Evaluation of Sildenafil Citrate on Claudication Distance in Peripheral Arterial Disease with Intermittent Claudication: A Phase III Randomized Controlled Trial

The primary objective of this clinical trial is to evaluate the efficacy of **sildenafil** compared to placebo in improving the walking capacity of patients with **peripheral arterial disease** and intermittent claudication at week 24. This is clinically relevant as enhanced walking capacity can significantly improve the quality of life and functional independence of affected patients.

Secondary objectives include:

• Determining whether sildenafil prevents surgical revascularization procedures at weeks 24 and 48.
• Assessing improvements in walking capacity at week 48.
• Evaluating the time to first event, defined as major adverse cardiovascular events, leg amputations, or non-cardiovascular death.
• Assessing improvements in quality of life at weeks 12, 24, and 48.
• Evaluating improvements in exercise oximetry results at weeks 12, 24, and 48.
• Assessing improvements in endothelial function at weeks 12, 24, and 48.
• Evaluating improvements in pulmonary function and diffusion capacity of the lungs for carbon monoxide at week 24.
• Assessing improvements in arterial stiffness and central blood pressure at weeks 12, 24, and 48.
• Evaluating improvements in arterial compliance and vascular resistance at weeks 12, 24, and 48.
• Determining changes in metabolomic signature and biological parameters between baseline and week 24.
• Evaluating compliance with the treatment.
• Assessing tolerance and perceived symptoms.

The clinical trial involves participants diagnosed with **peripheral arterial disease**, specifically those experiencing intermittent claudication. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a walking capacity of 500 meters or less on a treadmill and must have stable limiting claudication despite optimal medical treatment. The trial does not include a vulnerable population. Participants must be affiliated with a social security agency and have provided informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations include adherence to medical advice to walk for at least four weeks prior to the trial. The selection criteria ensure that participants have a documented decrease in ankle-brachial index (ABI) or toe-brachial index (TBI) or a significant post-exercise ABI decrease, indicating the presence of peripheral artery disease. The trial aims to assess the efficacy of sildenafil compared to placebo in improving walking capacity over a 24-week period.

The clinical trial is designed to evaluate the efficacy of **sildenafil citrate** in improving the walking capacity of patients with **peripheral arterial disease** and intermittent claudication. This is a phase III, national, multicenter, prospective, randomized, double-blind, placebo-controlled trial. The trial aims to compare the effects of sildenafil citrate against a placebo over a 24-week period. The study involves oral administration of the investigational product, with a maximum daily dose of 140 mg for sildenafil citrate and 100 mg for the placebo, which contains **microcrystalline cellulose** as an excipient. The total duration of the trial is estimated to be from November 24, 2021, to November 23, 2025, with recruitment having commenced on November 24, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), confirmed diagnosis of peripheral arterial disease, and a walking capacity of 500 meters or less on a treadmill. Following the screening, eligible participants will be randomized to receive either sildenafil citrate or placebo. Study visits will occur at baseline, weeks 12, 24, and 48, with assessments including treadmill tests to measure the absolute claudication distance (ACD), quality of life questionnaires, and various physiological measurements such as exercise oximetry and endothelial function. The primary endpoint is the absolute change in ACD from baseline to week 24, while secondary endpoints include surgical revascularization rates, event-free survival, and changes in various health parameters over the study period.

The expected length of participant involvement is up to 48 weeks, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. Participants are required to adhere to the study protocol, and any deviation may also lead to early termination. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **Sildenafil Citrate**, an experimental medication, to evaluate its efficacy in improving walking capacity in patients with intermittent claudication due to peripheral arterial disease. **Sildenafil Citrate** is provided in the form of a tablet and is administered orally. The maximum daily dose is 140 mg, with a total maximum dose of 23,520 mg over the course of the trial. The treatment period is set for 24 weeks. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, the trial includes the use of **Microcrystalline Cellulose** as a placebo. This substance is administered in the form of an oral powder. The maximum daily dose for the placebo is 100 mg, with a total maximum dose of 16,800 mg over the 24-week treatment period. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments. Compliance with the placebo administration is similarly monitored to maintain the integrity of the trial data.

The efficacy of sildenafil in patients with **intermittent claudication** due to peripheral arterial disease will be assessed through a series of primary and secondary endpoints. The primary endpoint is the absolute change in the absolute claudication distance (ACD) from baseline to week 24. ACD is measured in meters by having patients walk on a treadmill until they are unable to continue due to leg pain, with a maximum duration of 15 minutes per test. This measurement will be conducted at baseline and at week 24.

Secondary endpoints include the rate of patients undergoing surgical revascularization at weeks 24 and 48, and the absolute change in ACD from baseline to week 48. Event-free survival (EFS) will be evaluated from baseline until week 48, with events defined as major adverse cardiovascular events, leg amputations, or non-cardiovascular deaths. Additional assessments will include the SF36 and Peripheral Artery Questionnaires at baseline, weeks 12, 24, and 48, as well as changes in exercise oximetry, endothelial function, pulmonary function, arterial stiffness, arterial compliance, and metabolomics signature at specified timepoints. Compliance with treatment, tolerance, and perceived symptoms will also be monitored.