Tadalafil + Exercise for Duchenne Muscular Dystrophy

Overseen By Ruby Sullivan, MS

Age: Any Age

Sex: Male

Trial Phase: Phase 2

Sponsor: University of Florida

Must be taking: Glucocorticoids

Must not be taking: Nitrates, Alpha-blockers

Disqualifiers: Severe cardiomyopathy, Uncontrolled seizures, others

Stay on Your Current Meds You can continue your current medications while participating

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: 26 weeks

50 Participants Needed

Trial Summary

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 must be on a stable glucocorticoid regimen for more than 3 months. You cannot take certain medications like nitrates, alpha-adrenergic blockers, or other drugs that affect blood flow or muscle metabolism.

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

Research suggests that Tadalafil, a drug that blocks an enzyme called phosphodiesterase 5 (PDE5), may help improve muscle function in Duchenne Muscular Dystrophy by enhancing heart and muscle health. Studies in mice have shown that Tadalafil can improve muscle structure and function, which might be beneficial for patients with this condition. ^{1 2 3 4 5}

Is tadalafil safe for humans?

Tadalafil, also known as Cialis, is generally safe for humans, with most side effects being mild or moderate and temporary. It does not increase the risk of heart problems and can be safely used with medications for high blood pressure. ^{1 2 6 7 8}

How does the drug Tadalafil combined with exercise differ from other treatments for Duchenne Muscular Dystrophy?

Tadalafil, a drug typically used for erectile dysfunction, is being studied for Duchenne Muscular Dystrophy because it may help maintain muscle function by blocking an enzyme that breaks down a molecule important for muscle health. This approach is unique because it targets muscle preservation through a different mechanism than the standard use of corticosteroids, which are the only other treatment with a clear beneficial effect for this condition. ^{1 2 4 7 9}

What is the purpose of this trial?

Examining two strategies as potential adjuvant therapies for Duchenne muscular dystrophy (DMD); aerobic exercise training (to induce adaptations in skeletal muscle and improve cardiovascular health) and tadalafil, an FDA-approved vasodilator (to optimize blood flow and muscle perfusion which is impaired and often overlooked in DMD). Target: improved muscle function, vascular health, and DMD treatment.

Research Team

Tanja Taivassalo, Ph.D.

Principal Investigator

University of Florida, College of Medicine, Department of Physiology and Aging

Eligibility Criteria

This trial is for boys diagnosed with Duchenne muscular dystrophy (DMD), confirmed by a genetic report, who are at least 6 years old and can walk. They must be on a stable glucocorticoid regimen for over three months.

Inclusion Criteria

I can walk on my own without help.

I have been on a stable dose of steroids for more than 3 months.

My diagnosis of Duchenne Muscular Dystrophy is confirmed by a genetic report.

Exclusion Criteria

Contraindication to a Magnetic resonance Imaging examination (e.g. severe claustrophobia, magnetic implants, unable/unwilling to perform test)

I have a condition like cerebral palsy or a history of muscle breakdown without cause.

Participation in currently approved FDA trials or other investigational clinical trials during the period of the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Drug Responsiveness Testing

Testing for drug responsiveness after a single dose of tadalafil to assess increase in muscle oxygenation

up to 4 weeks

2 visits (in-person)

Treatment

Participants receive daily tadalafil or placebo combined with structured cycle exercise training for 6 months

26 weeks

Regular virtual monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Tadalafil

Trial Overview The study tests the effects of tadalafil, a vasodilator that improves blood flow, combined with aerobic exercise training to see if they improve muscle function and cardiovascular health in DMD patients.

Participant Groups

Group I: Tadalafil and Exercise Arm Experimental Treatment 2 Interventions

Participants receive tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).

Group II: Placebo and Exercise Arm Placebo Group 2 Interventions

Participants receive a tadalafil placebo tablet matching the tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Collaborator

Trials

508

Recruited

1,090,000+

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]

In a phase 3 trial involving 82 boys with Duchenne muscular dystrophy, tamoxifen was found to be safe and well tolerated, with no significant difference in motor function improvement compared to placebo after 48 weeks.

Although there were indications of slower disease progression in the tamoxifen group, the differences were not clinically or statistically significant, leading to the conclusion that tamoxifen cannot be recommended as a treatment option for Duchenne muscular dystrophy at this time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Henzi, BC., Schmidt, S., Nagy, S., 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]

In a study of 23 subjects with stable coronary artery disease (CAD), tadalafil did not significantly change the time to exercise-induced myocardial ischaemia compared to a placebo, indicating it may not improve exercise tolerance in these patients.

Tadalafil was associated with a notable reduction in resting and exercise-induced systolic blood pressure, which raises safety concerns about its use alongside nitrates due to the risk of hypotension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of tadalafil on the time to exercise-induced myocardial ischaemia in subjects with coronary artery disease. Patterson, D., Kloner, R., Effron, M., et al.[2018]

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]

In a study involving 12 healthy male volunteers with high cardiorespiratory fitness, a single dose of tadalafil (20 mg) led to increased levels of muscle damage markers, specifically creatine kinase (CK) and lactate dehydrogenase (LDH), 24 hours after ingestion.

Despite the increase in muscle damage markers, tadalafil did not affect redox homeostasis or antioxidant enzyme activities, suggesting that while it may have some effects on muscle damage, it does not enhance antioxidant status in fit individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Tadalafil Administration on Redox Homeostasis and Polyamine Levels in Healthy Men with High Level of Physical Activity. Duranti, G., Ceci, R., Di Luigi, L., et al.[2021]

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. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. [2023]

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. England pubmed.ncbi.nlm.nih.gov

The effect of tadalafil on the time to exercise-induced myocardial ischaemia in subjects with coronary artery disease. [2018]

8. China pubmed.ncbi.nlm.nih.gov

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

9. Switzerland pubmed.ncbi.nlm.nih.gov

Effect of Tadalafil Administration on Redox Homeostasis and Polyamine Levels in Healthy Men with High Level of Physical Activity. [2021]