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

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)

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.

Study Overview

• Status: Suspended
• Conditions: Vascular Ehlers-Danlos Syndrome
• Intervention / Treatment: Drug: Enzastaurin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 260
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Englewood, Colorado, United States, 80112
      • Aytu BioPharma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects aged 18 - 60 years old at time of initial screening.
2. Adolescent subjects aged 12 - 17 years old, may be considered to enroll later in the clinical trial pending interim analysis.
3. Diagnosis for VEDS (vascular Ehlers Danlos Syndrome), with a confirmed and documented COL3A1 genetic variant.
4. Subject should be stable, having no VEDS-related vascular events within the past 3 months prior to enrollment.
5. Confirmed use of contraception for both male and female participants.

Exclusion Criteria:

1. Inability to swallow or receive intact tablets.
2. Currently being treated with CYP3A4 inhibitors within 4 weeks prior to enrollment.
3. Known allergy or hypersensitivity to enzastaurin.
4. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Aytu BioPharma, Inc.
• Collaborators: Parexel
• Investigators: Principal Investigator: Sherene Shalhub, M.D., M.P.H., University of Washington; Principal Investigator: Shaine Morris, M.D.,M.P.H., Texas Children's Hospital and Baylor College of Medicine

Publications and helpful links

General Publications

• Bowen CJ, Calderon Giadrosic JF, Burger Z, Rykiel G, Davis EC, Helmers MR, Benke K, Gallo MacFarlane E, Dietz HC. Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome. J Clin Invest. 2020 Feb 3;130(2):686-698. doi: 10.1172/JCI130730.

Helpful Links

• 2. Bowen CJ et al. Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos Syndrome. J Clin Invest. 2020 Feb 3;130(2):686-698.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: April 6, 2022
• First Submitted That Met QC Criteria: July 14, 2022
• First Posted (Actual): July 19, 2022

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Disease; Congenital Abnormalities; Hematologic Diseases; Hemorrhagic Disorders; Genetic Diseases, Inborn; Connective Tissue Diseases; Hemostatic Disorders; Skin Diseases, Genetic; Skin Abnormalities; Aneurysm; Collagen Diseases; Dissection, Blood Vessel; Aortic Dissection; Syndrome; Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome, Type IV
• Other Study ID Numbers: AR101-PREVEnt

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No