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    EudraCT Number:2020-005193-94
    Sponsor's Protocol Code Number:WVE-004-001
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-10-15
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2020-005193-94
    A.3Full title of the trial
    A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-004 Administered Intrathecally to Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1b/2a Study of WVE-004 in Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)
    A.4.1Sponsor's protocol code numberWVE-004-001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04931862
    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 SponsorWave Life Sciences UK Limited
    B.1.3.4CountryUnited Kingdom
    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 supportWave Life Sciences UK Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace, Inc.
    B.5.2Functional name of contact pointRegulatory Submissions
    B.5.3 Address:
    B.5.3.1Street Address5375 Medpace Way
    B.5.3.2Town/ cityCincinnati
    B.5.3.3Post codeOH 45227
    B.5.3.4CountryUnited States
    B.5.4Telephone number0015135799911
    B.5.5Fax number0015135790444
    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.3.2Product code WVE-004
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrathecal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot yet assigned
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeWVE-004
    D.3.9.3Other descriptive nameSynthetic stereopure antisense oligonucleotide targeting human C9orf72 hexanucleotide repeat-containing mRNA transcripts
    D.3.9.4EV Substance CodeSUB219364
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Yes
    D. medicinal product typeantisense oligonucleotide
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntrathecal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

    E.1.1.1Medical condition in easily understood language
    motor neuron disease; dementia where the front and sides of the brain has been affected
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10002026
    E.1.2Term Amyotrophic lateral sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10068968
    E.1.2Term Frontotemporal dementia
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the safety and tolerability of WVE-004 in patients with ALS or FTD with a documented mutation in the C9orf72 gene.
    E.2.2Secondary objectives of the trial
    • Characterize the pharmacokinetics (PK) of WVE-004 in plasma.
    • Characterize cerebrospinal fluid (CSF) concentration of WVE-004.
    • Evaluate the pharmacodynamic (PD) effect of WVE-004 via measurement of poly-glycine-proline (poly-GP) in CSF.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ALS-Specific Inclusion Criteria:
    1. Diagnosis of ALS based on clinical manifestations.
    2. ALS: Clinically diagnosed possible, laboratory supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology revised El Escorial criteria.
    3. Patients receiving riluzole have been on a stable dose for a minimum of 30 days.
    4. Patients on edaravone have received a minimum of 1 cycle (28 days).
    5. Patients discontinuing riluzole or edaravone had the last dose administered ≥1 month prior to Screening.
    FTD-Specific Inclusion Criteria:
    6. FTD: Must have Global Clinical Dementia Rating – Frontotemporal Lobar Degeneration (CDR® plus NACC FTLD) score of 0.5 or 1.
    7. FTD: Able to undergo periodic magnetic resonance imaging (MRI) of the brain. Patients with mixed phenotype (ALS and FTD) need not undergo MRI if their ALS symptoms prevent it.
    Mixed Phenotype (ALS and FTD) Inclusion Criteria:
    8. Patients who are mixed phenotype (ALS and FTD) must meet both the ALS-specific and FTD-specific criteria.
    Inclusion Criteria Common to Both Diseases:
    9. Patient must have the ability and be willing to provide written informed consent prior to any trial-related procedures.
    10. Documented mutation (GGGGCC [G4C2] repeat expansion) in the first intronic region of the C9orf72 gene.
    11. Body mass index (BMI) ≤32 kg/m2.
    12. Forced vital capacity (FVC) of >50% predicted.
    13. Age of ≥18 and ≤80 years at Screening visit.
    14. Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, trial restrictions, and all trial procedures.
    15. Willingness to practice highly effective contraception for the duration of the trial and for 5 months after the last dose of study drug if patients or their partners are of childbearing potential. Non-childbearing potential and highly effective methods of contraception are defined in the protocol. In addition, willingness to forego sperm or ova (egg) donation for the duration of the study and 5 months after last dose.
    E.4Principal exclusion criteria
    Exclusion Criteria:
    1. Clinically significant medical finding on the physical examination other than C9orf72-associated ALS or FTD that, in the judgment of the Investigator, will make the patient unsuitable for participation in, and/or completion of the trial procedures, including, but not limited to:
    a. Prior or ongoing medical conditions, including acute illness, within 28 days of Screening visit;
    b. Clinically significant abnormality on laboratory testing at Screening, including, but not limited to:
    - Renal insufficiency, which is defined as creatinine clearance <40 mL/min.
    2. Positive hepatitis B surface antigen or hepatitis C antibody test.
    3. Known to be positive for human immunodeficiency virus (HIV).
    4. History of substance use disorder (except nicotine) within 6 months prior to the Screening Visit.
    5. Significant cognitive impairment; or unstable psychiatric illness, including active psychosis, active suicidal ideation, recent suicide attempt, or untreated major depression, within the last 90 days, as determined by the Investigator. Mental status, psychiatric medical history, and eligibility for the study must be documented in the screening questionnaire.
    6. Pregnant (as determined by a serum pregnancy test) or breast feeding at the Screening Visit, or plans to become pregnant during the trial.
    7. Clinically significant abnormality on Screening electrocardiogram (ECG), including, but not limited to, a confirmed QT interval using Fridericia’s correction method (QTcF) of ≥450 msec for males or ≥470 msec for females.
    8. Bone, spine, bleeding, (e.g. hemophilia, Von Willenbrand disease, liver disease) or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture.
    9. Dementia due to a condition other than C9orf72-associated ALS or FTD, including, but not limited to, Alzheimer disease, Parkinson disease, dementia with Lewy bodies, Huntington's disease, or vascular dementia.
    Prior or Concomitant Medications
    10. Positive for opioids (unprescribed), cocaine, amphetamines, methadone, barbiturates, methamphetamine, and phencyclidine at the Screening Visit.
    11. Changes in nutritional or herbal supplements or concomitant medications within 1 month prior to Screening visit or plans to modify dose or regimen during the trial.
    12. Received prior treatment with viral or cellular-based gene therapy.
    13. Received any other investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Received an investigational oligonucleotide, within the past 6 months or 5 half-lives of the drug, whichever is longer.
    14. Anticipates using antiplatelet or anticoagulant therapy during the course of the study. Patients who received antiplatelet or anticoagulant therapy must complete one of the following washout periods before the Screening Visit:
    a. A 7-day washout period for antiplatelet therapy,
    b. A 1-day washout period for anticoagulants (except warfarin), or
    c. A 5-day washout period for warfarin.

    Trial Compliance
    15. Implantable central nervous system (CNS) device that may interfere with ability to administer trial drug via lumbar puncture or undergo MRI scan.
    16. Deemed to be at significant risk for suicidal behavior based on Investigator assessment and/or active suicidal ideation.
    17. Known hypersensitivity to any oligonucleotide, as demonstrated by a systemic allergic reaction, such as changes in pulse, blood pressure, breathing function, etc., or any other drug that in the opinion of the Investigator may preclude study participation.
    18. Patient is directly or indirectly involved in the conduct and administration of this trial as an Investigator, sub investigator, trial coordinator, or other trial staff member, or the patient is a first-degree family member, significant other, or relative residing with one of the above persons involved directly or indirectly in the trial.
    E.5 End points
    E.5.1Primary end point(s)
    Incidence of patients with AEs, the incidence of patients with severe AEs, incidence of patients with SAEs, and the incidence of patients who withdraw due to AEs.

    E.5.1.1Timepoint(s) of evaluation of this end point
    Period 1: week 1 - 24
    Period 2: week 1 - 24
    E.5.2Secondary end point(s)
    • Pharmacokinetic parameters of WVE-004 in plasma
    • CSF concentration of WVE-004
    • Change from baseline in concentration of poly-GP levels in the CSF
    E.5.2.1Timepoint(s) of evaluation of this end point
    Period 1: week 1 - 24
    Period 2: week 1 - 24
    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 Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. 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 Yes
    E. trial design description
    Period 1: Single Ascending Dose, Period 2 Multiple Ascending Dose
    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 trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    New Zealand
    United States
    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
    Last patient Last Visit ( Including Follow-up Visit)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    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: 31
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 11
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 42
    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)
    Depending on the results of this study, subjects might be able to participate in an extension study ( after study approval by the authorities)
    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 Decision2021-11-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-01-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-06-28
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