Theophylline for Pseudohypoparathyroidism

Overseen By AMITA SHARMA, MD

Age: < 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Massachusetts General Hospital

Must not be taking: Chronic theophylline interactors

Disqualifiers: Kidney disease, Heart disease, Seizure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests theophylline, a medication, to determine if it aids individuals with pseudohypoparathyroidism, a condition where the body poorly responds to certain hormones. Researchers aim to discover if theophylline can enhance the body's hormone use by increasing cAMP, a chemical that transmits messages inside cells. The trial includes individuals diagnosed with specific types of pseudohypoparathyroidism (PHP1A and PHP1B) who are over five years old and do not have severe kidney, heart, or other major health issues. Participants will take the medication twice daily for a year. As a Phase 4 trial, theophylline is already FDA-approved and proven effective, and this research seeks to understand how it benefits more patients.

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.

What is the safety track record for theophylline?

Research has shown that theophylline is generally safe and well-tolerated in people with pseudohypoparathyroidism. Studies have found that long-term use of theophylline does not cause serious side effects, with most individuals experiencing only mild issues, if any.

Theophylline's approval for treating other conditions indicates a well-understood safety profile, providing reassurance about its safety for individuals.

Overall, existing evidence suggests that theophylline is a safe choice for those considering participation in a clinical trial for pseudohypoparathyroidism. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike standard treatments for pseudohypoparathyroidism, which typically focus on managing calcium and phosphate levels, theophylline targets a different pathway by increasing levels of cAMP, a second messenger. This unique mechanism helps decrease end organ resistance, potentially offering a more direct approach to addressing the underlying issue. Researchers are excited about theophylline because it could offer a novel therapeutic angle, providing benefits beyond what traditional medications currently achieve for this condition.

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

Research shows that theophylline, which participants in this trial will receive, can help treat pseudohypoparathyroidism. Studies suggest it may aid in weight loss, improve sugar metabolism, and slow the closing of growth plates in children. Theophylline boosts a substance in the body called cAMP, enhancing hormonal response. Since theophylline is already approved for other uses, researchers have confidence in its safety and effectiveness. ^{6 7 8 9 10}

Who Is on the Research Team?

AMITA SHARMA, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Theophylline

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.

How Is the Trial Designed?

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.

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?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Published Research Related to This Trial

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]

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]

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 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]

Citations

1. 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 ...

2. 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.

3. 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 ...

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. 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/NCT03718403?cond=Pseudopseudohypoparathyroidism%20OR%20%22aho-PPHP%20syndrome%22%20OR%20%22%20Albright%20Hereditary%20osteodystrophy%20with%20multiple%20hormone%20resistance%22%20OR%20%22%20Albright%20hereditary%20osteodystrophy-PPHP%20syndrome%22%20OR%20%22%20Normocalcemic%20pseudohypoparathyroidism%22%20OR%20%22%20Normocalcemic%20pseudohypoparathyroidism%20(disorder)%20%5Bambiguous%5D%22&aggFilters=status:not%20rec&viewType=Table&rank=6

Effect of Theophylline in Pseudohypoparathyroidism Also called a data safety and monitoring board, or DSMB. Early Phase 1 ... Safety continues to be evaluated, and short-term adverse events are studied.

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

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

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

Theophylline for Pseudohypoparathyroidism Prior Safety DataThis treatment has passed at least one previous human trial. Approved in 2 JurisdictionsThis treatment is already approved in other ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT04240821

Theophylline for Treatment of Pseudohypoparathyroidism The primary objective of this study is to evaluate the long-term safety of theophylline in patients with PHP. The secondary objectives of this study are to ...

10. ctv.veeva.com ctv.veeva.com/study/theophylline-for-treatment-of-pseudohypoparathyroidism

Theophylline for Treatment of Pseudohypoparathyroidism The primary objective of this study is to evaluate the long-term safety of theophylline in patients with PHP. The secondary objectives of ...