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    Summary
    EudraCT Number:2021-006574-23
    Sponsor's Protocol Code Number:AR101-PREVEnt
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-04-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-006574-23
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the efficacy, safety, and pharmacokinetics of enzastaurin for the prevention of arterial events in patients with vEDS confirmed with COL3A1 mutations
    A.3.2Name or abbreviated title of the trial where available
    PREVEnt (Prevention of Rupture with Enzastaurin in Vascular Ehlers-Danlos Syndrome Trial)
    A.4.1Sponsor's protocol code numberAR101-PREVEnt
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAytu BioPharma, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAytu BioPharma, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationParexel International (IRL) Limited
    B.5.2Functional name of contact pointProject Leadership
    B.5.3 Address:
    B.5.3.1Street Address70 Sir John Rogerson's Quay
    B.5.3.2Town/ cityDublin
    B.5.3.3Post code2
    B.5.3.4CountryIreland
    B.5.6E-mail264781-Aytu@parexel.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/22/2582
    D.3 Description of the IMP
    D.3.1Product nameEnzastaurin
    D.3.2Product code AR101
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEnzastaurin
    D.3.9.1CAS number 359017-79-1
    D.3.9.3Other descriptive nameENZASTAURIN HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB177929
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    vascular Ehlers-Danlos Syndrome (vEDS) confirmed with COL3A1 mutations
    E.1.1.1Medical condition in easily understood language
    vascular Ehlers-Danlos Syndrome (vEDS)
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10014316
    E.1.2Term Ehlers-Danlos syndrome
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Efficacy: To evaluate 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.
    E.2.2Secondary objectives of the trial
    Safety and Tolerability: To evaluate the safety and tolerability of enzastaurin.

    Efficacy: To evaluate the efficacy of enzastaurin in preventing all arterial events related to vEDS as well as non-arterial events such as intestinal rupture, pneumothorax, and retinal detachment, as adjudicated by an Event Committee
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Age
    1. Adult patients must be 18–60 years of age at the time of screening
    2. Adolescent patients aged 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 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 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 abstinence
    7. Male patient agrees to use barrier contraception (condom) during sexual intercourse with women of childbearing potential from the first administration of study drug until 3 months after last study drug administration. The male patient is willing to ensure that the female sexual partner unless surgically sterile (i.e., after hysterectomy or bilateral oophorectomy) or post-menopausal for at least 12 months uses at least 1 additional method of contraception with a low failure rate defined as <1% per year as follows:
    • 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
    • Sexual abstinence
    8. Patients and/or appropriate legal guardian must sign an informed consent form and/or assent, as described in Appendix 1, Section 10.1.3, according to local, regional and/or country-specific guidance for study participation.
    E.4Principal exclusion criteria
    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.
    E.5 End points
    E.5.1Primary end point(s)
    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
    E.5.1.1Timepoint(s) of evaluation of this end point
    throughout study
    E.5.2Secondary end point(s)
    Safety and tolerability:
    • Safety assessments include number of and proportion of patients with adverse events (AEs), or with abnormal vital signs, physical examinations, ophthalmological examinations, clinical laboratory values, or electrocardiograms (ECGs)
    • Number of and proportion of patients who discontinue study drug due to AEs

    Efficacy:
    • Time to intervention for repair (to include catheter-based procedures) of an arterial event (rupture, dissection, pseudoaneurysm, carotid-cavernous sinus fistula, or aneurysm, fatal or not), as adjudicated by an Event Committee
    • Reduction in the rate of intestinal rupture, pneumothorax, retinal detachment, as adjudicated by an Event Committee
    • Emergent hospitalization for management of an arterial event
    • Time to arterial event
    • Rate of arterial event
    • Time to arterial rupture
    • Rate of arterial rupture
    • Time to arterial dissection
    • Rate of arterial dissection
    • Time to pseudoaneurysm
    • Rate of pseudoaneurysm
    • Time to carotid-cavernous sinus fistula
    • Rate of carotid-cavernous sinus fistula
    • Time to aneurysm
    • Rate of aneurysm
    • Change in Health-Related Quality of Life (HRQL) SF-36
    • Change in Ped-QL (Pediatric Quality of Life Inventory
    E.5.2.1Timepoint(s) of evaluation of this end point
    throughout study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    France
    Sweden
    Netherlands
    Belgium
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 230
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Adolescents (12-17 years) - Patients and/or appropriate legal guardian must sign an informed consent form and/or assent, according to local, regional and/or country-specific guidance for study participation.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In the whole clinical trial 260
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Upon completion of the main study, patients will be automatically rolled over in the OLE phase part of the study.

    After completion of OLE phase, there are no post-treatment plans-None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-04-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-13
    P. End of Trial
    P.End of Trial StatusOngoing
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