VIRTUOSE : Efficiency of Sildenafil on the Absolute Claudication Distance of Peripheral Arterial Disease Patients With Intermittent Claudication. (VIRTUOSE)

VIRTUOSE : Efficiency of Sildenafil on the Absolute Claudication Distance of Peripheral Arterial Disease Patients With Intermittent Claudication. A Phase III, National, Multicentre, Prospective, Randomised, Double-blind, Placebo-Controlled Trial.

Peripheral Arterial Disease (PAD) is a highly debilitating disease that affects 202 million people around the world and about 7 million people in France. Morbi-mortality from cardiovascular events is increased in this population. Intermittent claudication is defined as a discomfort and/or pain in the legs during walking. It is the most common clinical feature of PAD.

In claudication, primary therapeutic approach is medical treatment and advice to walk. Revascularization is only proposed when medical treatment and advice to walk for at least 3 to 6 months have failed to improve symptoms and walking ability.

Optimal medical treatment includes Antiplatelet, Lipid Lowering Drugs, AT2 antagonists / ACE Inhibitors and advice to walk.

To date, no other drug has provided consistent evidence for functional improvement in claudication, except for Cilostazol, a type-3 phospho-diesterase inhibitor (PDEi). This compound has been scarcely used in France due to cost and frequent side effect (Headache, Flush, Diarrhea, etc.) and was withdrawn as a therapy in 2010.

Sildenafil, a type 5 PDEi, is well tolerated, largely used in impotence and has interesting clinical delay and duration of action in the concept of a potential use in claudication. Preliminary data from the literature and unpublished case reports, suggest that this drug could efficiently improve symptoms and walking capacity in patients with stage 2 claudication.

Study Overview

• Status: Recruiting
• Conditions: Peripheral Artery Disease
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebo

Detailed Description

Experimental design A Phase III, National, Multicentre, Prospective, Randomised, Double Blind, placebo-controlled clinical trial with two parallel groups.

Eligible patients will be randomised in two groups:

• Experimental group Sildenafil citrate 140 mg/day (single morning oral dose of 140 mg) for a total duration of 24 weeks.
• Control group Placebo (single morning oral dose) for a total duration of 24 weeks.

Treatment will be proposed in addition to optimal treatment (Antiplatelet / Direct Oral Anticoagulant + Lipid Lowering Drugs + AT2 antagonists / ACE Inhibitors; unless contra-indicated) + advice to walk.

The experimental drug will be delivered for a 4 weeks treatment period. Phone contact will be carried out at 7 and 14 days focusing on tolerance, compliance and eventual side effects.

First follow up visit at week 4 will focus on tolerance, compliance and side effects. If no major side effect is found, the study drug will be delivered for an additional 8 weeks.

Phone contact will be carried out at 8 weeks focusing on tolerance, compliance and eventual side effects.

Patients will be evaluated at week 12 (second follow-up visit) for persistent or non-persistent indication for revascularization and considered for revascularization if needed. In parallel, attention will be given to tolerance, compliance and eventual side effects. If no major side effect is found, the study drug will be delivered for an additional 12 weeks period.

Phone contact will be carried out at weeks 16 and 20 focusing on tolerance, compliance and eventual side effects.

Third and fourth follow-up visits are scheduled at week 24 (end of treatment) and week 48 (24 weeks after the end of experimental drugs).

Perspectives

• Improving quality of life of patients suffering a chronic debilitating disease is a major issue not only in vascular medicine.
• It is expected that the treatment may help patients change from a vicious circle (Pain > inactivity > disease progression > pain > increased morbi-mortality) to a virtuous circle (no Pain > improved ability for activity > collateral vessel development > slowing of disease progression > decreased morbi-mortality )
• We expect that half of the patients that fulfil inclusion criteria will be sufficiently improved not to require surgery anymore even 24 weeks after the end of the drug as a result of this virtuous circle.

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Loukman Omarjee, MD; Phone Number: 02.99.28.52.32; Email: loukman.omarjee@chu-rennes.fr

Study Locations

• France
  • Amiens, France
    • Recruiting
    • Amiens University Hospital
    • Contact: Marie-Antoinette SEVESTRE, MD; Phone Number: 03.22.45.59.30; Email: sevestre.marie-antoinette@chu-amiens.fr
    • Principal Investigator: 03.22.45.59.30 03.22.45.59.30, MD
  • Bordeaux, France
    • Recruiting
    • Bordeaux university hospital
    • Contact: Joel CONSTANS, MD; Phone Number: 05.56.79.58.16; Email: joel.constans@chu-bordeaux.fr
    • Principal Investigator: Joel CONSTANS, MD
  • Caen, France
    • Recruiting
    • CAEN University Hospital
    • Contact: Damien LANEELLE, MD; Phone Number: 02 31 06 53 27; Email: laneelle-d@chu-caen.fr
    • Principal Investigator: Damien LANEELLE, MD
  • Cholet, France
    • Recruiting
    • Cholet Hospital
    • Contact: Cédric FONTAINE, MD; Phone Number: 02 41 49 64 30; Email: cedric.fontaine@ch-cholet.fr
    • Principal Investigator: Cédric FONTAINE, MD
  • Grenoble, France
    • Recruiting
    • Grenoble University Hospital
    • Contact: Gilles PERNOD, MD; Phone Number: 04 76 76 57 17; Email: GPernod@chu-grenoble.fr
    • Principal Investigator: Gilles PERNOD, MD
  • Grenoble, France, 38000
    • Recruiting
    • Groupe Hospitalier Mutualiste de Grenoble
    • Contact: Benjamin SONNET
    • Contact: Benjamin SONNET; Email: benjamin.sonnet@avec.fr
  • Mulhouse, France
    • Suspended
    • Mulhouse Hospital
  • Nîmes, France
    • Recruiting
    • Nîmes University Hospital
    • Contact: Antonia PEREZ MARTIN, MD; Phone Number: 04 66 68 33 13; Email: antonia.perez.martin@chu-nimes.fr
    • Principal Investigator: Antonia PEREZ MARTIN, MD
  • Paris, France
    • Recruiting
    • AP-HP - Hôpital Europeen Georges Pompidou
    • Contact: Tristan MIRAULT, MD; Phone Number: 01 56 09 58 32; Email: tristan.mirault@aphp.fr
    • Principal Investigator: Tristan MIRAULT, MD
  • Paris, France
    • Recruiting
    • Hospital Paris Saint-Joseph and Hospital Marie Lannelongue
    • Contact: Ulrique MICHON-PASTUREL, MD; Phone Number: 01 44 12 75 91; Email: umichon-pastruel@ghpsj.fr
    • Principal Investigator: Ulrique MICHON-PASTUREL, MD
  • Saint-Etienne, France
    • Withdrawn
    • Saint-Etienne University Hospital
  • Toulouse, France
    • Withdrawn
    • Toulouse University Hospital
  • Bretagne
    • Rennes, Bretagne, France, 35033
      • Recruiting
      • Guillaume MAHE
      • Contact: Guillaume MAHE, MD
      • Contact: Guillaume MAHE, MD; Phone Number: 02.99.28.52.32; Email: guillaume.mahe@chu-rennes.fr
      • Principal Investigator: Guillaume MAHE, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient ≥ 18 years old;
2. with peripheral artery disease (ABI ≤ 0.90 or TBI ≤ 0.70 or post-exercise ABI decrease of 18.5% from rest or ABI Exercise TcPO2 with DROPmin ≤ - 15 mmHg) reporting stable limiting claudication despite optimal medical treatment (Antiplatelet / Direct Oral Anticoagulant + Lipid Lowering Drugs + AT2 antagonists / ACE Inhibitors; unless contra-indication) and advice to walk for at least 4 weeks;
3. with a walking capacity lower or equal to 500 meters on treadmill;
4. affiliation to a social security agency
5. Patient who has understood the protocol and signed the consent form to participate.

Exclusion Criteria:

1. Revascularization already decided and scheduled;
2. Critical limb ischemia;
3. Life threatening disease;

4. Contraindication related to Sildenafil:

   • Patients treated with nitrates or drugs interfering with the action of sildenafil
   • Ongoing treatment by Ritonavir or alpha-blockers
   • Hypersensitivity to sildenafil or any of the excipients (lactose monohydrate)
   • Recent history of myocardial infarction or stroke < 3 months
   • Severe cardiovascular disorders such as unstable angina, severe cardiac failure and cardiomyopathy
   • Hypotension (Blood pressure < 90/50 mmHg)
   • Severe renal or hepatic failure
   • Amblyopia
   • Loss of vision in one eye because of Non-arterial ischemic Ophtalmic Neuropathy (NAION)
   • Known hereditary degenerative retinal disorders such as retinitis pigmentosa
   • Leukemia, Drepanocytosis, Multiple Myeloma
5. Pregnancy or breastfeeding;
6. Subjects under reinforced protection, deprived of liberty by judicial or administrative decision, hospitalized without consent or admitted to a health or social care establishment for purposes other than research;
7. Being in an exclusion period for another clinical study or in an ongoing interventional clinical study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Sildenafil citrate 140 mg/day (single morning oral dose of 140 mg) for a total duration of 24 weeks.	Drug: Sildenafil; Sildenafil citrate 140 mg/day (single morning oral dose of 140 mg) for a total duration of 24 weeks. + advice to walk for a total duration of 6 months. Treatment will be proposed in addition to optimal treatment (Antiplatelet + Lipid Lowering Drugs + AT2 antagonists / ACE Inhibitors; unless contra-indicated) + advice to walk.
Placebo Comparator: Control group; Placebo (single morning oral dose) for a total duration of 24 weeks.	Drug: Placebo; Placebo (single morning oral dose) + advice to walk for a total duration of 24 weeks. Treatment will be proposed in addition to optimal treatment (Antiplatelet / Direct Oral Anticoagulant + Lipid Lowering Drugs + AT2 antagonists / ACE Inhibitors; unless contra-indicated) + advice to walk.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute claudication distance	Absolute change of the absolute claudication distance (ACD) from baseline to week 24	Baseline and week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgical re-vascularisation	Rate of patients with surgical re-vascularisation at weeks 24 and 48	baseline and weeks 24 and 48
ACD	Absolute change of the ACD from baseline to week 48	Baseline and week 48
Event free survival (EFS)	An "EVENT" is defined as either (1) major adverse cardiovascular events (MACE; including vascular deaths, non-fatal myocardial infarction and non-fatal stroke), (2) leg amputations, (3) Non Cardiovascular death. Event-free survival is defined as the time from inclusion to the first documented event. If no event is observed, event-free survival is defined as the delay of follow-up.	Through the study completion, an average of 1 year
36-Item Short Form Health Survey (SF36)	Quality of life : SF36 questionnaire at baseline and weeks 12, 24 and 48	Baseline and weeks 12, 24 and 48
Peripheral Artery Questionnaire	Peripheral Artery Questionnaire at baseline and weeks 12, 24 and 48	Baseline and weeks 12, 24 and 48
Oxymetry	Change in exercise oxymetry results between baseline and weeks 12, 24 and 48	Baseline and weeks 12, 24 and 48
Endothelial function by Laser Speckle	Change in endothelial function at weeks 12, 24 and 48	Baseline and weeks 12, 24 and 48
Pulmonary function	Pulmonary function and diffusion capacity of the lungs for carbon monoxide (DLCO) at week 24 from baseline	Baseline and week 24
Respect of prescribed dose	Compliance with the treatment	Through the study completion, an average of 1 year
Tolerance	Tolerance and side effects	Through the study completion, an average of 1 year
Arterial stifness	Changes in arterial stiffness (Pulse Wave Velocity) with pOpmetre® between baseline and weeks 12, 24 and 48	Baseline and weeks 12, 24 and 48
Central Blood Pressure	Changes in Central Blood Pressure with pOpmetre® between baseline and weeks 12, 24 and 48	Baseline and weeks 12, 24 and 48
Arterial compliance	Changes in arterial compliance with Finometer® between baseline and weeks 12, 24 and 48	Baseline and weeks 12, 24 and 48
Vascular resistance	Changes in vascular resistance with Finometer® between baseline and weeks 12, 24 and 48	Baseline and weeks 12, 24 and 48
Metabolomics signature	Change in metabolomics signature between baseline and week 24	Baseline and week 24

Collaborators and Investigators

• Sponsor: Rennes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2021
• Primary Completion (Estimated): November 24, 2024
• Study Completion (Estimated): June 24, 2025

Study Registration Dates

• First Submitted: September 24, 2018
• First Submitted That Met QC Criteria: September 25, 2018
• First Posted (Actual): September 26, 2018

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases; Intermittent Claudication; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: VIRTUOSE; 2020-000231-42 (EudraCT Number); 20 07 41 (Other Identifier: CPP); MEDAECNAT-2020-07- 00008 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No