Theophylline for Pseudohypoparathyroidism

Overseen By AMITA SHARMA, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Massachusetts General Hospital

Must not be taking: Chronic theophylline interactors

Disqualifiers: Kidney disease, Heart disease, Seizure, others

No Placebo Group

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests a medication in patients with a condition where the body doesn't respond well to hormones to help their bodies respond better.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on chronic drugs that interact with theophylline.

How does the drug theophylline work differently for pseudohypoparathyroidism compared to other treatments?

Theophylline is unique in treating 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

AMITA SHARMA, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for people over the age of 5 with a confirmed diagnosis of Pseudohypoparathyroidism types PHP1A and PHP1B. It's not suitable for those with muscle disorders, peptic ulcers, severe heart conditions, uncontrolled seizures, liver issues, bleeding problems, kidney stones or diseases, allergies to theophylline, infections or other neurological diseases.

Inclusion Criteria

I have been diagnosed with PHP1A or PHP1B.

I am older than 5 years.

Exclusion Criteria

I have a muscle disorder.

I have liver problems.

You are allergic to theophylline medication.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive theophylline to decrease end organ resistance by increasing levels of cAMP, dosed twice a day

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Theophylline (Methylxanthine)

Trial Overview The study is testing the effects of a drug called Theophylline on individuals with Pseudohypoparathyroidism. A total of 100 participants will be involved to see how this medication influences their condition.

Participant Groups

Group I: Single arm open labeled intervention study Experimental Treatment 1 Intervention

Subjects with PHP will be given theophylline to decrease the end organ resistance by increasing levels of cAMP, a second messenger. Theophylline will be dosed twice a day for a period of 52 weeks.

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Findings from Research

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]

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]

References

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

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

2. Germany pubmed.ncbi.nlm.nih.gov

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

3. 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]

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]