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    Summary
    EudraCT Number:2015-004098-33
    Sponsor's Protocol Code Number:233AS101
    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:2015-12-10
    Trial results View 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 number2015-004098-33
    A.3Full title of the trial
    A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics and
    Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics
    Study of BIIB067 in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
    A.3.2Name or abbreviated title of the trial where available
    Biogen 233AS101
    A.4.1Sponsor's protocol code number233AS101
    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 SponsorBiogen Idec Research 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 supportBiogen Idec Research Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBiogen
    B.5.2Functional name of contact pointMedical Director
    B.5.3 Address:
    B.5.3.1Street AddressInnovation House, 70 Norden Road
    B.5.3.2Town/ cityMaidenhead
    B.5.3.3Post codeSL6 4AY
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailclinicaltrials@biogen.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code BIIB067 (ISIS666853)
    D.3.4Pharmaceutical form 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.3.9.2Current sponsor codeBIIB067 (ISIS 666853)
    D.3.9.3Other descriptive nameBIIB067
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6.7
    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 Yes
    D.3.11.13.1Other medicinal product typesecond-generation chimeric 2′ methoxyethyl mixed backbone antisense 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 (ALS)
    E.1.1.1Medical condition in easily understood language
    Lou Gehrig's disease
    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 10077024
    E.1.2Term Familial amyotrophic lateral sclerosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    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.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of Parts A and B of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB067 in adult participants with ALS. The primary objective of Part C of this study is to evaluate the clinical efficacy of BIIB067 administered to adult participants with ALS and confirmed superoxide dismutase 1 (SOD1) mutation.
    E.2.2Secondary objectives of the trial
    The secondary objective of Parts A and B of this study is to evaluate the effects of BIIB067 on levels of SOD1 protein in the cerebrospinal fluid (CSF). The secondary objectives of Part C are to evaluate the safety, tolerability, and pharmacodynamic (PD) effects of BIIB067 administered to adult participants with ALS and confirmed SOD1 mutation.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Key Inclusion Criteria: Part A and B
    - Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2.
    - A forced vital capacity (FVC) ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position). Subjects with stable FVC <50% but ≥45%, whose FVC has not declined by more than 5% in the last 6 months may be considered for inclusion, at the discretion of the Investigator.
    - If taking riluzole, subject must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit.
    - Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.

    Key Inclusion Criteria: Part C
    - Weakness attributable to ALS and confirmed SOD1 mutation at Screening Visit.
    - If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit.
    - If taking edaravone, participant must have initiated edaravone ≥60 days (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study.
    - Medically able to undergo the study procedures and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.
    E.4Principal exclusion criteria
    Key Exclusion Criteria: Part A and B
    - History of or positive test result for human immunodeficiency virus.
    - History of or positive test result at Screening for hepatitis C virus antibody or hepatitis B virus (defined as positive for both hepatitis B surface antigen and hepatitis B core antibody).
    - Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) or vaccination defined as positive anti-HBs) are eligible to participate in the study.
    - Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering ribonucleic acid, stem cell therapy, or gene therapy is allowed.
    - Current enrollment in any other interventional study.
    - Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis(N4-methylthiosemicarbazone)) or pyrimethamine.
    - Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.


    Key Exclusion Criteria: Part C
    - History of or positive test result for human immunodeficiency virus.
    - Current hepatitis C infection (defined as positive hepatitis C virus [HCV] antibody and detectable HCV ribonucleic acid [RNA]). Subjects with positive HCV antibody and undetectable HCV RNA are eligible to participate in the study (United States Centers for Disease Control and Prevention)
    - Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
    - Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer.
    Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed.
    - Current enrollment in any other interventional study.
    - Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis(N4-methylthiosemicarbazone)) or pyrimethamine.
    - Current or anticipated need, in the opinion of the Investigator, of a DPS during the study period.

    NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
    E.5 End points
    E.5.1Primary end point(s)
    Part A and B:
    - Number of participants experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs).

    - Number of participants with clinically significant laboratory assessment abnormalities.

    - Number of participants with clinically significant vital sign abnormalities

    - Number of participants with clinically significant physical examination abnormalities.

    - Number of participants with clinically significant neurological examination abnormalities.

    - Number of participants with clinically significant 12-lead electrocardiograms (ECGs) abnormalities.

    - PK parameter of BIIB067 in plasma: Maximum observed concentration (Cmax)

    -PK parameter of BIIB067 in plasma: Time to reach maximum observed concentration (Tmax)

    -PK parameter of BIIB067 in plasma: Area under the concentration-time curve from time zero to infinity (AUCinf)

    -PK parameter of BIIB067 in plasma:
    Area under the concentration -time curve from time zero to the time of the last measurable concentration (AUClast)

    -PK parameter of BIIB067 in plasma: Apparent terminal elimination half-life (t1/2)

    - PK parameter of BIIB067 in CSF levels : Terminal elimination half-life (t1/2)

    Part C:
    - Slope of Amyotrophic Lateral Sclerosis functional Rating Scaled-Revised (ALSFRS-R) Score
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A and B: Up to Day 169
    Part C: Baseline to Day 197
    E.5.2Secondary end point(s)
    Part A, B and C:
    Change from baseline in CSF levels of SOD1 protein.
    Part C:
    Change from baseline in CSF levels of SOD1 protein.
    - Change from Baseline in Slow Vital Capacity (SVC)
    - Ventilation Assistance-Free Survival (VAFS)
    - Overall Survival
    - Change from Baseline in Muscle Strength Measured by Handheld
    Dynamometry (HHD)
    - Number of Participants Experiencing Adverse Events (AEs) and Serious
    Adverse Events (SAEs)
    - Change from Baseline in Phosphorylated Axonal Neurofilament heavy
    chain (p-NFH) Concentration in CSF
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part A, B and C: Up to Day 169
    Part C: Up to, or Baseline to, Day 197, except:
    - VAFS, Overall Survival and No of Participants with AEs and SAEs - Baseline to Day 225
    - p-NFH in CSF - Baseline to Day 169
    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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    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 Yes
    E.8.1.7.1Other trial design description
    3 part - multiple ascending dose followed by pivotal efficacy
    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 trial3
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Belgium
    Canada
    Denmark
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Sweden
    United Kingdom
    United States
    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 for Part C
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days17
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days17
    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: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 146
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 37
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 63
    F.4.2.2In the whole clinical trial 183
    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)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-02-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-18
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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