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

• ClinicalTrials.gov Identifier: NCT05463679
• Recruitment Status: Suspended
• First Posted: July 19, 2022
• Last Update Posted: October 14, 2022
• Sponsor: Aytu BioPharma, Inc.
• Collaborator: Parexel
• Information provided by (Responsible Party): Aytu BioPharma, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Vascular Ehlers-Danlos Syndrome	Drug: Enzastaurin; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 260 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention 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 (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: 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)
• Estimated Study Start Date: January 2024
• Estimated Primary Completion Date: June 2025
• Estimated Study Completion Date: March 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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 Frame: 30 months ]
   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

Secondary Outcome Measures :

1. 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. [ Time Frame: 30 months ]
   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.
2. Number of and proportion of patients who discontinue study drug due to adverse events [ Time Frame: 30 months ]
   Discontinuation or withdrawal from the study

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Colorado

Aytu BioPharma

Englewood, Colorado, United States, 80112

Sponsors and Collaborators

Aytu BioPharma, Inc.

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

More Information

Additional Information:

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. 

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.

• Responsible Party: Aytu BioPharma, Inc.
• ClinicalTrials.gov Identifier: NCT05463679
• Other Study ID Numbers: AR101-PREVEnt
• First Posted: July 19, 2022
• Last Update Posted: October 14, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome, Type IV; Syndrome; Disease; Pathologic Processes; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Skin Abnormalities; Congenital Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Collagen Diseases; Connective Tissue Diseases; Skin Diseases; Aortic Dissection; Dissection, Blood Vessel; Aneurysm