Tadalafil for Duchenne Muscular Dystrophy

Age: < 18

Sex: Male

Trial Phase: Phase 2 & 3

Sponsor: University of Florida

Must not be taking: Nitrates, Alpha-blockers, PDE5A inhibitors

Disqualifiers: Older than 13, Unstable medical problems, 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: 2

Duration: 1 day

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This Trial will test if tadalafil can improve blood flow in the leg muscles of boys with DMD and see if it can help slow down the disease progression. Tadalafil is a medication that is approved for the treatment of certain conditions in men.

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 using nitrates, alpha-adrenergic blockers, or other PDE5A inhibitors.

What data supports the effectiveness of the drug tadalafil for Duchenne Muscular Dystrophy?

Research shows that tadalafil, a drug that helps improve blood flow, may delay heart problems in Duchenne Muscular Dystrophy by maintaining muscle function and reducing muscle damage. Studies in mice have shown that tadalafil can improve muscle health and function, suggesting potential benefits for patients with this condition. ^{1 2 3 4 5}

Is tadalafil generally safe for humans?

Tadalafil, also known as Cialis, is generally safe for humans. It is well tolerated with mild to moderate side effects that are usually temporary. It is safe for people with cardiovascular conditions, but should not be used with nitrate medications due to potential blood pressure issues. ^{6 7 8 9 10}

How does the drug tadalafil differ from other treatments for Duchenne muscular dystrophy?

Tadalafil is unique for Duchenne muscular dystrophy because it works by inhibiting phosphodiesterase type 5 (PDE5), which helps maintain higher levels of cGMP, a molecule that can improve muscle function and delay heart problems. Unlike corticosteroids, the only other treatment with a clear benefit, tadalafil specifically targets pathways that enhance muscle metabolism and organization. ^{1 2 4 5 11}

Research Team

Tanja Taivassalo

Principal Investigator

University of Florida

Eligibility Criteria

Boys aged 7 to 13 with Duchenne Muscular Dystrophy (DMD) confirmed by clinical history, physical exam, elevated creatine kinase levels, and lack of dystrophin protein. They must be able to walk and have no other conditions affecting muscle function or metabolism. Those with contraindications for MRI scans or taking certain medications like nitrates cannot participate.

Inclusion Criteria

I have been diagnosed with DMD based on my early symptoms, physical exams, high creatine kinase levels, and specific tests showing lack of dystrophin.

I have been diagnosed with DMD based on my symptoms, tests, and genetic confirmation.

I can walk on my own without help.

Exclusion Criteria

I am older than 13 years.

Contraindication to an MR examination (e.g. aneurysm clip, severe claustrophobia, magnetic implants)

I have medical conditions that are not well-controlled.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of tadalafil and undergo assessments using Doppler ultrasound or BOLD-MRI to measure vascular responsiveness and exercise testing

1 day

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Tadalafil

Trial Overview The trial is testing the effects of a single dose of Tadalafil, a drug that widens blood vessels, on leg muscle blood flow in boys with DMD using MRI or Doppler ultrasound after exercise. The goal is to see if this drug can improve blood flow and potentially slow disease progression.

Participant Groups

Group I: Tadalafil plus Doppler ultrasound (Schedule B) Experimental Treatment 1 Intervention

The intervention is the same as in Schedule A; this arm will use Doppler ultrasound as the technique to monitor drug impact on skeletal muscle.

Group II: Tadalafil plus BOLD-MRI (Schedule A) Experimental Treatment 1 Intervention

The intervention is the same as in Schedule B; this arm will use BOLD-MRI as the technique to monitor drug impact on skeletal muscle.

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Findings from Research

In a randomized trial involving 331 boys aged 7 to 14 with Duchenne muscular dystrophy (DMD), tadalafil did not significantly reduce the decline in walking ability over 48 weeks, as measured by the 6-minute walk distance (6MWD).

While tadalafil showed no overall effect on primary and secondary outcomes, it did suggest a potential benefit in upper limb function for boys over 10 years old, indicating that earlier initiation of treatment might be worth exploring in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy. Victor, RG., Sweeney, HL., Finkel, R., et al.[2022]

Tadalafil, a phosphodiesterase type 5 inhibitor, has shown promise in preventing cardiomyopathy in models of Duchenne muscular dystrophy, including mdx mice and golden retriever muscular dystrophy dogs, by blunting the adrenergic response and promoting cardioprotective signaling.

In golden retriever muscular dystrophy dogs treated with tadalafil before the onset of cardiomyopathy, cardiac function was preserved and histopathological improvements were observed, suggesting that tadalafil could be an effective therapy to delay cardiomyopathy in Duchenne muscular dystrophy patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin-Deficient Hearts. Hammers, DW., Sleeper, MM., Forbes, SC., et al.[2023]

Chronic treatment with the PDE5 inhibitor tadalafil in mdx mice showed significant improvements in skeletal muscle function, indicating its potential as a therapeutic approach for Duchenne and Becker Muscular Dystrophy.

Tadalafil treatment led to multiple beneficial effects, including enhanced lipid metabolism, a shift towards slow oxidative muscle fibers, improved protein synthesis efficiency, and better organization of the actin network, suggesting a multifaceted mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy. De Arcangelis, V., Strimpakos, G., Gabanella, F., et al.[2016]

In a randomized, double-blind, placebo-controlled trial involving adults with Duchenne and Becker muscular dystrophies (DBMD) and cardiomyopathy, sildenafil did not show significant improvement in cardiac function compared to placebo, as indicated by no statistically significant differences in left ventricular end-systolic volume after 6 months.

The study was terminated early due to a higher number of subjects worsening on sildenafil, suggesting that this treatment may not be beneficial for improving cardiac health in DBMD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. Leung, DG., Herzka, DA., Thompson, WR., et al.[2022]

Tadalafil is generally safe and well-tolerated for chronic treatment of erectile dysfunction, even in high-risk populations, with most side effects being mild or moderate and reversible without stopping the medication.

It does not increase the risk of cardiovascular issues and can be safely used alongside antihypertensive medications and selective alpha-receptor blockers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and tolerance of tadalafil in the treatment of erectile dysfunction]. He, XY.[2015]

Tadalafil, a new oral treatment for erectile dysfunction, is highly effective with a duration of action lasting up to 36 hours, making it a convenient option for patients.

The medication has a strong safety profile, with only a few mild to moderate side effects reported, which is particularly important for patients who may have other medical conditions or take multiple medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tadalafil for erectile dysfunction: excellent safety and tolerance]. Bai, WJ.[2015]

Tadalafil, a PDE-5 inhibitor, is effective for treating erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia, showing good tolerance in patients.

The drug is considered safe for patients with cardiovascular comorbidities and may even provide beneficial effects on cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety of tadalafil in patients with cardiovascular comorbidities]. Nikitina, IL., Gaysina, GG., Galimov, SN., et al.[2019]

In a 24-week study involving patients aged 18 and older, tadalafil dosed once daily significantly improved erectile function compared to placebo, as measured by the International Index of Erectile Function and Sexual Encounter Profile responses.

Tadalafil was well tolerated, with a low discontinuation rate due to adverse events (6.3% for 2.5 mg and 4.1% for 5 mg), and common side effects included nasopharyngitis and back pain, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US. Rajfer, J., Aliotta, PJ., Steidle, CP., et al.[2015]

References

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

A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin-Deficient Hearts. [2023]

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

Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy. [2018]

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

Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy. [2016]

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

Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. [2022]

6. China pubmed.ncbi.nlm.nih.gov

[Safety and tolerance of tadalafil in the treatment of erectile dysfunction]. [2015]

7. China pubmed.ncbi.nlm.nih.gov

[Tadalafil for erectile dysfunction: excellent safety and tolerance]. [2015]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Safety of tadalafil in patients with cardiovascular comorbidities]. [2019]

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

Cardiovascular effects of tadalafil. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US. [2015]

11. India pubmed.ncbi.nlm.nih.gov

Efficacy of tadalafil in Egyptian and Turkish men with erectile dysfunction. [2018]