Tadalafil for Fontan Physiology

Recruiting at 1 trial location

Overseen By ACHD Research Team

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Mayo Clinic

Must not be taking: Alpha-blockers, Pulmonary vasodilators, Nitrates

Disqualifiers: Under 18, Pregnancy, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if Tadalafil (Cialis) can improve heart function in individuals who have undergone Fontan Palliation, a surgery for specific heart defects. Participants will take either Tadalafil or a placebo (a pill with no active medicine) for one year. It is suitable for those 18 or older who have had Fontan surgery and can exercise on a special bike. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

If you are currently using intravenous inotropic drugs, alpha-blockers, pulmonary vasodilators, or nitrates, you will need to stop taking them to participate in this trial.

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

Research has shown that Tadalafil is generally well-tolerated. In studies with patients who have Fontan circulation, Tadalafil improved exercise ability, suggesting its safety for regular use. Another study found that Tadalafil enhanced lung function in adults with Fontan physiology, indicating safety, as better function usually correlates with fewer side effects.

While these studies don't detail specific side effects, they suggest Tadalafil is safe for long-term use. This is significant because the FDA has approved Tadalafil for other uses, such as treating erectile dysfunction, meaning the drug has passed thorough safety checks.

Overall, evidence suggests Tadalafil is a safe option for those with Fontan circulation, though individual experiences may vary. Always consult a doctor before starting new treatments. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Fontan physiology?

Researchers are excited about Tadalafil for Fontan physiology because it offers a promising new approach compared to current treatments, which primarily focus on managing symptoms with diuretics and other supportive therapies. Unlike these standard options, Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor that may enhance blood flow by relaxing blood vessels, potentially improving exercise capacity and heart function in patients with Fontan physiology. This unique mechanism of action could provide significant benefits in managing the condition more effectively, offering hope for better long-term outcomes.

What evidence suggests that Tadalafil might be an effective treatment for Fontan physiology?

Research shows that tadalafil might help people with Fontan physiology. Some studies found that tadalafil improved exercise performance in individuals who had Fontan surgery, helping them breathe better and increasing the oxygen in their blood. Another study found that tadalafil lowered Fontan pressure, benefiting heart function. Additionally, tadalafil improved exercise ability over six months without causing harmful side effects. These findings suggest that tadalafil could effectively improve heart and lung function in people who have had Fontan surgery. Participants in this trial will receive either tadalafil or a placebo to further evaluate its effectiveness. ^{1 3 6 7 8}

Who Is on the Research Team?

Alexander Egbe, MBBS, MPH

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

Adults over 18 who've had a Fontan Palliation, can exercise on a supine bike, and are able to have an MRI. They must be willing to give written consent and be scheduled for cardiac catheterization. It's not for those under 18, pregnant or breastfeeding women, people on certain heart medications, or unable to exercise.

Inclusion Criteria

Patients must be able to exercise using a supine bike

I am willing and able to sign a consent form.

I have had a Fontan procedure for my heart condition.

Exclusion Criteria

I am under 18 years old.

I am not on any IV drugs to strengthen my heart muscle.

I am not currently taking alpha-blockers, pulmonary vasodilators, or nitrates.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Tadalafil or placebo for 52 weeks to assess hemodynamic and end-organ function

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Tadalafil

Trial Overview The trial is testing if Tadalafil can improve blood flow (hemodynamics), the health of blood vessels (endothelial function), and organ function in patients with Fontan Physiology compared to a placebo (a substance with no active drug).

How Is the Trial Designed?

Group I: Tadalafil Group Experimental Treatment 1 Intervention

Study participants will receive 10 mg of Tadalafil daily for 1 week, then 20 mg daily for 1 week, and finally 40 mg daily for 50 weeks for a total therapy time of 52 weeks. Tadalafil will be taken orally in capsule form once daily.

Group II: Placebo Group Placebo Group 1 Intervention

Study participants will receive a placebo capsule that looks identical to the Tadalafil capsule. The placebo will be taken orally once daily for 52 weeks.

Tadalafil is already approved in United States, European Union for the following indications:

Approved in United States as Cialis for:

• Erectile dysfunction
• Pulmonary hypertension

Approved in European Union as Tadalafil for:

• Erectile dysfunction
• Pulmonary hypertension

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a clinical trial involving 15 patients who underwent the modified Fontan operation, tadalafil significantly improved myocardial function and exercise performance, as well as the patients' functional class after 6 weeks of treatment.

Tadalafil was found to be safe and well-tolerated, with a notable reduction in intima-media thickness (IMT), suggesting potential benefits in reducing long-term complications for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Tadalafil on Myocardial and Endothelial Function and Exercise Performance After Modified Fontan Operation. Sabri, MR., Zolfi-Gol, A., Ahmadi, A., et al.[2018]

Fontan patients, who have undergone a specific heart surgery, often experience reduced exercise capacity due to their heart's inability to increase blood flow during physical activity, leading to serious health complications.

The use of sildenafil, a medication that can lower pulmonary vascular resistance, shows promise in potentially improving cardiac output and exercise capacity in these patients, suggesting a new therapeutic approach for managing their condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of pulmonary vascular resistance as a target for therapeutic interventions in Fontan patients: focus on phosphodiesterase inhibitors. Ciliberti, P., Schulze-Neick, I., Giardini, A.[2015]

In a study of 30 pediatric patients who underwent Fontan operations, those treated with oral sildenafil showed significantly lower drainage loss and improved hemodynamic parameters, including reduced mean pulmonary artery pressure compared to the control group.

Sildenafil administration was associated with a lower inotropic score and shorter intubation time, with no reported complications, suggesting it is a safe and effective option for managing postoperative outcomes in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First experience with sildenafil after Fontan operation: short-term outcomes. Giordano, R., Palma, G., Poli, V., et al.[2015]

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 27 Fontan patients, a single dose of sildenafil significantly improved exercise capacity, as measured by peak oxygen uptake (VO2), with an increase of 9.4% compared to only 0.3% in the control group.

Sildenafil also enhanced key hemodynamic responses, increasing both pulmonary blood flow and cardiac index during exercise, without causing any serious adverse events, indicating it is a safe option for improving exercise performance in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Giardini, A., Balducci, A., Specchia, S., et al.[2015]

In a study of six patients with failing Fontan physiology, sildenafil treatment significantly improved systemic arterial oxygen saturation from 82.8% to 91.0%, indicating enhanced oxygen delivery.

Sildenafil also led to a notable reduction in pulmonary artery pressure and pulmonary vascular resistance, suggesting its effectiveness as a pulmonary vasodilator in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil Increases Systemic Saturation and Reduces Pulmonary Artery Pressure in Patients with Failing Fontan Physiology. Morchi, GS., Ivy, DD., Duster, MC., et al.[2021]

In a study of 23 patients aged 12-31 with Fontan circulation, a one-week course of oral sildenafil significantly improved oxygen saturation and enhanced ventricular systolic elastance, indicating better heart function.

Sildenafil was well tolerated, with only one patient (4%) experiencing intolerable side effects, suggesting it is a safe option for improving heart dynamics in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil and ventriculo-arterial coupling in Fontan-palliated patients: a noninvasive echocardiographic assessment. Shabanian, R., Shahbaznejad, L., Razaghian, A., et al.[2021]

A 9.5-year-old girl with hypoplastic left heart syndrome developed recurrent protein-losing enteropathy (PLE) after a Fontan procedure, which improved significantly after 6 weeks of treatment with Sildenafil.

Sildenafil treatment normalized her serum albumin and fecal alpha-1-antitrypsin levels, increased her exercise tolerance, and improved mesenteric arterial flow patterns, suggesting it may be an effective option for managing PLE post-Fontan procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resolution of protein-losing enteropathy and normalization of mesenteric Doppler flow with sildenafil after Fontan. Uzun, O., Wong, JK., Bhole, V., et al.[2015]

In a study of nine children post-Fontan surgery, intravenous sildenafil significantly improved cardiac output by 10% and stroke volume by 22%, indicating its efficacy in enhancing heart function in this population.

Sildenafil also reduced systemic and pulmonary vascular resistance, leading to lower pulmonary arterial pressures and increased blood flow, all while remaining within safe exposure levels similar to those observed in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil exposure and hemodynamic effect after Fontan surgery. Tunks, RD., Barker, PC., Benjamin, DK., et al.[2023]

In a study of 391 pediatric patients with pulmonary arterial hypertension (PAH) treated with tadalafil over up to 2 years, the overall incidence of adverse drug reactions (ADRs) was relatively low at 16.6%, indicating an acceptable safety profile for this medication in children.

Tadalafil treatment led to significant improvements in WHO functional classification and reductions in pulmonary arterial pressure (PAP) and tricuspid regurgitation pressure gradient (TRPG), demonstrating its effectiveness in managing PAH in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension: a sub-group analysis based on Japan post-marketing surveillance. Yamazaki, H., Kobayashi, N., Taketsuna, M., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9896416/

A Systematic Review and Meta-analysis - PMC Conclusion: This meta-analysis shows that people with Fontan circulation may benefit from using bosentan as it decreases postexercise heart rate and improves ...

2. ahajournals.org ahajournals.org/doi/10.1161/circ.128.suppl_22.A16024

Abstract 16024: Effect of Tadalafil on Exercise Parameters ... Conclusions: Short term therapy with once daily dosing of tadalafil improved ventilatory efficiency and oxygen saturation, but exercise capacity was unchanged ...

3. journals.lww.com journals.lww.com/rcvm/fulltext/2018/07020/tadalafil_and_exercise_capacity_after_fontan.3.aspx

Tadalafil and Exercise Capacity after Fontan Operation Tadalafil use for 6 months was effective in improving exercise performance of Fontan patients with no adverse side effects. Further studies to determine other ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9671729/

Selective Use of Pulmonary Vasodilators in Patients with ... Nine patients (17%) underwent posttherapy follow-up catheterization. The mean Fontan pressure decreased from 15.4 ± 3.3 mmHg to 13.3 ± 2.5 mmHg ...

5. withpower.com withpower.com/trial/phase-3-fontan-palliation-2-2022-e639d

Tadalafil for Fontan Physiology In a study of 30 pediatric patients who underwent Fontan operations, those treated with oral sildenafil showed significantly lower drainage loss and improved ...

6. ahajournals.org ahajournals.org/doi/10.1161/JAHA.121.023035

Use of Pulmonary Arterial Hypertension Therapies in ... However, outcomes in patients after Fontan‐type operations are far from optimal; a “failing Fontan” circulation is an almost inevitable long‐ ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0914508716300387

Adult patients with Fontan circulation: What we know and ... Better pulmonary circulation is crucial for better long-term outcome in Fontan physiology. ... tadalafil (1 mg/kg) for 6 weeks also improved exercise ...

8. e-kcj.org e-kcj.org/Synapse/Data/PDFData/0054KCJ/kcj-55-e68.pdf

Pulmonary Vasodilator Therapy in Patients With Fontan ... Key findings of our meta-analysis indicate that pulmonary vasodilators significantly improve exercise capacity (measured by oxygen consumption ...