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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out more about the effectiveness of Tadalafil in improving hemodynamic capabilities, endothelial function, and end-organ function in patients who have previously undergone a Fontan Palliation.

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.

What data supports the effectiveness of the drug Tadalafil for Fontan Physiology?

Research shows that Tadalafil significantly improves heart function, exercise performance, and quality of life in patients who have undergone the Fontan procedure, which is a heart surgery for certain congenital heart defects. ^{1 2 3 4 5}

Is tadalafil safe for humans?

Tadalafil is generally safe for humans, with most side effects being mild or moderate and often disappearing without stopping the medication. It does not increase the risk of heart problems and can be safely used with blood pressure medications. ^{1 3 6 7 8}

How does the drug Tadalafil differ from other treatments for Fontan physiology?

Tadalafil is unique in its use for Fontan physiology as it specifically targets myocardial and endothelial function, improving heart function and exercise performance, which is not the primary focus of other treatments like Sildenafil that mainly reduce pulmonary artery pressure and increase oxygen saturation. ^{1 3 5 9 10}

Research Team

Alexander Egbe, MBBS, MPH

Principal Investigator

Mayo Clinic

Eligibility Criteria

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

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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]

References

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

Effect of Tadalafil on Myocardial and Endothelial Function and Exercise Performance After Modified Fontan Operation. [2018]

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

First experience with sildenafil after Fontan operation: short-term outcomes. [2015]

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

Sildenafil and ventriculo-arterial coupling in Fontan-palliated patients: a noninvasive echocardiographic assessment. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. [2015]

5. England pubmed.ncbi.nlm.nih.gov

Modulation of pulmonary vascular resistance as a target for therapeutic interventions in Fontan patients: focus on phosphodiesterase inhibitors. [2015]

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

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

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

Sildenafil exposure and hemodynamic effect after Fontan surgery. [2023]

8. England 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. [2018]

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

Sildenafil Increases Systemic Saturation and Reduces Pulmonary Artery Pressure in Patients with Failing Fontan Physiology. [2021]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Resolution of protein-losing enteropathy and normalization of mesenteric Doppler flow with sildenafil after Fontan. [2015]