Table 4 Intercurrent events for survival co-primary endpoint

A. Stopping riluzole during study

Riluzole will extend the life of patients by 2–3 months on average. Audit data suggest that 15–20% of participants will stop riluzole during the course of MND-SMART. As the trial is taking a pragmatic treatment policy approach, this event will be handled using a treatment policy strategy

B. Starting riluzole during study

As riluzole treatment is generally initiated close to diagnosis it is expected that few participants (< 10%) will start riluzole during MND-SMART. Again, as the trial is taking a pragmatic treatment policy approach, this event will be handled using a treatment policy strategy

C. Concomitant illness unrelated to MND condition

This may reduce survival compared to what it would be if the patient did not have the concomitant illness. A treatment policy strategy will be used to handle this event

D. Discontinuation of memantine due to intolerance or adverse event

These discontinuations will mostly occur early, in about 10% of participants, who will then continue in the study via telephone follow-up. The treatment policy perspective of MND-SMART means that a treatment policy strategy can be used to handle this event

E. Discontinuation of trazodone due to intolerance or adverse event

These discontinuations will mostly occur early, in about 15% of participants, who will then continue in the study via telephone follow-up. Will be addressed in the same way as Event D: treatment policy

F. Discontinuation of memantine due to lack of efficacy

The treatment policy strategy will be used, as this event is expected to be rare: perceived lack of efficacy withdrawal rare in literature (2% of withdrawals) as is progression (3% of withdrawals)

G. Discontinuation of trazodone due to lack of efficacy

The treatment policy strategy will be used, as this event is expected to be rare: perceived lack of efficacy withdrawal rare in literature (2% of withdrawals) as is progression (3% of withdrawals)

H. Use of memantine in placebo group

The treatment policy strategy will be used, as this event is expected to be extremely rare

I. Use of trazodone in placebo group

The treatment policy strategy will be used, as this event is expected to be extremely rare

J. Implementation of life extending treatment—gastrostomy

Enteral feeding—affects quality of life rather than survival and occurs in 10–20% of patients. Gastrostomy extends life by about 3 months based on data in Gorrie et al. al. [23] As the trial is taking a treatment policy perspective, this event will be handled by a treatment policy strategy

K. Implementation of life extending treatment—ventilation

Trachaeostomy extends life but is very rare. Non-invasive ventilation (NIV) via a mask is more common, occurring in 5% of patients soon after diagnosis and overall 10–20% would be expected over 18 months. NIV does not affect whether ALS-FRS-R can be measured. This event will be dealt with in the same way as Event J: treatment policy strategy