Clinical trial NCT03120533: Treprostinil Iontophoresis in Systemic Sclerosis Digital UlcErations. A Proof of Concept Study
Official title: Therapeutic Iontophoresis of Treprostinil in Systemic Sclerosis Digital UlcErations. A Proof of Concept Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Scleroderma, Systemic
Keywords: iontophoresis
treprostinil
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
Collaborators: name: Linksium
name: University Grenoble Alps
First posted: 2017-04-19
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of side-effects graduated according to NIH CTCAE 4.03
timeFrame: every day of iontophoresis from day 0 to day 9
Secondary outcomes:
measure: Pharmacodynamical effect of iontophoresis of treprostinil hydrogel in healthy volunteers on pulp finger, leg and foot
timeFrame: day 0
measure: Pharmacodynamical effect of 10 days of iontophoresis of treprostinil hydrogel in systemic sclerosis patients
timeFrame: day 0 and day 9
measure: Pharmacodynamical effect of 10 days of iontophoresis of treprostinil hydrogel in systemic sclerosis patients
timeFrame: day 0 and day 9
measure: Effect of iontophoresis of treprostinil hydrogel on peri and intra ulcer flow
timeFrame: day 0 and day 9
measure: Systemic diffusion of the treprostinil hydrogel administered by iontophoresis
timeFrame: day 0 and day 9
Other outcomes:
Locations:
city: Grenoble
country: France
facility: Grenoble Alps University Hospital
Study officials:
affiliation: CIC 1406
name: Jean-Luc CRACOWSKI, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gaillard-Bigot F, Roustit M, Blaise S, Cracowski C, Seinturier C, Imbert B, Carpentier P, Cracowski JL. Treprostinil Iontophoresis Improves Digital Blood Flow during Local Cooling in Systemic Sclerosis. Microcirculation. 2016 Apr;23(3):266-70. doi: 10.1111/micc.12272.
citation: Hellmann M, Roustit M, Gaillard-Bigot F, Cracowski JL. Cutaneous iontophoresis of treprostinil, a prostacyclin analog, increases microvascular blood flux in diabetic malleolus area. Eur J Pharmacol. 2015 Jul 5;758:123-8. doi: 10.1016/j.ejphar.2015.03.066. Epub 2015 Apr 3.
citation: Kotzki S, Roustit M, Arnaud C, Godin-Ribuot D, Cracowski JL. Effect of continuous vs pulsed iontophoresis of treprostinil on skin blood flow. Eur J Pharm Sci. 2015 May 25;72:21-6. doi: 10.1016/j.ejps.2015.02.012. Epub 2015 Feb 21.
citation: Roustit M, Gaillard-Bigot F, Blaise S, Stanke-Labesque F, Cracowski C, Seinturier C, Jourdil JF, Imbert B, Carpentier PH, Cracowski JL. Cutaneous iontophoresis of treprostinil in systemic sclerosis: a proof-of-concept study. Clin Pharmacol Ther. 2014 Apr;95(4):439-45. doi: 10.1038/clpt.2013.255. Epub 2014 Jan 23.
citation: Kotzki S, Roustit M, Arnaud C, Boutonnat J, Blaise S, Godin-Ribuot D, Cracowski JL. Anodal iontophoresis of a soluble guanylate cyclase stimulator induces a sustained increase in skin blood flow in rats. J Pharmacol Exp Ther. 2013 Sep;346(3):424-31. doi: 10.1124/jpet.113.205484. Epub 2013 Jul 9.
citation: Blaise S, Roustit M, Hellmann M, Millet C, Cracowski JL. Cathodal iontophoresis of treprostinil induces a sustained increase in cutaneous blood flux in healthy volunteers. J Clin Pharmacol. 2013 Jan;53(1):58-66. doi: 10.1177/0091270011434352. Epub 2013 Jan 24.
citation: Blaise S, Roustit M, Millet C, Ribuot C, Boutonnat J, Cracowski JL. Cathodal iontophoresis of treprostinil and iloprost induces a sustained increase in cutaneous flux in rats. Br J Pharmacol. 2011 Feb;162(3):557-65. doi: 10.1111/j.1476-5381.2010.01045.x.