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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how tadalafil, a drug known to improve blood flow, affects leg muscles in boys with Duchenne muscular dystrophy (DMD). Researchers will use imaging techniques like MRI or ultrasound to observe muscle response after a single dose. The goal is to determine if tadalafil can slow muscle damage caused by DMD and identify any boys who might not respond to the treatment. Boys diagnosed with DMD, who can walk independently and are between 7 and 13 years old, may be suitable for this trial. As a Phase 2 trial, this study measures how well tadalafil works in an initial, smaller group of boys with DMD, offering a chance to contribute to important research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tadalafil is generally safe for people. In studies with boys who have Duchenne muscular dystrophy (DMD), tadalafil did not raise major safety concerns, but it did not slow the decline in their ability to walk.

The FDA has already approved tadalafil for other uses, such as treating erectile dysfunction, so its safety profile is well understood. Common side effects for these uses include headaches and a warm, red feeling in the skin, but these are usually mild.

In summary, tadalafil appears safe, with no major safety issues reported in studies with boys who have DMD. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Unlike the standard treatments for Duchenne Muscular Dystrophy, which often include corticosteroids like prednisone and deflazacort, Tadalafil offers a unique approach by enhancing blood flow to muscles. Researchers are excited about Tadalafil because it works by inhibiting the enzyme phosphodiesterase 5 (PDE5), which may help improve muscle oxygenation and function. Additionally, the trial uses advanced techniques like Doppler ultrasound and BOLD-MRI to monitor the drug's impact on skeletal muscle, potentially providing more precise insights into its effectiveness. This combination of a novel mechanism and cutting-edge monitoring could lead to significant improvements in managing Duchenne Muscular Dystrophy.

What evidence suggests that tadalafil might be an effective treatment for Duchenne muscular dystrophy?

Research has shown that tadalafil, a drug that widens blood vessels, can improve blood flow in the muscles of boys with Duchenne muscular dystrophy (DMD). Some studies suggest that tadalafil helps restore normal blood flow during muscle activity, potentially slowing the progression of DMD. However, other research found that tadalafil does not significantly slow the decline in walking ability in boys with DMD. Early findings indicate that tadalafil could improve muscle blood flow, but its overall effect on slowing the disease's progression remains uncertain. In this trial, participants will receive tadalafil, and researchers will use either Doppler ultrasound or BOLD-MRI to monitor the drug's impact on skeletal muscle. ^{1 6 7 8 9}

Who Is on the Research Team?

Tanja Taivassalo

Principal Investigator

University of Florida

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05195775?term=Tadalafil&rank=1

NCT05195775 | Tadalafil as Adjuvant Therapy for DMD This project will assess the vascular responsiveness in leg muscles of boys with Duchenne muscular dystrophy (DMD) to one single dose of tadalafil , a common ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5664308/

A phase 3 randomized placebo-controlled trial of tadalafil ... This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy.

3. fda.gov fda.gov/media/112224/download

Clinical Review Rainer W. Paine, MD, PhD NDA ... Primary Objective: To test the hypothesis that once-daily tadalafil administered orally for 48 weeks lessened the decline in ambulatory ability ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8325615/

Postcontractile blood oxygenation level-dependent (BOLD) ... Our findings indicate that the postcontractile BOLD response is impaired in DMD after brief muscle contractions, is correlated to disease severity,

5. mdaconference.org mdaconference.org/abstract-library/assessing-leg-vascular-responsiveness-to-tadalafil-using-mri-in-boys-with-dmd-implications-for-adjuvant-vasodilator-therapy/

Assessing leg vascular responsiveness to tadalafil using ... RESULTS: Tadalafil increased the BOLD-response from 1.9 (SD 1.6)% to 3.2 (SD 0.8)% in DMD (p=0.09), whereby the BOLD-response in unaffected controls was 4.4 (SD ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01865084

A Study of Tadalafil for Duchenne Muscular Dystrophy The main purpose of this study is to determine if tadalafil can slow the decline in walking ability of boys who have Duchenne muscular dystrophy (DMD).

7. fda.gov fda.gov/media/109428/download

Tadalafil Amendment 2 The Written Request will include one phase 3 study to investigate the potential use of tadalafil in the treatment of Duchenne muscular dystrophy (DMD).

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28972192/

A phase 3 randomized placebo-controlled trial of tadalafil for ... This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy.

9. fda.gov fda.gov/files/drugs/published/Tadalafil-Amendment-3.pdf

Tadalafil Amendment 3 The Written Request will include one phase 3 study to investigate the potential use of tadalafil in the treatment of Duchenne muscular dystrophy.