Oral Sildenafil for COPD

Overseen By Rhys Beaudry, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alberta

Must not be taking: Nitrates, Opioids, Azole antifungals, others

Disqualifiers: Cardiac conditions, Pulmonary hypertension, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

Duration: 8 weeks

160 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether sildenafil, a medication known for widening blood vessels, can help individuals with mild COPD (chronic obstructive pulmonary disease) improve exercise tolerance and reduce shortness of breath. Researchers believe that blood flow issues in the lungs contribute to these symptoms, even when the airways aren't severely blocked. Participants will receive either sildenafil (also known as sildenafil citrate) or a placebo (a pill with no active drug) to determine any differences in symptoms. This trial targets individuals with mild COPD who experience significant shortness of breath during activities like walking or climbing stairs. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

If you are currently taking phosphodiesterase type-5 inhibitors, nitrates, opioids, azole antifungals, macrolide antibiotics, protease inhibitors, alpha blockers, riociguat, mifepristone, or rifamycin, you will need to stop these medications to participate in the trial.

Is there any evidence suggesting that sildenafil citrate is likely to be safe for humans?

Research shows that sildenafil is generally safe for people with certain lung conditions. Studies have found it effective and safe for those with pulmonary hypertension, which is high blood pressure in the lungs related to COPD. However, sildenafil might not improve exercise ability for COPD patients without this specific high blood pressure condition.

There are some warnings. Sildenafil may cause issues for people with pulmonary veno-occlusive disease, a rare lung condition, as it could worsen heart and lung function. Those with concerns or existing health conditions should consult a doctor before considering participation in a trial involving sildenafil. ^{1 2 3 4 5}

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

Unlike the standard treatments for COPD, which often focus on bronchodilators and steroids to manage symptoms, sildenafil citrate works differently by targeting blood flow. Sildenafil, commonly known for its use in erectile dysfunction, is a vasodilator that helps relax and widen blood vessels, potentially improving oxygen delivery in the lungs. Researchers are excited about this treatment because it offers a novel approach by addressing pulmonary vascular function, which could lead to better outcomes for COPD patients beyond the typical symptom relief.

What evidence suggests that sildenafil might be an effective treatment for COPD?

In this trial, participants will receive either sildenafil or a placebo. Previous studies have shown that sildenafil may help with conditions related to COPD. Research suggests that sildenafil eases blood flow through the lungs by reducing resistance in the lung's blood vessels. This effect has been linked to improved exercise ability in some patients. However, one study found that sildenafil did not significantly enhance exercise tolerance in COPD patients with normal pulmonary blood pressure. For those with high pulmonary blood pressure related to COPD, sildenafil improved walking distances. The evidence is mixed, but sildenafil shows potential to aid exercise tolerance in mild COPD through its effect on the lung's blood vessels. ^{1 3 4 6 7}

Who Is on the Research Team?

Michael K Stickland, Ph.D.

Principal Investigator

University of Alberta

Are You a Good Fit for This Trial?

This trial is for adults with mild COPD who experience significant shortness of breath. Participants must have a specific lung function level (FEV1 >30% predicted) and can't be on certain medications or have heart conditions that limit exercise. Women able to bear children must use contraception, and postmenopausal women must be amenorrheic for at least 12 months.

Inclusion Criteria

Your FEV1 (a measure of lung function) is greater than 30% of what is expected for someone with severe COPD.

Your lung function test shows that you have normal airflow in your lungs after using a bronchodilator.

I have never been diagnosed with COPD.

Exclusion Criteria

I am using or willing to use birth control if I can have children.

I have a heart condition that could affect my ability to do physical tests.

I was diagnosed with high blood pressure in my lungs before my lung disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive oral sildenafil or placebo in a randomized, double-blinded, placebo-controlled cross-over design

8 weeks

7 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

• Placebo
• Sildenafil Citrate

Trial Overview The study tests if Sildenafil, an oral medication that widens blood vessels in the lungs, can improve exercise capacity and reduce shortness of breath in people with mild COPD compared to a placebo (a pill without active medicine).

How Is the Trial Designed?

Group I: Sildenafil Experimental Treatment 1 Intervention

Participants will be administered a 25 mg oral dose of sildenafil.

Group II: Placebo Placebo Group 1 Intervention

Participants will be administered an oral placebo indistinguishable from the sildenafil pill.

Who Is Running the Clinical Trial?

University of Alberta

Lead Sponsor

Trials

957

Recruited

437,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Published Research Related to This Trial

Sildenafil citrate is a highly effective treatment for erectile dysfunction (ED), having been used successfully by over 20 million men worldwide, including those with challenging conditions like radical prostatectomy and severe diabetes.

The medication is generally safe for cardiovascular patients not on nitrate medications, with no increased risk of adverse cardiovascular events compared to the general population, and it can be used alongside various other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil: a 4-year update in the treatment of 20 million erectile dysfunction patients. Carson, CC.[2019]

In a 6-week study involving 424 patients with COPD, cilomilast at a dose of 15 mg twice daily significantly improved lung function (FEV1) compared to placebo, with an increase of 130 mL versus a decrease of 30 mL in the placebo group.

Cilomilast also showed improvements in forced vital capacity (FVC) and peak expiratory flow, with no significant differences in serious adverse events, suggesting it may be a safe and effective maintenance treatment for COPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Compton, CH., Gubb, J., Nieman, R., et al.[2015]

Roflumilast, the only approved PDE4 inhibitor for chronic obstructive pulmonary disease (COPD), has shown efficacy in reducing exacerbations specifically in patients with severe airflow obstruction and chronic bronchitis symptoms, based on targeted clinical trials.

The current clinical data does not clearly define which specific types of COPD exacerbations roflumilast is most effective against, highlighting the need for better identification of patient phenotypes to optimize its use as a first-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discovery of roflumilast for the treatment of chronic obstructive pulmonary disease. Cazzola, M., Calzetta, L., Rogliani, P., et al.[2017]

Sildenafil citrate, administered in both orally disintegrating film (ODF) and film-coated tablet (FCT) forms, showed no significant differences in pharmacokinetics when given orally to healthy beagle dogs, indicating that ODF can be a viable alternative to FCT for treating pulmonary hypertension (PH).

Rectal administration of the ODF formulation resulted in lower peak plasma concentrations compared to oral administration, but no serious adverse events were reported, suggesting that rectal ODF could be a useful option for dogs unable to take medication orally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative single-dose pharmacokinetics of sildenafil after oral and rectal administration in healthy beagle dogs. Yang, HJ., Oh, YI., Jeong, JW., et al.[2018]

In two patients with severe COPD and erectile dysfunction, taking oral sildenafil led to improvements in their breathing difficulties (dyspnea) and lung function, as measured by FEV(1), which increased by 24% and 12%.

The findings suggest that sildenafil does not harm lung function in COPD patients and may even provide a modest benefit in improving airflow.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does sildenafil also improve breathing? Charan, NB.[2019]

Cilomilast showed some improvement in lung function (FEV1) in COPD patients compared to placebo, but only one of the studies demonstrated a statistically significant and clinically meaningful difference, leading to mixed results regarding its efficacy.

While cilomilast was associated with more gastrointestinal side effects, safety assessments did not reveal serious safety concerns, but the overall lack of consistent efficacy led to the termination of its development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of cilomilast in COPD. Rennard, S., Knobil, K., Rabe, KF., et al.[2021]

In a study of 37 patients with severe COPD, those treated with sildenafil showed a significant improvement in exercise capacity, measured by a 190-meter increase in the six-minute walk test compared to no change in the placebo group after 12 weeks.

Sildenafil also significantly reduced pulmonary artery pressure in the treatment group, indicating its potential to improve both exercise capacity and hemodynamic parameters in severe COPD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil improves six-minute walk distance in chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Rao, RS., Singh, S., Sharma, BB., et al.[2015]

Sildenafil citrate inhaled formulations complexed with cyclodextrins (CDs) significantly improved water solubility and enhanced the vasodilatory effect, reducing umbilical blood pressure by 67.1-73.7% compared to 39.0% with formulations without CDs.

The study demonstrated that the inhaled sildenafil formulations had effective delivery characteristics, with fine particle fractions of 60.5% and a mass median aerodynamic diameter of 2.3μm, indicating potential for rapid onset of action in treating pulmonary hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of sildenafil pressurized metered dose inhalers as a vasodilator in umbilical blood vessels of chicken egg embryos. Sawatdee, S., Hiranphan, P., Laphanayos, K., et al.[2015]

Roflumilast, an oral medication approved for severe chronic obstructive pulmonary disease (COPD), has been shown to improve lung function and reduce exacerbations in patients, particularly those with chronic bronchitis and frequent exacerbations, based on large-scale clinical trials lasting six to twelve months.

While effective, roflumilast can cause gastrointestinal upset and headaches, leading to a higher dropout rate among patients, especially in the initial weeks of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Giembycz, MA., Field, SK.[2021]

In a study of 72 COPD patients, those treated with Sildenafil showed a significant reduction in pulmonary arterial systolic pressure compared to the control group, indicating its efficacy in managing pulmonary hypertension associated with COPD.

Sildenafil also led to a notable increase in the six-minute walk distance for patients, suggesting improved exercise capacity, while it positively affected dyspnoea grading but did not significantly change overall functional class after four weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Sildenafil Citrate on Pulmonary Arterial Systolic Pressure and Sub-maximal Exercise Capacity in Chronic Obstructive Pulmonary Disease. [2019]

In a study of 380 patients with erectile dysfunction (ED), sildenafil citrate (Viagra) demonstrated an overall efficacy rate of 77%, with the highest success in hormonal patients (100%) and psychogenic ED (88%).

Sildenafil was found to be well-tolerated, with only mild to moderate side effects reported, indicating it is a safe treatment option for men with ED of various causes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil: efficacy and safety in daily clinical experience. Palumbo, F., Bettocchi, C., Selvaggi, FP., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4904720/

Sildenafil for Chronic Obstructive Pulmonary Disease Sildenafil leads to decreased pulmonary vascular resistance and improved outcomes in pulmonary arterial hypertension (15, 16) and preserves (or even improves) ...

2. publications.ersnet.org publications.ersnet.org/content/erj/42/4/982

Sildenafil to improve respiratory rehabilitation outcomes in ... In a recent randomised controlled trial conducted in COPD patients with normal PAP, sildenafil also failed to improve exercise tolerance [22]. The severity of ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0024320520307517

Efficacy and safety of Sildenafil treatment in pulmonary ... Available clinical evidence indicates that Sildenafil seems to be safe and effective for COPD-PH and can improve the patients' 6WMD.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32634428/

Efficacy and safety of Sildenafil treatment in pulmonary ... Available clinical evidence indicates that Sildenafil seems to be safe and effective for COPD-PH and can improve the patients' 6WMD.

5. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.068107

Randomized, Multicenter Study to Assess the Effects of ... Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2014/021845s011,022473s004,0203109s002lbl.pdf

REVATIO (sildenafil) Label - accessdata.fda.gov Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno- occlusive disease (PVOD). Since there are no clinical ...

7. jhltonline.org jhltonline.org/article/S1053-2498(16)30114-0/pdf

Sildenafil in severe pulmonary hypertension associated ... We included patients between the ages of 40 and 80 years and diagnosed with COPD according to the Global Initiative for. Chronic Obstructive Lung Disease ...