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    Summary
    EudraCT Number:2019-000099-41
    Sponsor's Protocol Code Number:AC18082
    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:2019-07-25
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-000099-41
    A.3Full title of the trial
    Motor Neurone Disease Systematic Multi-arm Adaptive Randomised Trial (MND-SMART)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MND-SMART
    A.3.2Name or abbreviated title of the trial where available
    MND-SMART
    A.4.1Sponsor's protocol code numberAC18082
    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 SponsorUniversity of Edinburgh
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuan MacDonald Centre, University of Edinburgh
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportMND Scotland
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportMy Name'5 Doddie Foundation
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Edinburgh
    B.5.2Functional name of contact pointRachel Dakin
    B.5.3 Address:
    B.5.3.1Street AddressAnne Rowling Regenerative Neurology Clinic, 49 Little France Crescent
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH16 4SB
    B.5.4Telephone number01314659518
    B.5.6E-mailrachel.dakin@ed.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorNHS Lothian
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.2.1.1.2Name of the Marketing Authorisation holderGenus Pharmaceuticals Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameMemantine
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPEnteral use (Noncurrent)
    Nasogastric use (Noncurrent)
    Gastroenteral use
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmemantine hydrochloride
    D.3.9.1CAS number 41100-52-1
    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 number2
    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.IMP: 2
    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.2.1.1.1Trade name Trazodone Hydrochloride 100mg/5ml Oral Solution
    D.2.1.1.2Name of the Marketing Authorisation holderCreo Pharma Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameTrazodone
    D.3.4Pharmaceutical form Oral liquid
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPEnteral use (Noncurrent)
    Nasogastric use (Noncurrent)
    Gastroenteral use
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTrazodone hydrochloride 100mg/5ml Oral solution
    D.3.9.1CAS number 25332-39-2
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 liquid
    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
    Motor Neurone Disease
    E.1.1.1Medical condition in easily understood language
    Motor Neurone 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 LLT
    E.1.2Classification code 10028002
    E.1.2Term Motor neuron 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
    To determine if potential neuroprotective drugs that may fix, regenerate or stabilise the nervous system, can slow the rate of progression of motor neurone disease (MND). This will be measured by assessing the effects the drugs have on patient function, using the ALS Function Rating Scale, and survival.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to establish the safety profile of potential neuroprotective drugs in people with MND and also to assess the effects of potential neuroprotective drugs on:
    o time to nutritional failure, need for a feeding tube
    o time to respiratory failure, need for some assistance with breathing
    o cognitive function and behaviour, assessed by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)
    o respiratory function measured by forced vital capacity (FVC) and sniff nasal inspiratory pressure (SNIP)
    o anxiety and depression measured by the Hospital Anxiety and Depression Scale
    o overall quality of life measured using a standard questionnaire
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    · Confirmed diagnosis of MND (including the following subtypes: ALS by El Escorial Criteria (possible, probable, and definite), Primary Lateral Sclerosis, and Progressive Muscular Atrophy)
    · Over 18
    · Women of childbearing potential according to CTFG guidelines (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf) must have a negative pregnancy test within 7 days prior to the baseline visit
    · Women of childbearing potential and fertile men (according to CTFG guidelines) must be using an appropriate method of contraception to avoid any unlikely teratogenic effects of the selected drugs from time of consent, to 4 weeks after treatment inclusive
    · Willing and able to comply with the trial protocol and ability to understand and complete questionnaires
    · Written informed consent (this can be signed by a proxy in the case of limb dysfunction)
    E.4Principal exclusion criteria
    • Patients diagnosed with Fronto-temporal Dementia (FTD-MND) or any other significant psychiatric disorder that prevents informed consent being given.
    • Patients in the manic phase of bipolar disorder.
    • Alcoholism (self-reported)
    • Active suicide ideation assessed using the Columbia-Suicide Severity Rating Scale
    • On concurrent investigational medication (including biological therapy)
    • Known hypersensitivity, including hereditary fructose intolerance, or adverse reaction to the active substances and their excipients or any past medical history contraindicating use of any of the IMPs
    • Pregnancy or breast-feeding females
    • If ALT, ALP, bilirubin or GGT >3 times the upper limit of normal.
    • If creatinine clearance (creatinine clearance or eGFR) <30 ml/min.
    • If Serum free T4 >25pmol/l or TSH <0.2mU/l
    • If corrected QT interval on 12 lead ECG >450 ms
    • Patient’s diagnosed with ventricular arrhythmias, heart block or in the immediate recovery period after myocardial infarction (< 6 weeks).
    • Already taking any of the IMPs in this protocol
    • Patient’s contraindicated to any of the IMPs
    • Taking a medication that interacts with the active substances and their excipients, including but not limited to; Dextromethorphan, Amantadine; Ketamine, Monoamine-oxidase inhibitors ((MAOIs), Rasagiline, Selegiline, Safinamide, Tranylcypromine, Phenelzine, Isocarboxazid, Moclobemide).
    E.5 End points
    E.5.1Primary end point(s)
    ALS-FRS and overall survival are co-primary outcome measures and power calculations have been performed for both these outcome measures. To ensure protection of the type I error a closed test procedure will be followed in which overall survival outcome data will only be analysed inferentially for a treatment arm conditional on there being a significant result for ALS-FRS(R) in that treatment arm.
    In the situation that the ALS-FRS outcome measure does not produce a statistically significant result overall survival data will be analysed to provide supporting information but will not provide pivotal evidence of efficacy.
    E.5.1.1Timepoint(s) of evaluation of this end point
    ALS-FRS(R) will be measured at baseline and every 2 months for 18 months. After 18 months participants will be followed-up for survival only.
    E.5.2Secondary end point(s)
    Secondary outcomes are to establish the safety profile of the IMPs in people with MND and also assess the effects of candidate putative neuroprotective drugs on:
    o time to King’s stage 4a (nutritional failure)
    o time to King’s stage 4b (respiratory failure)
    o Cognitive function and behaviour assessed by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)
    o Respiratory function measured by forced vital capacity (FVC) and sniff nasal inspiratory pressure (SNIP)
    o Anxiety and depression measured by the Hospital Anxiety and Depression Scale (HADS)
    o Quality of life evaluation – EQ-5D-5L
    E.5.2.1Timepoint(s) of evaluation of this end point
    The timing of evaluation of secondary outcome measure is as below:
    King's staging will be completed at baseline and every 2 months for 18 months.
    The ECAS will be completed at baseline, 12 months and 18 months.
    Respiratory function will be measured at baseline, 6 months, 12 months and 18 months.
    The HADS and EQ-5D-5L will be completed at baseline, 6 months, 12 months and 18 months.
    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 No
    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) 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 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.8.2.3.1Comparator description
    Placebo
    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 concerned12
    E.8.5The trial involves multiple Member States No
    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
    The end of study is defined as the last participant’s last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days29
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days29
    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: 375
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 375
    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 state750
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 750
    F.4.2.2In the whole clinical trial 750
    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)
    No provision has been made to continue to supply the IMPs to be tested in this trial. However, the study has included in the protocol that positive results will trigger an application to the Early Access to Medicine Scheme to expedite the availability of treatments to all people with MND.
    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 Edinburgh Clinical Trials Unit
    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 Decision2019-09-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-02
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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