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    Summary
    EudraCT Number:2019-004345-32
    Sponsor's Protocol Code Number:ANAVEX2-73-RS-002
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-02-07
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-004345-32
    A.3Full title of the trial
    A Double-Blind, Randomised, Placebo-Controlled, Safety and Efficacy Study of ANAVEX2-73 in Patients with Rett Syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The use of ANAVEX2-73 as a new therapeutic treatment for Patients with Rett Syndrome
    A.3.2Name or abbreviated title of the trial where available
    The Safety and Efficacy of ANAVEX2-73 in Patients with Rett Syndrome
    A.4.1Sponsor's protocol code numberANAVEX2-73-RS-002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03941444
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAnavex Germany GmbH
    B.1.3.4CountryGermany
    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 supportAnavex Germany GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAnavex Germany GmbH
    B.5.2Functional name of contact pointStephan Toutain
    B.5.3 Address:
    B.5.3.1Street AddressAm Klopferspitz 19a, 82152 Planegg
    B.5.3.4CountryGermany
    B.5.4Telephone number1 (646) 435-0026
    B.5.6E-mailstoutain@anavexcorp.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/3/19/2195
    D.3 Description of the IMP
    D.3.1Product nameANAVEX2-73
    D.3.4Pharmaceutical form Oral liquid
    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 INNANAVEX2-73 (blarcamesine)
    D.3.9.2Current sponsor codeANAVEX2-73
    D.3.9.3Other descriptive nameANA001XHCl (Syntagon) or VEXA-04 (Patheon)
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 placeboOral solution
    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
    Rett Syndrome
    E.1.1.1Medical condition in easily understood language
    Rett Syndrome is a rare genetic neurodevelopmental disorder related to a gene mutation. Males die before birth or in early infancy and Females suffer severe developmental regression and disability
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10077709
    E.1.2Term Rett 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
    The main objective of PART B will be to evaluate the safety, tolerability, and efficacy of ANAVEX2-73 in RTT, as well as to determine the most appropriate dose.

    E.2.2Secondary objectives of the trial
    Secondary outcome measures include a measure of the change or proposed improvement in daily functioning and the quality of life measures of participants with Rett Syndrome and the change or proposed improvement in caregiver burden

    The following assessments will be completed at end of the 48 week Open Label Extension (OLE) treatment period:

    1. Physical examination, including body weight,
    2. Neurological examination
    3. Vital signs measurement (heart rate, SBP and DBP, respiratory rate, oxygen saturation [pulse oximetry], and body temperature).
    4. Safety laboratory assessments
    5. Glutamate Plasma Concentration
    6. GABA Plasma Concentration
    7. RNA profiles (sample collection)
    8. 12-Lead ECG
    9. Adverse Events
    10. Concurrent Medications, including supplements
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Aged ≥ 18 years, inclusive.
    2. Diagnosis of classic Rett Syndrome, according to 2010 criteria (Neul et al., 2010), and a MECP2 mutation.
    3. Rett Syndrome Behaviour Questionnaire (RSBQ) total score ≥40.
    4. Patients with a Clinical Global Impression – Severity (CGI-S) score of 4 or greater at Screening.
    5. Current pharmacological treatment regimen, including supplements, has been stable for at least 4 weeks.
    6. If on antiepileptic drugs (AEDs), 1-4 AEDs allowed. Treatment must be stable (drug, dose, interval of administration) for 30 days prior to enrollment.
    7. If the subject is already receiving stable non-pharmacologic educational, behavioral, and/or dietary interventions, participation in these programs must have been continuous during the 90 days prior to the screening visit and subjects or their parent/caregiver/legally authorized representative (LAR) will not electively initiate new or modify ongoing interventions for the duration of the study. ‘Study duration’ is defined as lasting from the screening visit until the treatment is terminated. For participants in the 18-21 years range, typical school vacations are not considered modifications of stable programming.
    8. Ability to keep accurate seizure diaries or have caregiver who can keep accurate seizure diaries.
    9.If participant is a woman of childbearing potential, a negative urine or serum pregnancy test is required to confirm she is not pregnant.
    Female patients of childbearing potential are to use adequate contraception as recommended by their health care provider. For participants that are sexually active, highly effective contraception may be used as recommended by their health care provider.Highly effective methods of contraception may include:
    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: Oral, intravaginal or transdermal
    • Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral, injectable, implantable
    • Intrauterine device
    • Intrauterine hormone-releasing system
    • Bilateral tubal occlusion
    10. Prior to the conduct of study-specific procedures, the subject’s parent/caregiver/LAR must provide written informed consent. If applicable, the research team must attempt to obtain consent from both parents.
    E.4Principal exclusion criteria
    1. Patients who have a progressive medical or neurological condition that in the opinion of the Investigator would interfere with the conduct of the study.
    2. Patients with a current clinically significant systemic illness that is likely to result in deterioration of the patient’s condition or affect the patient’s safety during the study.
    3. History of clinically evident stroke or clinically significant carotid or vertebrobasilar stenosis or plaque or other history of neurologic (e.g., head trauma with loss of consciousness) or psychiatric condition that the Investigator deems may interfere with interpretability of data.
    4. Indication of liver disease, defined by serum levels of ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3x upper limit of normal (ULN) as determined during screening.
    5. Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last 3 years.
    6. Other clinically significant abnormality on physical, neurological, laboratory, or electrocardiogram (ECG) examination (e.g., atrial fibrillation) that could compromise the study or be detrimental to the participant.
    7. Any known hypersensitivity to any of the excipients contained in the study drug or placebo formulation.
    8. Other co-morbid or chronic illness beyond that known to be associated with Rett Syndrome.
    9. Subjects who plan to initiate or change pharmacologic or nonpharmacologic intervention during the course of the study.
    10. Subjects taking another investigational drug currently or within the last 30 days.
    11. Any other criteria (such as a clinically significant screening blood test result), which in the opinion of the Investigator could interfere with the study conduct or outcome.
    12. Treatment with strong inhibitors or inducers of CYP3A4 or CYP2C19 is not stable (drug, dose) for 30 days prior to screening. Although these medications are not excluded, caution is advised when enrolling participants on potent CYP3A4 or CYP2C19 inducers or inhibitors.
    13. Patients with hepatic and renal impairment.
    E.5 End points
    E.5.1Primary end point(s)
    Include safety and tolerability measures:
    • Physical and neurological examination.
    • Vital signs (heart rate, respiratory rate, systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse oximetry, and oral body temperature).
    • Recording of adverse events (AEs).
    • 12-lead ECG; three consecutive ECGs where participants should be in a resting position for ≥5 minutes prior to each ECG evaluation.
    • Clinical laboratory tests
    • Concomitant medication log.
    • PK of ANAVEX2-73 and ANAVEX19-144.
    E.5.1.1Timepoint(s) of evaluation of this end point
    55 week study period
    E.5.2Secondary end point(s)
    Efficacy:
    Include two clinical tests, which consist of change from baseline to end of treatment in the modified intent-to-treat (mITT) population in the:
    • RSBQ total score; and
    • the CGI-I score, with anchors specifically designed for RTT, at EOT, in the mITT population.

    Safety and tolerability:
    The objective is to characterize the population PK of ANAVEX2-73 and its active metabolite, ANAVEX19-144, in patients with RTT. Details will be provided in the Pharmacometrics Analysis Plan (PAP).

    AUC of ANAVEX2-73 and ANAVEX19-144 will be estimated using PK modeling approach.
    E.5.2.1Timepoint(s) of evaluation of this end point
    55 weeks
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.6.13.1Other scope of the trial description
    Outcome measures
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    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 No
    E.8.5.1Number of sites anticipated in the EEA0
    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
    Australia
    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 years1
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days10
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days20
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-02-07. Yes
    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
    Patients will be unable to consent to the trial from the start. Consent will be sought from the Medical Treatment Decision Maker.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 30
    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)
    Patients can continue with their normal standard of care if they discontinue from the trial or, after the initial 7 week phase, participants can benefit from entering the 48 week voluntary open label extension
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation CRN South London
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-03-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-26
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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