NL-OMON51515尚未招募3 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) - AR-101-PREVEnt
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 50
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
- 年龄范围
- 12 至 64（—）
入选标准
- •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
- •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
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 (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.
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