Table 5.

Protocol versions and substantial amendments to date

Protocol update	Protocol version	Protocol date	Reason for amendment
NA	V1	11 July 2019	N/A
Substantial amendment	V2*	20 August 2019	Addition of Clinical Trials Coordination and Facilitation Group (CTFG) definition of women of childbearing potential; and information on highly effective contraceptive methods. Additional pregnancy test added at the end of systemic exposure for women of childbearing potential
Substantial amendment—SA01	V3	24 October 2019	Clarification on trial design: Treatment and follow-up duration will continue until 200 patients/group have 18 months of follow-up (whichever is later) Guidance on prioritising primary endpoints, completing modified King’s staging in remote appointments and timescale for completing carer part of the ECAS, within 2 weeks of participant part of assessment. Addition that adverse events that are consistent with pre-existing medical conditions and/or the progression of MND do not need to be recorded in the CRF or reported (if serious) but should be noted in medical records. Confirmation of the procedure for assigning expectedness to adverse reactions by the central expectedness team.
Substantial amendment—SA02	V3	24 October 2019	Addition of site
Substantial amendment—SA03	V3	24 October 2019	Addition of sites
Substantial amendment—SA04	V3	24 October 2019	Change of PI
Substantial amendment—SA05	V5	1 March 2021	Updates to exclusion criteria. Confirmation on prescreening process and addition of remote consent using electronic software. Update to allow use of clinical results for eligibility review and outcome assessments and addition of possibility for CI to unblind. Confirmation patients who withdraw can consent to follow-up of survival from medical records. Addition of ability to cross cover for sites and updates to requirements to courier drugs direct to participants including removing need to return IMP bottles to site for compliance. Addition of sending patient-reported outcome questionnaires direct by email and clarification on assessments which can be performed remotely.
Substantial amendment—SA06	V5	1 March 2021	Addition of sites
Substantial amendment—SA07	V6	1 November 2021	Update to sample size based on move from family wise to pair wise type I error control. Removal of SNIP (sniff nasal inspiratory pressure) as a secondary outcome measure. Confirmation removal of IMPs from trial does not constitute study end, new IMPs will be added. Addition of exploratory objective to investigate ALSFRS-R post 18 months participation. Clarifications on consent for patients with limb dysfunction, coenrolment, IMP discontinuation and other points.

*Protocol version 2.0 was given CTA.

ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale Revised; CRF, case report form; CTA, Clinical Trial Authorisation; ECAS, Edinburgh Cognitive and Behavioural ALS Screen; IMP, investigational medicinal product; MND, motor neuron disease; PI, Principal Investigator.