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

April 8, 2020 updated by: University Hospital, Grenoble

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Grenoble, France, 38043
        • Grenoble Alps University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Treprostinil
the participant will receive 10 days of iontophoresis of treprostinil on a first site, each day the same site.
Drug: Iontophoresis of treprostinil
the participant will receive 10 days of iontophoresis of treprostinil on a first site
PLACEBO_COMPARATOR: Placebo
the participant will receive 10 days of iontophoresis of NaCl on a second site, but the same time than treprostinil
Drug: Iontophoresis of placebo
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of side-effects graduated according to NIH CTCAE 4.03
Time Frame: every day of iontophoresis from day 0 to day 9
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
Time Frame: day 0
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
Time Frame: day 0 and day 9
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
Time Frame: day 0 and day 9
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
Time Frame: day 0 and day 9
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
Time Frame: day 0 and day 9
Plasmatic concentration of treprostinil
day 0 and day 9

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Grenoble

Collaborators

University Grenoble Alps
Linksium

Investigators

  • Principal Investigator: Jean-Luc CRACOWSKI, MD,PhD, CIC 1406

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 20, 2017

Primary Completion (ACTUAL)

June 3, 2019

Study Completion (ACTUAL)

June 3, 2019

Study Registration Dates

First Submitted

March 23, 2017

First Submitted That Met QC Criteria

April 13, 2017

First Posted (ACTUAL)

April 19, 2017

Study Record Updates

Last Update Posted (ACTUAL)

April 10, 2020

Last Update Submitted That Met QC Criteria

April 8, 2020

Last Verified

April 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 38RC16.005

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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