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Treprostinil Iontophoresis in Systemic Sclerosis Digital UlcErations. A Proof of Concept Study (TISSUE-PoC)

Primary Purpose

Scleroderma, Systemic

Status

Completed

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

Iontophoresis of treprostinil

Iontophoresis of placebo

About this trial

This is an interventional treatment trial for Scleroderma, Systemic focused on measuring iontophoresis, treprostinil

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Grenoble Alps University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Treprostinil

Placebo

Arm Description

the participant will receive 10 days of iontophoresis of treprostinil on a first site, each day the same site.

the participant will receive 10 days of iontophoresis of NaCl on a second site, but the same time than treprostinil

Outcomes

Primary Outcome Measures

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 ".

Secondary Outcome Measures

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

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

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

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

Systemic diffusion of the treprostinil hydrogel administered by iontophoresis

Plasmatic concentration of treprostinil

Full Information

NCT ID

NCT03120533

First Posted

March 23, 2017

Last Updated

April 8, 2020

Sponsor

University Hospital, Grenoble

Collaborators

Linksium, University Grenoble Alps

1. Study Identification

Unique Protocol Identification Number

NCT03120533

Brief Title

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

Acronym

TISSUE-PoC

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2020

Overall Recruitment Status

Completed

Study Start Date

June 20, 2017 (Actual)

Primary Completion Date

June 3, 2019 (Actual)

Study Completion Date

June 3, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Grenoble

Collaborators

Linksium, University Grenoble Alps

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Scleroderma, Systemic

Keywords

iontophoresis, treprostinil

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treprostinil

Arm Type

Experimental

Arm Description

the participant will receive 10 days of iontophoresis of treprostinil on a first site, each day the same site.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

the participant will receive 10 days of iontophoresis of NaCl on a second site, but the same time than treprostinil

Intervention Type

Drug

Intervention Name(s)

Iontophoresis of treprostinil

Intervention Description

the participant will receive 10 days of iontophoresis of treprostinil on a first site

Intervention Type

Drug

Intervention Name(s)

Iontophoresis of placebo

Intervention Description

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

Primary Outcome Measure Information:

Title

Number of side-effects graduated according to NIH CTCAE 4.03

Description

Side effects will be reported according to NIH CTCAE 4.03, particularly " Skin and subcutaneous tissue disorders " et " Vascular disorders ".

Time Frame

every day of iontophoresis from day 0 to day 9

Secondary Outcome Measure Information:

Title

Pharmacodynamical effect of iontophoresis of treprostinil hydrogel in healthy volunteers on pulp finger, leg and foot

Description

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

Time Frame

day 0

Title

Pharmacodynamical effect of 10 days of iontophoresis of treprostinil hydrogel in systemic sclerosis patients

Description

cutaneous vascular conductance after the iontophoresis of the gel of treprostinil compared to the iontophoresis of NaCl measured by laser speckle imaging

Time Frame

day 0 and day 9

Title

Pharmacodynamical effect of 10 days of iontophoresis of treprostinil hydrogel in systemic sclerosis patients

Description

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

Time Frame

day 0 and day 9

Title

Effect of iontophoresis of treprostinil hydrogel on peri and intra ulcer flow

Description

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

Time Frame

day 0 and day 9

Title

Systemic diffusion of the treprostinil hydrogel administered by iontophoresis

Description

Plasmatic concentration of treprostinil

Time Frame

day 0 and day 9

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jean-Luc CRACOWSKI, MD,PhD

Organizational Affiliation

CIC 1406

Official's Role

Principal Investigator

Facility Information:

Facility Name

Grenoble Alps University Hospital

City

Grenoble

ZIP/Postal Code

38043

Country

France

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

26833587

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.

Results Reference

background

PubMed Identifier

25843412

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.

Results Reference

background

PubMed Identifier

25712367

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.

Results Reference

background

PubMed Identifier

24458011

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.

Results Reference

background

PubMed Identifier

23838678

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.

Results Reference

background

PubMed Identifier

23400744

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.

Results Reference

background

PubMed Identifier

20860718

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.

Results Reference

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

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