Treprostinil Iontophoresis in Systemic Sclerosis Digital UlcErations. A Proof of Concept Study

Study Overview
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Brief Summary
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The study is conducted to confirm the good tolerance of a continuous cathodal iontophoresis of the treprostinil hydrogel administered during 10 days on the pulp of the finger of healthy volunteer and on the ischemic digital ulcerations of Systemic Sclerosis patients, particularly to estimate the cutaneous tolerance of the procedure and the effect on the blood pressure.

Detailed Description
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Systemic Sclerosis is a rare disease characterized by microvascular affection and cutaneous fibrosis. The digital ulcers are a severe and very invalidating complication. The vascular dysfunction is a key element in the pathogenesis of this disease, preceding the fibrosis. The physiopathology involves a vascular ischemia and mechanical factors or cutaneous calcinoses, or local trauma. The treatment of the digital ulcerations of the Systemic Sclerosis is at first preventive within the a good cutaneous and ungual hygiene, with recourse, as a preventive measure, to Bosentan, an endothelin antagonist. Iloprost by intravenous route is the recommended curative treatment, but patients present very frequent and dose - limiting side effects (headaches, vasomotor flushing, nausea, vomiting, maxillary pains, myalgia). The paradox is that the decrease of the capillary density and the lower microvascular reactivity limits the distribution of the drug at its site of action when it is administered by intravenous route. High doses are then necessary to reach a sufficient concentration in the region of the wound, which generates side effects. The local administration of the drug could allow to by-pass this problem. The investigator uses a technique for the topical administration of a vasodilator close to iloprost, treprostinil. This technique is iontophoresis. In the previous clinical trials INFLUX-IT and TIPPS, the investigator showed that the local cutaneous administration of treprostinil by cathodal iontophoresis at 0.03 milliAmper(mA)/cm2 is well tolerated (no local or systematic side effect in healthy volunteer, Systemic Sclerosis patients and diabetics). Iontophoresis induced a steady increase of the cutaneous blood flow of fingers. The investigator also showed that treprostinil was detectable in the dermis until 8 hours after the iontophoresis, without significant increase in the plasma. Thus, daily repeated iontophoresis on 10 days on ulcerated areas could allow to obtain therapeutic tissular concentrations.

Official Title
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Therapeutic Iontophoresis of Treprostinil in Systemic Sclerosis Digital UlcErations. A Proof of Concept Study

Conditions
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Scleroderma, Systemic

Intervention / Treatment
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* Drug: Iontophoresis of treprostinil
* Drug: Iontophoresis of placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy Volunteers: Age of at least 18 years Existence of a contraceptive method for women of child-bearing age Person affiliated to social security or beneficiary of such a scheme Signed consent form Systemic sclerosis patients: Systemic sclerosis meeting the EULAR criteria. Presence of 1 ischemic digital cutaneous ulceration , with digital ulcer classified as active ulcers according to the North American working group definition: epithelial denudation is clearly Visible at one place and the bed of de-epithelialized ulcer can be seen; Ulcerations distal to the proximal interphalangeal joint, not associated with calcinosis or bony relief. Ulcers whose major axis measured with the electronic caliper is ≥ 2 mm Age greater than or equal to 18 years Existence of a contraceptive method for women of reproductive age A person who is or is a beneficiary of social security Informed and signed consent signed by the patient or his / her legal representative. Exclusion Criteria: Healthy Volunteers Treprostinil contraindications: Known hypersensitivity to treprostinil or any of the excipients, Pulmonary arterial hypertension related to veno-occlusive disease, Congestive heart failure due to severe left ventricular dysfunction, Severe hepatic insufficiency (Child-Pugh stage C), Evolving gastrointestinal ulcer, intracranial hemorrhage, recent trauma or other clinical condition that may lead to bleeding, Congenital or acquired valvular abnormalities with cardiac repercussions, Severe ischemic heart disease or unstable angina; Myocardial infarction in the last six months; Decompensated cardiac insufficiency not medically controlled; Severe arrhythmias; Cerebrovascular lesions (such as transient ischemic attack, stroke) that occurred within the last three months. Persons referred to in Articles L1121-5 to L1121-8 of the French Public health Code: pregnant woman, parturient, nursing mother, person deprived of liberty by judicial or administrative decision, person subject to a legal protection measure, can not Be included in clinical trials. Subject in an exclusion period from another study, Subject who would receive more than 4500 euros of compensation due to his participation in other biomedical research in the 12 months preceding this study Systemic sclerosis patients: Iloprost cure carried out in the previous month or planned in the following month. Initiation or change of dosage of bosentan, sildenafil or calcium channel blockers in the previous month or in the following month Digital Sympathectomy or botulinum toxin injection planned in the following month. Clinically superinfected digital ulcers Treprostinil contraindications: Known hypersensitivity to treprostinil or any of the excipients, Pulmonary arterial hypertension related to veno-occlusive disease, Congestive heart failure due to severe left ventricular dysfunction, Severe hepatic insufficiency (Child-Pugh stage C), Evolving gastrointestinal ulcer, intracranial hemorrhage, recent trauma or other clinical condition that may lead to bleeding, Congenital or acquired valvular abnormalities with cardiac repercussions, Severe ischemic heart disease or unstable angina; Myocardial infarction in the last six months; Decompensated cardiac insufficiency not medically controlled; Severe arrhythmias; Cerebrovascular lesions (such as transient ischemic attack, stroke) that occurred within the last three months. Persons referred to in Articles L1121-5 to L1121-8 of the French Public health Code: pregnant woman, parturient, nursing mother, person deprived of liberty by judicial or administrative decision, person subject to a legal protection measure, can not Be included in clinical trials. Subject in an exclusion period from another study, Subject who would receive more than 4500 euros of compensation due to his participation in other biomedical research in the 12 months preceding this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treprostinil<br>the participant will receive 10 days of iontophoresis of treprostinil on a first site, each day the same site. | Drug: Iontophoresis of treprostinil<br>* the participant will receive 10 days of iontophoresis of treprostinil on a first site<br>|
| Placebo Comparator: Placebo<br>the participant will receive 10 days of iontophoresis of NaCl on a second site, but the same time than treprostinil | Drug: Iontophoresis of placebo<br>* the participant will receive 10 days of iontophoresis of NaCl on a second site, but the same time than treprostinil; it's like a design of cross-over study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of side-effects graduated according to NIH CTCAE 4.03 | Side effects will be reported according to NIH CTCAE 4.03, particularly  Skin and subcutaneous tissue disorders  et  Vascular disorders . | every day of iontophoresis from day 0 to day 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamical effect of iontophoresis of treprostinil hydrogel in healthy volunteers on pulp finger, leg and foot | area under curve of the increase of the flow after the iontophoresis of the gel of treprostinil compared to the iontophoresis of Sodium Chloride (NaCl) measured by laser speckle imaging | day 0 | 
| Pharmacodynamical effect of 10 days of iontophoresis of treprostinil hydrogel in systemic sclerosis patients | cutaneous vascular conductance after the iontophoresis of the gel of treprostinil compared to the iontophoresis of NaCl measured by laser speckle imaging | day 0 and day 9 | 
| Pharmacodynamical effect of 10 days of iontophoresis of treprostinil hydrogel in systemic sclerosis patients | Area under curve of the cutaneous flow after the iontophoresis of the gel of treprostinil compared to the iontophoresis of NaCl measured by laser speckle imaging | day 0 and day 9 | 
| Effect of iontophoresis of treprostinil hydrogel on peri and intra ulcer flow | cutaneous vascular conductance of the ulceration areas after the iontophoresis of the gel of treprostinil compared to the iontophoresis of NaCl measured by laser speckle imaging | day 0 and day 9 | 
| Systemic diffusion of the treprostinil hydrogel administered by iontophoresis | Plasmatic concentration of treprostinil | day 0 and day 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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iontophoresis, treprostinil