Systemic and Local Diffusion of Ethanol After Administration of Ethanol 96% Formulated in a Gel and Ethanol 98% Solution by the Percutaneous Route, in Patients With Congenital Venous Malformations:Pharmacokinetic, Pharmacodynamic and Clinical Study.

Absolute ethanol has been used "off-label" as an unmodified formulation (solution) in Congenital Venous Malformations (CVM). Despite its effectiveness, absolute ethanol appears difficult to handle because of its high diffusion capacity outside the CVM and in the blood circulation. A less diffusible ethanol-based product (ethanol gel) has been developed in order to minimize systemic and local diffusion capacities of ethanol. Therefore, the pharmacokinetic parameters and their clinical and paraclinical outcomes between ethanol gel 96% and absolute ethanol need to be carried out.

FDA Office of Orphan Products Development (FDA OOPD) : Funding source.

Study Overview

• Status: Completed
• Conditions: Congenital Venous Malformation
• Intervention / Treatment: Drug: Ethanol 96% Gel; Drug: Ethanol 98% Solution

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Tours Cedex 1, France, 37044
    • Hôpital Bretonneau Service de neuroradiologie
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Medical Institutions

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients of both sexes, of at least 12 years of age,
• For women of childbearing potential, negative pregnancy test at baseline,
• Patients with one clinically and radiologically (MRI) documented lesion diagnosed as CVM (pure or predominant),
• Patients for which an embolosclerotherapy by the percutaneous route is indicated as first line therapy of the test lesion, or for which previous treatments (i.e. surgery, embolosclerotherapy, laser) have been unsuccessful or insufficient,
• Patients with CVM lesional size of at least 12 cm3 (maximum craniocaudal dimension X mean dimension of 3 transverse equispaced measurements X mean dimension of 3 deepness equispaced measurements dimension) at MRI,
• Patients with focal or multifocal CVM lesion, i.e. with one or several well-interconnecting venous spaces and well-defined margins,
• Patients or parents able to follow study instructions and attend study visits,
• Written informed consent from the patients or parents.

Exclusion criteria:

• Patients under 12 years of age,
• Pregnant women, nursing mothers and women of childbearing potential with no reliable contraception from more than 2 months,
• Women of childbearing potential with a positive pregnancy test at baseline,
• Patients with CVM of non venous predominance,
• Patients with CVM that are not reachable by the percutaneous route,
• Patients with extensive superficial skin CVM (i.e. with high risk of skin necrosis),
• Patients with a test lesion adjacent to major nerves (e.g. facial nerve in the parotid region, intramuscular regions adjacent to major nerves),
• Patients with facial CVM or bone involvement,
• Patients with small CVM lesion (<12 cm3 at MRI),
• Patients requiring more than 1 ml/Kg body weight (b.w.) in USA or more than 0.5 ml/Kg b.w. in France, or more than 30 mL of absolute ethanol to infuse,
• Patients with a known allergy to one of the components of the test products,
• Patients with a suspected allergy to iodinate.ed products,
• Patients with abnormal clotting parameters (platelets, partial thromboplastin, prothrombin time),
• Patients with an active inflammatory episode of the test lesion (i.e. acute or subacute swelling of the test lesion),
• Patients with complex malformations (e.g. Klippel-Trenaunay syndrome, Blue Rubber Bled Nevus syndrome, Muco-cutaneous familial venous malformations, Mafucci's syndrome),
• Patients in which a surgery, laser therapy or embolosclerotherapy of the test lesion has been performed within the last 12 weeks prior to study entry,
• Asthmatic patients who require daily medications,
• Patients with a non treated or non stabilized cardiac disease,
• Patients with a suspected right-left shunt,
• Patients with an intercurrent condition or a concomitant treatment which may interfere with a good conduct or the evaluation parameters of the study,
• Patients who participated in a study within the 12 weeks prior to study entry,
• Patients or parents who are not able or willing to follow the study instructions,
• Patients or parents who refuse to give written informed consent.

Study Plan

How is the study designed?

Design Details

• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; Ethanol gel	Drug: Ethanol 96% Gel
ACTIVE_COMPARATOR: 2; Ethanol solution	Drug: Ethanol 98% Solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic Exposure to Ethanol With the Two Test Products: Determination of the Maximum Plasma Concentration (Cmax)	Blood samples were performed, just before infusion, then 5 min, 10 min, 20 min, 40 min, 60 min, 90 min, and 120 min after infusion at the first site, then every 60 min onwards until ethanol levels are found under the detection limit. Cmax was estimated directly from experimental data. If all the ethanol concentrations of a patient was below the limit of quantification of the laboratory (LOQ), Cmax was reported as LOQ/2 for this patient.	Baseline visit (just before and during test product infusion procedure)

Secondary Outcome Measures

Outcome Measure	Time Frame
Systemic (Cardiopulmonary, Hematological, Metabolic) and Local Outcome of the Two Test Products.	Study end
Change in Volume of Congenital Venous Malformation (CVM) From Screening to Study End (Day 112 Visit).	Screening and study end (Day 112)
Patient Benefit	study end

Collaborators and Investigators

• Sponsor: Orfagen
• Collaborators: FDA Office of Orphan Products Development
• Investigators: Study Director: PATRICK DUPUY, MD, ORFAGEN LABORATORIES (France); Principal Investigator: SALLY E MITCHELL, MD, Johns Hopkins Medical Institution (Baltimore, USA); Principal Investigator: Denis HERBRETEAU, MD, Hôpital Bretonneau (Tours, France)

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (ACTUAL): June 1, 2010
• Study Completion (ACTUAL): June 1, 2010

Study Registration Dates

• First Submitted: April 16, 2007
• First Submitted That Met QC Criteria: April 18, 2007
• First Posted (ESTIMATE): April 19, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): January 15, 2015
• Last Update Submitted That Met QC Criteria: January 6, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Congenital Abnormalities; Physiological Effects of Drugs; Anti-Infective Agents, Local; Anti-Infective Agents; Central Nervous System Depressants; Ethanol
• Other Study ID Numbers: L00122 GI 201 (ORF)