Clinical trial NCT01295736: Sildenafil Effect on Digital Ulcer Healing in sClerodErma SEDUCE STUDY
Official title: Evaluation of the Efficacy of Sildenafil on Time to Healing in Patients With Scleroderma and Ischaemic Digital Ulcers: a Prospective, Longitudinal, Randomized, Comparative, Double-blind, 2-parallel-arm, Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Systemic Scleroderma
Keywords: scleroderma
digital
ulcer
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
First posted: 2011-02-14
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Digital ulcers (DUs) are an expression of the microangiopathy in patients with scleroderma (SSc). DUs lead to pain and impaired hand use. DUs remain a severe complication for many patients and effective therapy remains elusive. In the present study, the investigators propose to evaluate the efficacy of Sildenafil in DUs healing in a randomized double blind control study in SSc patients.

Detailed description: This is a multicenter, prospective, longitudinal, randomized, comparative, double-blind, 2-parallel-arm, placebo-controlled study aimed to evaluate the efficacy of sildenafil 20 mg TID study on time to healing of DUs in SSc patients with ischaemic DUs.

Approximately 120 patients aged from 18 years and above will be allocated to receive either placebo or sildenafil 20mg TID during 90 days. All potential subjects will present with ischaemic digital ulcers complicating scleroderma. An eligible digital ulcer must be beyond the proximal interphalangeal joint, on finger surface (included periungual ulcers), of ischemic origin according to the physician, and not over subcutaneous calcifications or bone relief.

Eligibility criteria: Inclusion Criteria:

* Patient with systemic sclerosis (ScS) according to the classification criteria of the American College of Rheumatology or of "LeRoy" and "Medsger".
* ScS patient with at least one ongoing ischaemic hand digital ulcer at baseline (see below the eligibility conditions of a digital ulcer).
* Patient must have provided written informed consent prior to enrolment. Patient agrees to come to the follow up visits inside the protocol specified range.
* Relative to each DU: DU must be beyond the proximal interphalangeal joint, on finger surface, of ischemic origin according to the physician, and not over subcutaneous calcifications or bone relief.

Exclusion Criteria:

* PAH requiring PDE5 inhibitors or prostacyclin history of stroke, myocardial infarction or life threatening arrhythmia within the last 6 months
* severe cardiac failure (NYHA IV) or unstable angina within the last 6 months.
* hereditary degenerative retinal disorders non-arteritic anterior ischemic optic neuropathy or untreated proliferative diabetic retinopathy
* uncontrolled diabetes mellitus
* Patient with known severe lung obstructive disease (FEV1\<70% on last available pulmonary function tests).
* severe hepatic impairment
* Patient with known impairment of renal function (serum creatinine \> 2.5 ULN).
* Patient with severe malabsorption or any severe organ failure (e.g., lung, kidney) or any life-threatening condition.
* Patient who has had surgical sympathectomy performed in the previous 12 months.
* Patient with a history of upper extremity deep vein thrombosis or lymphedema within the previous 3 months.
* Patient participating in a clinical trial or having participated in a clinical trial within the previous 3 months.
* Patient having received a treatment with sildenafil for digital ulcers or pulmonary arterial hypertension within 3 months prior to inclusion.
* Patient having received a treatment with parenteral prostanoids (prostaglandin E, epoprostenol, treprostinil sodium or other prostacyclin analogs) within 3 months prior to inclusion.
* Patient having received a treatment with inhaled or oral prostanoids one month prior to inclusion.
* Patient with previous intolerance or allergy to PDE5 inhibitors or a history of multiple clinically significant allergies.
* Pregnant or lactating female.
* Patient with uncontrolled tachyarrhythmias or bradyarrhythmias, or placement of pacemaker or implantable defibrillator within 60 days prior to randomization.
* Patient with hemodynamic instability or systolic arterial pressure less than 90 mmHg and/or symptomatic orthostatic hypotension.
* Patient receiving all forms of prostacyclin or nitrates or nitric oxide donors in any form including Nicorandil.
* Patient receiving potent inhibitors of CYP3A4 such as ketoconazole, itraconazole, ritonavir.
* Patient with any condition that prevents compliance with the protocol or adhering to therapy.
* Patient who has donated blood during the previous month or intends to donate blood or blood products during the study or for one month following completion of the study.
* Patient under guardianship (including curators) or deprived of liberty.
* Patient presenting with an anatomic malformation of penis (such as an angulation, sclerosis of erectile tissue or "Lapeyronie's disease").
* Patient presenting with a disease which predisposes to priapism (such as sickle-cell disease, myeloma or leukemia).
* Patient presenting with at least one digital ulcer meeting the exclusion criteria (see below).
* Relative to each DU:
* Digital ulcer due to conditions other than scleroderma.
* Non ischaemic digital ulcer.
* Infected digital ulcer requiring systemic antibiotherapy.
* Digital ulcer requiring urgent surgery.

Primary outcomes:
measure: time to healing of ischemic digital ulcers (DUs) in patients with scleroderma treated by sildenafil 20 mg TID versus placebo for 90 days
timeFrame: 90 days
Secondary outcomes:
measure: To evaluate the time to healing of ischemic DUs (2 mm at entry and > 1 month and <3 months old) in patients with scleroderma treated by sildenafil 20 mg TID versus placebo for 90 days.
timeFrame: 90 days
measure: To evaluate the change in the number of ischaemic DUs between baseline and day 90.
timeFrame: 90 days
measure: To evaluate the proportion of patients with complete healing of all DUs present at baseline at day 90.
timeFrame: 90 days
measure: To evaluate the proportion of patients with complete healing of all DUs (baseline DUs and new DUs) at day 90.
timeFrame: 90 days
measure: To evaluate the proportion of patients who do not develop any new DU after 28 days of treatment with the study drug up to day 90.
timeFrame: 90 days
measure: To evaluate the change between baseline and day 90 in hand function and pain.
timeFrame: 90 days
measure: To evaluate the proportion of patients with complicated DUs (infection, gangrene, amputation, DU requiring IV prostanoids) over the 90 days period of treatment.
timeFrame: 90 days
measure: To evaluate the evolution of the severity of Raynaud's phenomenon between baseline and day 90.
timeFrame: 90 days
Other outcomes:
Locations:
city: Nice
country: France
facility: University Hospital, Nice
state: Alpes-Maritimes
city: Strasbourg
country: France
facility: Hautepierre Hospital
state: Bas-Rhin
city: Marseille
country: France
facility: Nord Hospital
state: Bouches du Rhone
city: Caen
country: France
facility: CHU de Caen
state: Calvados
city: Dijon
country: France
facility: CHU Dijon
state: Côte d'Or
city: Limoges
country: France
facility: CHU Dupuytren / dermatology
state: Haute Vienne
city: Limoges
country: France
facility: CHU Dupuytren / Médecine Interne
state: Haute Vienne
city: Bondy
country: France
facility: Jean Verdier Hospital
state: Ile de France
city: Paris
country: France
facility: La Pitié - Salpétriêre Hospital
state: Ile de France
city: Paris
country: France
facility: Cochin Hospital / Médecine Interne
state: Ile de France
city: Paris
country: France
facility: Cochin Hospital
state: Ile de France
city: Paris
country: France
facility: Saint Antoine Hospital
state: Ile de France
city: Paris
country: France
facility: Groupe Hospitalier Paris Saint Joseph
state: Ile de France
city: Rennes
country: France
facility: CHU de Rennes
state: Ile et Vilaine
city: Tours
country: France
facility: University Hospital, Tours
state: Indre-et-Loire
city: Grenoble
country: France
facility: University Hospital, Grenoble
state: Isère
city: Nantes
country: France
facility: University Hospital, Nantes
state: Loire-Atlantique
city: Reims
country: France
facility: CHU de Reims
state: Marne
city: Fort de France
country: France
facility: University Hospital, Fort de France
state: Martinique
city: Lille
country: France
facility: University Hospital, Lille
state: Nord
city: Rouen
country: France
facility: University Hospital, Rouen
state: Seine-Maritime
city: Amiens
country: France
facility: University Hospital, Amiens
state: Somme
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Paris
country: France
facility: St Louis Hospital
Study officials:
affiliation: University Hospital, Lille
name: Eric HACHULLA, PU-PH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hachulla E, Hatron PY, Carpentier P, Agard C, Chatelus E, Jego P, Mouthon L, Queyrel V, Fauchais AL, Michon-Pasturel U, Jaussaud R, Mathian A, Granel B, Diot E, Farge-Bancel D, Mekinian A, Avouac J, Desmurs-Clavel H, Clerson P; SEDUCE study group. Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study. Ann Rheum Dis. 2016 Jun;75(6):1009-15. doi: 10.1136/annrheumdis-2014-207001. Epub 2015 May 20.