Investigate Efficacy, Safety, and Pharmacokinetics of Enzastaurin for the Prevention of Arterial Events in Patients With Vascular Ehlers-Danlos Syndrome.

Study Overview
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Brief Summary
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The purpose of this study is to investigate the efficacy of enzastaurin compared to placebo in preventing arterial events (rupture, dissection, pseudoaneurysm, carotid-cavernous sinus fistula, or aneurysm, fatal or not) leading to intervention or mortality attributable to an arterial event in patients with vEDS confirmed with pathogenic heterozygous COL3A1 gene mutations predicted to derive a mutant protein.

Detailed Description
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The primary efficacy endpoint of this study will be defined as the time to intervention for an arterial event (rupture, dissection, pseudoaneurysm, carotid-cavernous sinus fistula, or aneurysm, fatal or not) or mortality attributable to an arterial event, as adjudicated by an Event Committee, and will be analyzed for difference of active vs. placebo treatments on top of background standard of care, using survival statistical analysis. Furthermore, secondary endpoints will include the rate of intestinal rupture, pneumothorax, and retinal detachment, as adjudicated by an Event Committee, safety and tolerability, as well as hospitalizations and Health Related Quality of Life (HQRL) measures.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled Study of Enzastaurin for the Prevention of Arterial Events in Patients With Vascular Ehlers-Danlos Syndrome (vEDS) Confirmed With COL3A1 Mutations, Followed by an Open Label Extension (OLE)

Conditions
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Vascular Ehlers-Danlos Syndrome

Intervention / Treatment
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* Drug: Enzastaurin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged 18 - 60 years old at time of initial screening. Adolescent subjects aged 12 - 17 years old, may be considered to enroll later in the clinical trial pending interim analysis. Diagnosis for VEDS (vascular Ehlers Danlos Syndrome), with a confirmed and documented COL3A1 genetic variant. Subject should be stable, having no VEDS-related vascular events within the past 3 months prior to enrollment. Confirmed use of contraception for both male and female participants. Exclusion Criteria: Inability to swallow or receive intact tablets. Currently being treated with CYP3A4 inhibitors within 4 weeks prior to enrollment. Known allergy or hypersensitivity to enzastaurin. Patient currently pregnant or breast feeding. Other criteria will be reviewed at the first study visit to determine if you are able to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two-arm, multicenter, randomized, double-blind, placebo-controlled study in patients with vEDS receiving enzastaurin 500 mg once daily (QD) compared to placebo, in addition to background standard of care, followed by an OLE phase. Approximately 260 patients with vEDS are planned to be randomized in a 1:1 ratio of enzastaurin or placebo. Patients will be enrolled in the study if they meet all eligibility criteria.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enzastaurin 500 mg QD<br>Receive 500 mg enzastaurin QD plus background standard of care. | Drug: Enzastaurin<br>* 500 mg QD orally in the form of four 125 mg tablets with background standard of care<br>|
| Placebo Comparator: Placebo QD<br>Matching placebo QD plus background standard of care. | Drug: Placebo<br>* Placebo to match enzastaurin 500 mg QD orally in the form of four 125 mg tablets with background standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to intervention for an arterial event (rupture, dissection, pseudoaneurysm, carotid-cavernous sinus fistula, or aneurysm, fatal or not) or mortality attributable to an arterial event. | Time to intervention for an arterial event (rupture, dissection, pseudoaneurysm, carotid-cavernous sinus fistula, or aneurysm, fatal or not) or mortality attributable to an arterial event, as adjudicated by an Event Committee and analyzed for difference in the time-to-composite-event of active vs. placebo treatments, using survival analysis until end of study | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of and proportion of patients with adverse events, or with abnormal vital signs, physical examinations, ophthalmological examinations, clinical laboratory values, or electrocardiograms (ECGs) medical attention. | An Adverse Event (AE) is defined as any untoward medical occurrence associated with the use of the investigational product in humans, whether or not considered related to investigational product. An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with any use of the investigational product, without any judgment about causality and irrespective of route of administration, formulation, or dose, including an overdose. | 30 months | 
| Number of and proportion of patients who discontinue study drug due to adverse events | Discontinuation or withdrawal from the study | 30 months |