial?

Interventions

• Theophylline

Trial Overview The study tests Theophylline against a placebo to see if it helps with weight loss and reduces hormone resistance in kids with pseudohypoparathyroidism. It's a phase 2 trial where some kids will get the real drug while others will get an inactive substance without knowing which one they're taking.

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: Placebo Placebo Group 1 Intervention

Placebo capsule by mouth once daily or Placebo 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+

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]

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]

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]

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]

Citations

1. 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 ...

2. 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.

3. vanderbilt.trialstoday.org vanderbilt.trialstoday.org/trial/NCT03029429

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

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT03029429/theophylline-treatment-for-pseudohypoparathyroidism

Theophylline Treatment for Pseudohypoparathyroidism This phase 2 clinical trial will test the efficacy of theophylline, a phosphodiesterase inhibitor, in pseudohypoparathyroidism.

5. 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.

6. 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.

7. reporter.nih.gov reporter.nih.gov/search/t_kbDTVMR0KOnhtdmsXJ0w/project-details/11003699

RePORT RePORTER - National Institutes of Health (NIH) | In this revised proposal, we have included additional safety and efficacy data from adults in adolescents treated with theophylline. In response to reviewer ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03029429?term=UNIPHYL&viewType=Table&rank=8

Theophylline Treatment for Pseudohypoparathyroidism The investigators primary outcome is change in body mass index. Secondary outcome measures include change in glucose tolerance and HRT dose. Anticipating a 10% ...

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

Theophylline for Pseudohypoparathyroidism This trial tests theophylline, a medication that helps important body signals last longer, in children and young adults with pseudohypoparathyroidism (PHP).

10. researchgate.net researchgate.net/publication/374502089_FRI597_Impact_Of_Theophylline_On_BMI_In_Pseudohypoparathyroidism_Type_1a_-_Results_Of_An_Open_Label_Extension_Trial

(PDF) FRI597 Impact Of Theophylline On BMI In ... theophylline demonstrated an improvement in BMI95. Theophylline was safe and well tolerated. Presentation: Friday, ...