Congenital Venous Malformation
Conditions
Brief summary
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.
Interventions
DRUGEthanol 96% Gel
DRUGEthanol 98% Solution
Sponsors
FDA Office of Orphan Products Development
Orfagen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Systemic Exposure to Ethanol With the Two Test Products: Determination of the Maximum Plasma Concentration (Cmax) | Baseline visit (just before and during test product infusion procedure) | 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. |
Secondary
| 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 |
Countries
France, United States
Participant flow
Pre-assignment details
32 patients were enrolled in the study, but 31 received the study product (1 patient not treated; inclusion mistake).
Participants by arm
| Arm | Count |
|---|---|
| L0122 Gel Group Patients who received one intralesional administration of L0122 gel | 17 |
| Absolute Ethanol Group Patients who received one intralesional administration of Absolute Ethanol | 14 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Total | L0122 Gel Group | Absolute Ethanol Group |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 5 Participants | 2 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 11 Participants | 11 Participants |
| Lesional volume | 298.926 cm3 STANDARD_DEVIATION 801.306 | 82.712 cm3 STANDARD_DEVIATION 156.316 | 561.472 cm3 STANDARD_DEVIATION 1147.306 |
| Region of Enrollment France | 15 participants | 8 participants | 7 participants |
| Region of Enrollment United States | 16 participants | 9 participants | 7 participants |
| Sex: Female, Male Female | 19 Participants | 11 Participants | 8 Participants |
| Sex: Female, Male Male | 12 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 17 | 10 / 14 |
| serious Total, serious adverse events | 2 / 17 | 4 / 14 |
Outcome results
Primary
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.
Time frame: Baseline visit (just before and during test product infusion procedure)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| L0122 Gel Group | Systemic Exposure to Ethanol With the Two Test Products: Determination of the Maximum Plasma Concentration (Cmax) | 0.0604 g/L |
| Absolute Ethanol Group | Systemic Exposure to Ethanol With the Two Test Products: Determination of the Maximum Plasma Concentration (Cmax) | 0.202 g/L |
Secondary
Change in Volume of Congenital Venous Malformation (CVM) From Screening to Study End (Day 112 Visit).
Time frame: Screening and study end (Day 112)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L0122 Gel Group | Change in Volume of Congenital Venous Malformation (CVM) From Screening to Study End (Day 112 Visit). | -10.328 cm3 | Standard Deviation 36.667 |
| Absolute Ethanol Group | Change in Volume of Congenital Venous Malformation (CVM) From Screening to Study End (Day 112 Visit). | -126.944 cm3 | Standard Deviation 367.229 |
Secondary
Patient Benefit
Time frame: study end
Secondary
Systemic (Cardiopulmonary, Hematological, Metabolic) and Local Outcome of the Two Test Products.
Time frame: Study end