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

• ClinicalTrials.gov Identifier: NCT04302870
• Recruitment Status: Recruiting
• First Posted: March 10, 2020
• Last Update Posted: March 9, 2023
• Sponsor: University of Edinburgh
• Collaborators: University College, London; University of Warwick; NHS Lothian
• Information provided by (Responsible Party): University of Edinburgh

Tracking Information

• First Submitted Date: March 4, 2020
• First Posted Date: March 10, 2020
• Last Update Posted Date: March 9, 2023
• Actual Study Start Date: February 27, 2020
• Estimated Primary Completion Date: September 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 6, 2020)

• Change in decline of ALS-FRS(R) over 18months [ Time Frame: 18 months ]
  Co-primary outcome measure
• Survival [ Time Frame: 18 months ]
  Co-primary outcome measure

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 10, 2022)

• Cognition and behaviour [ Time Frame: 18 months ]
  Using Edinburgh Cognitive and Behavioural ALS Screen (ECAS)
• Respiratory function - Forced vital capacity [ Time Frame: 18 months ]
  Change in FVC
• King's ALS Clinical stage [ Time Frame: 18 months ]
  Time to reach King's stage IV, scale range I - V
• Changes in anxiety and depression [ Time Frame: 18 months ]
  Measured using the hospital anxiety and depression scale (HADS), scale range 0 - 42
• Changes in Quality of Life [ Time Frame: 18 months ]
  Measured using EQ-5D-5L
• Safety and tolerability of IMPs [ Time Frame: 18 months ]
  Measured using adverse events

Original Secondary Outcome Measures (submitted: March 6, 2020)

• Cognition and behaviour [ Time Frame: 18 months ]
  Using Edinburgh Cognitive and Behavioural ALS Screen (ECAS)
• Respiratory function - Forced vital capacity [ Time Frame: 18 months ]
  Change in FVC
• King's ALS Clinical stage [ Time Frame: 18 months ]
  Time to reach King's stage IV, scale range I - V
• Changes in anxiety and depression [ Time Frame: 18 months ]
  Measured using the hospital anxiety and depression scale (HADS), scale range 0 - 42
• Changes in Quality of Life [ Time Frame: 18 months ]
  Measured using EQ-5D-5L
• Safety and tolerability of IMPs [ Time Frame: 18 months ]
  Measured using adverse events
• Respiratory function - Sniff nasal inspiratory pressure [ Time Frame: 18 months ]
  Change in SNIP

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial
• Official Title: Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

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. In the first instance the trial will have 3 arms; drug 1, drug 2 and placebo (dummy drug). This allows the evaluation of drug 1 versus placebo and separately drug 2 versus placebo. Participants will be randomly allocated to either drug 1, drug 2 or placebo. 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 first 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.

• Detailed Description: For further information, please visit: https://mnd-smart.org/
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Motor Neuron Disease, Amyotrophic Lateral Sclerosis

Intervention

• Drug: Memantine Hydrochloride Oral Solution
  Memantine hydrocholoride taken once daily
• Drug: Trazodone Hydrochloride oral solution
  Trazodone Hydrochloride taken once daily
• Drug: Placebo oral solution
  Placebo taken once daily

Study Arms

• Experimental: Memantine
  Intervention: Drug: Memantine Hydrochloride Oral Solution
• Experimental: Trazodone
  Intervention: Drug: Trazodone Hydrochloride oral solution
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo oral solution

• Publications *: 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 6, 2020): 750
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2026
• Estimated Primary Completion Date: September 2026 (Final data collection date for primary outcome measure)

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) <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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Professor Chandran; 0131 465 9612; siddharthan.chandran@ed.ac.uk

Contact: Amy Stenson; 0131 242 9122; astenson@exseed.ed.ac.uk

• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT04302870
• Other Study ID Numbers: AC18082
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Yes

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.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Analytic Code
• Time Frame: After publication of study results, no end date.

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.

• Current Responsible Party: University of Edinburgh
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Edinburgh
• Original Study Sponsor: Same as current

Collaborators

• University College, London
• University of Warwick
• NHS Lothian

Investigators

• Study Director: Professor Chandran; University of Edinburgh

• PRS Account: University of Edinburgh
• Verification Date: March 2023