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    Summary
    EudraCT Number:2021-003164-27
    Sponsor's Protocol Code Number:TW001-AD-C2.01
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-03-22
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2021-003164-27
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Pharmacodynamics and Pharmacokinetics of TW001 in Alzheimer Patients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of Safety, Pharmacodynamics and Pharmacokinetics of TW001 in Alzheimer Patients
    A.3.2Name or abbreviated title of the trial where available
    Evaluation of Safety, Pharmacodynamics and Pharmacokinetics of TW001 in Alzheimer Patients
    A.4.1Sponsor's protocol code numberTW001-AD-C2.01
    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 SponsorTreeway TW001AD B.V.
    B.1.3.4CountryNetherlands
    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 supportTreeway TW001AD B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTreeway TW001AD B.V.
    B.5.2Functional name of contact pointChief Development Officer
    B.5.3 Address:
    B.5.3.1Street AddressMaidstone 48a
    B.5.3.2Town/ citySK Tilburg
    B.5.3.3Post code5026
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031135348272
    B.5.6E-mailRonald@treeway.nl
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTW001 granules for oral solution
    D.3.2Product code TEST
    D.3.4Pharmaceutical form Granules for oral solution
    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 INNEDARAVONE
    D.3.9.1CAS number 89-25-8
    D.3.9.4EV Substance CodeSUB06453MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 placeboGranules for oral 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
    Alzheimer´s Disease (AD)
    E.1.1.1Medical condition in easily understood language
    Alzheimer's disease is a brain disorder that slowly destroys memory and thinking skills, and, eventually, the ability to carry out the simplest tasks.
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of the present trial is:
    • to evaluate the effect of TW001 on oxidative stress biomarkers
    • to evaluate the safety of TW001 in patients with Alzheimer’s Disease
    E.2.2Secondary objectives of the trial
    The secondary objective of the present trial is:
    • to evaluate the pharmacokinetics of TW001 in patients with Alzheimer’s Disease.
    Exploratory objectives of the present trial are:
    - to explore the early effect of TW001 on the CDR-SB and the Cognitive Functional Composite (CFC) endpoint as a clinical outcome measur
    - to explore the early effect of TW001 on a variety of individual biomarkers to define a composite biomarker to be used in a follow-up, long-term clinical study to predict disease progression
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible for participation in this trial, a patient must meet the following criteria:
    [1] Age 55 – 80 years (both inclusive), male or female.
    [2] Body mass index between 18.5 to 30.0 kg/m2 (both inclusive).
    [3] Should meet the criteria for early clinical stage AD according to the NIA-AA criteria research framework:
    a. Gradual and progressive change in memory function reported by patient or informant over more than 6 months,
    b. Clinical syndrome of MCI due to AD or mild AD dementia,
    c. An MMSE score ≥ 20 at screening,
    d. Biomarker classification A+T+N+ or A+T+N- based upon:
    I. CSF profile consistent with AD (an Aβ42 concentration of <1000 pg/mL AND phosphorylated tau (p-Tau) >19 pg/mL, or a ratio of p-tau/Aβ42 of ≥0.020) taken during the screening period prior to the day of the first dose of study medication or,
    II. Documented evidence of a CSF profile consistent with AD obtained within the previous 12 months, or
    III. Documented amyloid positron emission tomography (PET) scan evidence acquired within the previous 12 months.
    [4] A reliable and competent trial partner/caregiver who can assist and witness dosing and is willing to accompany the patient to all visits. The trial partner/caregiver should understand the nature of the trial and adhere to trial requirements (e.g., visit schedules, evaluations) and confirm this by co-signing the informed consent of the patient or signing of a separate informed consent of the partner/caregiver according to the local requirements.
    [5] If a patient is taking medication, supplements or vitamins, the dose must be stable for at least the last 3 months before screening, and the patient must be willing to remain on the same dose for the duration of the trial.
    [6] A male patient abstains from sexual intercourse, or is vasectomized (> 6 months), or will use a condom with spermicide during sexual intercourse during the trial and for three months after participation in the trial and will abstain from sperm donation during the trial and for three months after participation in the trial.
    [7] A female patient should not be of reproductive potential:
    A female patient who is not of reproductive potential is defined as one who:
    (a) Has reached natural menopause (defined as 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone [FSH] levels in the postmenopausal range as determined by the local laboratory, or 12 months of spontaneous amenorrhea);
    (b) Is 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy; or
    (c) Has undergone bilateral tubal ligation. Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g., anorexia nervosa).
    [8] Capable of providing informed consent and complying with trial procedures.
    E.4Principal exclusion criteria
    Patients presenting at screening visit that meet any of the following criteria will not be included in the trial:
    [1] A known history of stroke that is clinically important in the investigator’s opinion.
    [2] Evidence of a clinically relevant neurological disorder other than AD at screening, including but not limited to: vascular dementia, Parkinson’s disease, frontotemporal dementia, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, dementia with Lewy bodies, other types of dementia, neurosyphilis or head trauma with loss of consciousness that led to persistent cognitive deficits.
    [3] A history of seizures or epilepsy within the last 5 years before screening.
    [4] Evidence of a clinically relevant or unstable psychiatric disorder, based on DSM-5TM criteria, including schizophrenia or other psychotic disorder, bipolar disorder, major depression, or delirium. Major depression in remission is not exclusionary.
    [5] Renal impairment as indicated by a creatinine clearance of less than 50 mL/min as calculated by the Cockcroft Gault equation78.
    [6] Patient has a history of any of the following conditions:
    a. Clinically significant hepatic disease,
    b. AST or ALT levels of ≥ 2 times upper limit of normal (ULN),
    c. Biliary tract disease,
    d. Patient has a positive screening test for HIV, hepatitis B or C.
    [7] Presence of any of the following clinical conditions:
    a. Unstable cardiac, pulmonary, endocrine, hematologic or active infectious disease,
    b. Unstable psychiatric illness defined as psychosis, untreated major depression within 90 days of the screening visit,
    c. A history of cancer within 3 years prior to screening, except adequately treated squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
    [8] History or signs/symptoms of lumbar spine/disc disease including but not limited to scoliosis, herniation, or any other contraindication to lumbar puncture.
    [9] History of known sensitivity or intolerability to edaravone, related substances of edavarone, or to any of the excipients.
    [10] Use of OAT-3 inhibitors such as probenecid, cimetidine, and diclofenac.
    [11] Current substance abuse or alcohol dependence.
    [12] Exposure to any investigational drug within 30 days of the screening visit.
    E.5 End points
    E.5.1Primary end point(s)
    Pharmacodynamics
    Evaluate the effect of TW001 on oxidative stress biomarkers, including:
    - 8-hydroxy-2’-deoxyguanosine (8-OHdG) / 8-hydroxyguanosine (8-OHG) in plasma and CSF
    - 3-nitrotyrosine (3-NT) in plasma and CSF
    - Uric acid in plasma
    Safety
    - Nature, frequency and severity of adverse events
    - Values and changes from baseline in vital signs and 12-lead electrocardiogram (ECG)
    - Values and changes from baseline in safety laboratory tests (hematology, biochemistry, coagulation, urinalysis)
    - Changes in physical and neurological examinations
    - Changes in Electroencephalogram (EEG)
    E.5.1.1Timepoint(s) of evaluation of this end point
    After completion of the clinical part of the trial and database closure.
    E.5.2Secondary end point(s)
    Pharmacokinetics
    The following plasma PK parameters will be obtained for plasma edaravone after orally administered TW001:
    - AUC(0-t), Cmax and tmax of edaravone
    Exploratory Endpoints
    Explore the effect of TW001 on surrogate markers of AD pathogenesis and progression, such as:
    - Amyloid β (Aβ) 42-residue (Aβ42) in plasma and CSF
    - Amyloid β (Aβ) 40-residue (Aβ40) in plasma and CSF
    - Phosphorylated tau epitopes in plasma and CSF
    - Total tau (t-tau) in CSF
    - Glial Fibrillary acidic protein (GFAP) in plasma and CSF
    - Chitinase-3-like protein 1 (YKL-40) in CSF
    - Neurofilament light (NFL) in plasma and CSF
    - Neurogranin (NRGN) in CSF
    Explore the effect of TW001 on oxidative stress biomarkers, including:
    - 8-hydroxy-2’-deoxyguanosine (8-OHdG) / 8-hydroxyguanosine (8-OHG) in urine
    - 3-nitrotyrosine (3-NT) in urine
    Explore the early effect of TW001 on:
    - Cognitive functioning using the CDR-SB and the CFC
    - Neuronal activity and connectivity through EEG
    E.5.2.1Timepoint(s) of evaluation of this end point
    After completion of the clinical part of the trial and database closure.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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) 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 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 EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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. Follow-up visit (not earlier than 14 days after the last dosing)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 75
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state75
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 150
    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)
    All patients will be subjected to a pre- and post-study safety examination and a Follow-up visit (not earlier than 14 days after the last dosing). No further post-treatment procedures are considered to be required.
    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 Decision2022-06-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-05
    P. End of Trial
    P.End of Trial StatusOngoing
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