EUCTR2021-006574-23-BE进行中（未招募）1 期
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) - PREVEnt (Prevention of Rupture with Enzastaurin in Vascular Ehlers-Danlos Syndrome Trial)
适应症
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 260
研究概览
简要总结
暂无简介。
研究设计
- 研究类型
- Interventional
入排标准
- 性别
- All
入选标准
- •1. Adult patients must be 18–60 years of age inclusive, at the time of screening.
- •2. Adolescent patients 12–17 years of age at the time of screening may be considered to enroll pending interim analysis.
- •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 past 3 months.
- •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 contraception associated with inhibition of
- •ovulation (oral, injectable, implantable)
- •An intra-uterine device (IUD)
- •An intra-uterine hormone releasing system
- •Bilateral tubal occlusion
- •Vasectomized partner
- •Sexual absti
排除标准
- •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
- •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 Visit 1.
- •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%), OR
- •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.
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