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
- connective tissue disordervascular Ehlers-Danlos Syndrome10010761
- Registration Number
- NL-OMON51515
- Lead Sponsor
- Aytu BioPharma, Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Pending
- Sex
- Not specified
- Target Recruitment
- 50
1. Adult patients must be 18-60 years of age inclusive, at the time of
screening may be considered to enroll pending interim analysis.
2. Adolescent patients must be 12-17 years of age inclusive, at the time of
screening.
3. Confirmed pathogenic COL3A1 genetic mutation via validated Laboratory
Development Test (LDT) performed in a Clinical Laboratory Improvement
Amendments (CLIA) laboratory or regulatory equivalent outside of the United
States or an assay performed by a laboratory accredited according to the ISO
15189 standard by a national or regional accreditation body. As part of the
assessment of inclusion and exclusion criteria, all COL3A1 genetic variants
will be reviewed by the Genetic Variant Adjudication Committee. The diagnosis
of vEDS, and inclusion in the study, rests on the identification of a
pathogenic variant in one allele of COL3A1 that is shown or predicted to result
in production of an abnormal protein. Individuals with these *dominant-
negative* variants tend to have more severe clinical presentations of vEDS.
This is the most common class of variants that causes vEDS and includes:
• Missense variants that result in substitution of glycines in the Gly-Xaa-Yaa
repeat of the triple helical domain of COL3A1:
o The triple helical domain extends from amino acid positions 168-1196 of the
protein. Eligible variants will cause the replacement of the invariant glycines
at every 3rd amino acid position of this domain, following the sequence
Gly-Xaa-Yaa-Gly-Xaa-Yaa-Gly-Xaa-Yaa*etc. where Xaa and Yaa represent any other
amino acid. Substitutions of Gly residues that happen to occur at the Xaa or
Yaa position are not eligible for inclusion as they are unlikely to cause vEDS.
• Splice site variants:
o A few nucleotides that precede and follow the coding regions (exons) in
flanking regions called introns specify the site of the cleavage that removes
the introns between exons to create a full-length mRNA. These nucleotides occur
at the -2, -1 (before the exon), +1 and +2 (after the exon) positions of the
introns that flank each block of coding sequence (called exons). Substitutions
at these sites will alter correct splicing. The one exception that will
generally not be eligible is the -1G>A substitution because it usually will
result in mRNA instability.
• In-frame insertion or deletion:
o Insertions or deletions that are entirely within the coding sequence and are
a multiple of 3 nucleotides (i.e., 3, 6, 9, etc.) will result in an *in-frame*
mRNA that will be stable and give rise to an abnormal protein. Such variants
will only be eligible if they occur in the triple helical domain of type III
collagen (amino acids 168-1196).
4. The patient should be stable with no vEDS-related events in the within 3
months before screening.
5. Patients must have a negative SARS-CoV-2 test, regardless of vaccination
status prior to starting treatment.
6. Sexually active female patients: unless surgically sterile or
post-menopausal for at least 12 months, use 2 forms of contraception with
failure rate of <1% per year continuously from the first administration of
study drug until 3 months after last study drug administration.
• Combined (estrogen and progestogen containing) hormonal contraception (oral,
intravaginal, transdermal)
• Progestogen-only hormonal contrace
1. Individuals with reduced amount of COL3A1 protein which are the result of
*haploinsufficient* alleles tend to have milder clinical presentations of vEDS
and are excluded from this study because these patients are at a reduced risk
of arterial events. These variants are rarer and include:
• Variants that change the codon for an amino acid to one that encodes a
premature termination codon (a *nonsense* variant).
• Splice site variants that are predicted or have been shown to lead to an
unstable mRNA (due to *frameshift").
• *Frameshift* variants that involve the insertion or deletion of a block of
nucleotides that is not a multiple of 3 nucleotides (i.e., 1, 2, 4, 5, 7,
etc.). Such variants will *shift* the reading frame of the mRNA and will
predictably lead to a premature termination codon and an unstable mRNA.
2. Currently being treated with strong or moderate inducers of cytochrome P450
3A4 (CYP3A4), such as carbamazepine and phenytoin or strong CYP3A4 inhibitors,
such as ketoconazole, within 4 weeks prior to Visit 1. (FDA 2020)
3. Currently being treated with QTc prolonging medication within 4 weeks prior
to Visit 1 (see Appendix 5).
4. Contraindications related to enzastaurin (known allergy or hypersensitivity
to enzastaurin or any of its components or required use of a medication that is
contraindicated in combination with enzastaurin).
5. Unable to swallow tablets or receive intact tablets.
6. Prior participation in any interventional clinical study in which patient
received investigational therapeutic within 4 weeks prior to Visit1.
7. QTc interval by Fridericia*s formula is > 450 msec in males and > 470 msec
in females or if the patient has a known personal or family history of long QT
syndrome during Screening.
8. The patient has one of the following conditions:
a. Any of the following clinical laboratory parameters exceeding the upper
limit of normal (ULN): alanine aminotransferase (ALT), aspartate
aminotransferase (AST), serum creatinine and/or total bilirubin (>1.5 x ULN
total bilirubin if known Gilbert*s syndrome). If a patient has elevations only
in total bilirubin that are >1 x ULN and <1.5 x ULN, bilirubin will be
fractionated to identify possible undiagnosed Gilbert*s syndrome (i.e., direct
bilirubin <35%).
b. Thyroid-stimulating hormone outside the normal range.
9. Patient with a prior diagnosis of liver cancer or cirrhosis, chronic viral
hepatitis, or some other defined etiology for chronic liver inflammation known
to predispose to hepatocellular carcinoma.
10. Patient who is pregnant or breast feeding.
11. Women of childbearing potential on inadequate contraception.
12. An individual who has a medical, psychological or social condition that, in
the opinion of the Principal Investigator, would interfere with the patient*s
safety, obtaining informed consent, or compliance to the study procedures.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary efficacy endpoint<br /><br>• Time to intervention for an arterial event (rupture, dissection,<br /><br>pseudoaneurysm, carotid-cavernous sinus fistula, or aneurysm, fatal or not) or<br /><br>mortality attributable to an arterial event, as adjudicated by an Event<br /><br>Committee and analyzed for difference in the time-to-composite-event of active<br /><br>vs. placebo treatments, using survival analysis until end of study</p><br>
- Secondary Outcome Measures
Name Time Method