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

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ClinicalTrials.gov Identifier: NCT03120533
Recruitment Status : Recruiting
First Posted : April 19, 2017
Last Update Posted : March 13, 2019
Sponsor:
Collaborators:
Linksium
University Grenoble Alps
Information provided by (Responsible Party):
University Hospital, Grenoble

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.

Condition or disease Intervention/treatment Phase
Scleroderma, Systemic Drug: Iontophoresis of treprostinil Drug: Iontophoresis of placebo Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Therapeutic Iontophoresis of Treprostinil in Systemic Sclerosis Digital UlcErations. A Proof of Concept Study
Actual Study Start Date : June 20, 2017
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2019


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




Primary Outcome Measures :
  1. 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 ".


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. Systemic diffusion of the treprostinil hydrogel administered by iontophoresis [ Time Frame: day 0 and day 9 ]
    Plasmatic concentration of treprostinil



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03120533


Contacts
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Contact: Adeline PARIS, PharmD,PhD +33476769260 aparis@chu-grenoble.fr
Contact: Matthieu ROUSTIT, PharmD, PhD +33476769260 mroustit@chu-grenoble.fr

Locations
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France
Grenoble Alps University Hospital Recruiting
Grenoble, France, 38043
Contact: Jean-Luc Cracowski, MD,PhD    +33476769260    jlcracowski@chu-grenoble.fr   
Contact: Matthieu Roustit, PharmD, PhD    +33476769260    mroustit@chu-grenoble.fr   
Principal Investigator: Jean-Luc CRACOWSKI, MD,PhD         
Sub-Investigator: Claire CRACOWSKI, MD         
Sub-Investigator: Enkelejda HODAJ, MD         
Sub-Investigator: Sophie BLAISE, MD,PhD         
Sub-Investigator: Christophe SEINTURIER, MD         
Sub-Investigator: Patrick CARPENTIER, MD,PhD         
Sub-Investigator: Bernard IMBERT, MD         
Sponsors and Collaborators
University Hospital, Grenoble
Linksium
University Grenoble Alps
Investigators
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Principal Investigator: Jean-Luc CRACOWSKI, MD,PhD CIC 1406

Publications:

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Responsible Party: University Hospital, Grenoble
ClinicalTrials.gov Identifier: NCT03120533     History of Changes
Other Study ID Numbers: 38RC16.005
First Posted: April 19, 2017    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Grenoble:
iontophoresis
treprostinil
Additional relevant MeSH terms:
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Scleroderma, Systemic
Scleroderma, Diffuse
Connective Tissue Diseases
Skin Diseases
Treprostinil
Antihypertensive Agents