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Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART)

Primary Purpose

Motor Neuron Disease, Amyotrophic Lateral Sclerosis

Status
Recruiting
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Memantine Hydrochloride Oral Solution
Trazodone Hydrochloride oral solution
Placebo oral solution
Amantadine Hydrochloride Oral Solution
Sponsored by
University of Edinburgh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Motor Neuron Disease, Amyotrophic Lateral Sclerosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 Clinical Trials Facilitation and Coordination Group (CTFG) guidelines must have a negative pregnancy test within 7 days prior to, or at, the baseline visit
  • Women of childbearing potential and fertile men 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)

Exclusion Criteria:

  • Patients diagnosed with Frontotemporal 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 (SPCs section 6.1) 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 TSH <0.2mU/l (if possible to test free T4, then Serum free T4 >25pmol/l)
  • If corrected QT interval on 12 lead ECG >450 ms
  • Patient's diagnosed with ventricular arrhythmias, significant heart block (at the investigator's discretion) 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 according to SPC section 4.3
  • Taking a medication that interacts with the active substances and their excipients according to the SPCs, including but not limited to; Dextromethorphan, Amantadine; Ketamine, Monoamineoxidase inhibitors ((MAOIs), Rasagiline, Selegiline, Safinamide, Tranylcypromine, Phenelzine, Isocarboxazid, Moclobemide).
  • Patients who the PI considers will not be able to comply with the study protocol.

Sites / Locations

  • Southern Health and Social Care Trust, Craigavon Area HospitalRecruiting
  • Aberdeen Royal InfirmaryRecruiting
  • University Hospitals of Birmingham NHS Foundation TrustRecruiting
  • West Suffolk NHS Foundation TrustRecruiting
  • Cambridge University Hospitals NHS Foundation TrustRecruiting
  • Cardiff and Vale University Local Health BoardRecruiting
  • Clinical Research Centre , Ninewells HospitalRecruiting
  • Anne Rowling Regenerative Neurology ClinicRecruiting
  • Royal Devon and Exeter HospitalRecruiting
  • Queen Elizabeth University Hospital Clinical Research FacilityRecruiting
  • NHS Highland Clinical Research Facility, Raigmore HospitalRecruiting
  • East Suffolk and North Essex NHS Foundation TrustRecruiting
  • Royal London HospitalRecruiting
  • St George's University Hospitals NHS Foundation TrustRecruiting
  • Newcastle upon Tyne Hospitals NHS Foundation TrustRecruiting
  • Norfolk and Norwich University Hospitals NHS Foundation TrustRecruiting
  • University Hospitals of Dorset NHS TrustRecruiting
  • Clinical Research Facility Salford Royal NHS Foundation TrustRecruiting
  • Sheffield Teaching Hospitals NHS Foundation TrustRecruiting
  • Clinical Research Facility University Hospital SouthamptonRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Placebo Comparator

Experimental

Arm Label

Memantine

Trazodone

Placebo

Amantadine

Arm Description

Outcomes

Primary Outcome Measures

Change in decline of ALS-FRS(R) over 18months
Co-primary outcome measure
Survival
Co-primary outcome measure

Secondary Outcome Measures

Cognition and behaviour
Using Edinburgh Cognitive and Behavioural ALS Screen (ECAS)
Respiratory function - Forced vital capacity
Change in FVC
King's ALS Clinical stage
Time to reach King's stage IV, scale range I - V
Changes in anxiety and depression
Measured using the hospital anxiety and depression scale (HADS), scale range 0 - 42
Changes in Quality of Life
Measured using EQ-5D-5L
Safety and tolerability of IMPs
Measured using adverse events

Full Information

First Posted
March 4, 2020
Last Updated
September 28, 2023
Sponsor
University of Edinburgh
Collaborators
University College, London, University of Warwick, NHS Lothian
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1. Study Identification

Unique Protocol Identification Number
NCT04302870
Brief Title
Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial
Acronym
MND-SMART
Official Title
Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 27, 2020 (Actual)
Primary Completion Date
September 2026 (Anticipated)
Study Completion Date
December 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Edinburgh
Collaborators
University College, London, University of Warwick, NHS Lothian

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
MND-SMART is investigating whether selected drugs can slow down the progression of motor neurone disease (MND) and improve survival. The study is 'multi-arm' meaning more than one treatment will be tested at the same time. The trial started with 3 arms; drug 1 (memantine), drug 2 (trazodone) and placebo (dummy drug). A third drug, amantadine, was added in April 2023. The first two drugs, memantine and trazodone, were removed from the trial in September 2023 due to lack of benefit. The trial currently has 2 recruiting arms; amantadine and placebo. This allows the evaluation of each drug versus placebo. Participants will be randomly allocated to either of the recruiting arms. Medicines being tested are already approved for use in other conditions. MND-SMART has an 'adaptive' design. This means medicines being studied can change according to emerging results. Treatments shown to be ineffective can be dropped and new drugs can be added over the duration of the study. This will allow many treatments, over time, to be efficiently and definitively evaluated. The medicines being tested have been selected following a rigorous process involving a systematic, unbiased, and comprehensive review of past clinical trials data, as well as information from pre-clinical research (studies in laboratories), for MND and other related neurodegenerative disorders. Drugs have been ranked for inclusion in MND-SMART by a group of independent MND experts according to set criteria. These include consideration of how the drugs work, their safety profiles, and the quality of previous studies. New drugs will be selected for investigation in MND-SMART based on continuous review of constantly updated scientific evidence as well as findings from state-of-the-art human stem cell based drug discovery platforms. These can be added by substantial amendment to the protocol.
Detailed Description
For further information, please visit: https://mnd-smart.org/

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Motor Neuron Disease, Amyotrophic Lateral Sclerosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
800 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Memantine
Arm Type
Experimental
Arm Title
Trazodone
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Title
Amantadine
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Memantine Hydrochloride Oral Solution
Intervention Description
Memantine hydrocholoride taken once daily
Intervention Type
Drug
Intervention Name(s)
Trazodone Hydrochloride oral solution
Intervention Description
Trazodone Hydrochloride taken once daily
Intervention Type
Drug
Intervention Name(s)
Placebo oral solution
Intervention Description
Placebo taken once daily
Intervention Type
Drug
Intervention Name(s)
Amantadine Hydrochloride Oral Solution
Intervention Description
Amantadine Hydrochloride taken once daily
Primary Outcome Measure Information:
Title
Change in decline of ALS-FRS(R) over 18months
Description
Co-primary outcome measure
Time Frame
18 months
Title
Survival
Description
Co-primary outcome measure
Time Frame
18 months
Secondary Outcome Measure Information:
Title
Cognition and behaviour
Description
Using Edinburgh Cognitive and Behavioural ALS Screen (ECAS)
Time Frame
18 months
Title
Respiratory function - Forced vital capacity
Description
Change in FVC
Time Frame
18 months
Title
King's ALS Clinical stage
Description
Time to reach King's stage IV, scale range I - V
Time Frame
18 months
Title
Changes in anxiety and depression
Description
Measured using the hospital anxiety and depression scale (HADS), scale range 0 - 42
Time Frame
18 months
Title
Changes in Quality of Life
Description
Measured using EQ-5D-5L
Time Frame
18 months
Title
Safety and tolerability of IMPs
Description
Measured using adverse events
Time Frame
18 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 Clinical Trials Facilitation and Coordination Group (CTFG) guidelines must have a negative pregnancy test within 7 days prior to, or at, the baseline visit Women of childbearing potential and fertile men 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) Exclusion Criteria: Patients diagnosed with Frontotemporal 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 (SPCs section 6.1) 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) <35 ml/min. If TSH <0.2mU/l (if possible to test free T4, then Serum free T4 >25pmol/l) corrected QT interval on 12 lead ECG >500 ms Active Epilepsy History of proven peptic ulcer confirmed on endoscopy Patient's diagnosed with ventricular arrhythmias, significant heart block (at the investigator's discretion) 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 according to SPC section 4.3 Taking a medication that interacts with the active substances and their excipients according to the SPCs, including but not limited to; Dextromethorphan, Amantadine; Ketamine, Monoamineoxidase inhibitors ((MAOIs), Rasagiline, Selegiline, Safinamide, Tranylcypromine, Phenelzine, Isocarboxazid, Moclobemide). Patients who the PI considers will not be able to comply with the study protocol.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Professor Chandran
Phone
0131 465 9612
Email
siddharthan.chandran@ed.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Amy Stenson
Phone
0131 242 9122
Email
astenson@exseed.ed.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Professor Chandran
Organizational Affiliation
University of Edinburgh
Official's Role
Study Director
Facility Information:
Facility Name
Southern Health and Social Care Trust, Craigavon Area Hospital
City
Portadown
State/Province
County Armagh
ZIP/Postal Code
BT63 5QQ
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Raeburn Forbes
Facility Name
Aberdeen Royal Infirmary
City
Aberdeen
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Callum Duncan
Facility Name
University Hospitals of Birmingham NHS Foundation Trust
City
Birmingham
ZIP/Postal Code
B15 2TH
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Venkatamaran Srinivasan
Facility Name
West Suffolk NHS Foundation Trust
City
Bury Saint Edmunds
ZIP/Postal Code
IP33 2QZ
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Francesca Crawley
Facility Name
Cambridge University Hospitals NHS Foundation Trust
City
Cambridge
ZIP/Postal Code
CB2 0QQ
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rhys Roberts
Facility Name
Cardiff and Vale University Local Health Board
City
Cardiff
ZIP/Postal Code
CF14 4XW
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ken Dawson
Facility Name
Clinical Research Centre , Ninewells Hospital
City
Dundee
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ian Morrison
Facility Name
Anne Rowling Regenerative Neurology Clinic
City
Edinburgh
ZIP/Postal Code
EH16 4SB
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Judith Newton
Phone
0131 465 9517
Email
loth.mndsmart@nhslothian.scot.nhs.uk
Facility Name
Royal Devon and Exeter Hospital
City
Exeter
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Timothy Harrower
Facility Name
Queen Elizabeth University Hospital Clinical Research Facility
City
Glasgow
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
George Gorrie
Facility Name
NHS Highland Clinical Research Facility, Raigmore Hospital
City
Inverness
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Javier Carod Artal
Facility Name
East Suffolk and North Essex NHS Foundation Trust
City
Ipswich
ZIP/Postal Code
CO4 5JL
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clare Galton
Facility Name
Royal London Hospital
City
London
ZIP/Postal Code
E1 1FR
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aleks Radunovic
Facility Name
St George's University Hospitals NHS Foundation Trust
City
London
ZIP/Postal Code
SW17 0QT
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pablo Garcia Reitboeck
Facility Name
Newcastle upon Tyne Hospitals NHS Foundation Trust
City
Newcastle Upon Tyne
ZIP/Postal Code
NE7 7DN
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tim Williams
Facility Name
Norfolk and Norwich University Hospitals NHS Foundation Trust
City
Norwich
ZIP/Postal Code
NR4 7UY
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Godwin Mamutse
Facility Name
University Hospitals of Dorset NHS Trust
City
Poole
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Charles Hillier
Facility Name
Clinical Research Facility Salford Royal NHS Foundation Trust
City
Salford
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hisham Hamdalla
Facility Name
Sheffield Teaching Hospitals NHS Foundation Trust
City
Sheffield
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christopher McDermott
Facility Name
Clinical Research Facility University Hospital Southampton
City
Southampton
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ashwin Pinto

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
To ensure data transparency, the results of any closed comparisons will be published in a peer reviewed journal as soon as it is possible when the integrity of the trial will not be affected. Individual level participant data will be shared ,after deidentification, upon receipt of a valid request. Some data may be shared prior to the publication of study results depending on the requirements, however no end point data will be released without explicit need and permission from the TSC. Each data request form will be individually reviewed to ensure the proposal has a valid rationale and appropriate methodology. Only data required for the project will be shared. A summary of results will be provided to all participants via newsletters and the trial website.
IPD Sharing Time Frame
After publication of study results, no end date.
IPD Sharing Access Criteria
Data will be shared with researchers who provide a methodologically sound proposal to achieve the aims of the proposal only. Data sharing request forms are available from mnd-smart@Ed.ac.uk. Requesters will need to sign a data access agreement prior to being provided with access to data.
Citations:
PubMed Identifier
35798516
Citation
Wong C, Dakin RS, Williamson J, Newton J, Steven M, Colville S, Stavrou M, Gregory JM, Elliott E, Mehta AR, Chataway J, Swingler RJ, Parker RA, Weir CJ, Stallard N, Parmar MKB, Macleod MR, Pal S, Chandran S. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease. BMJ Open. 2022 Jul 7;12(7):e064173. doi: 10.1136/bmjopen-2022-064173.
Results Reference
derived

Learn more about this trial

Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

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