Grade A: Shown in a peer-reviewed publication to act on a relevant mechanism in humans

Grade B: Shown in a peer-reviewed publication to act on a relevant mechanism in pre-clinical model(s)

Grade C: Theoretically and plausibly acts on an ALS-relevant mechanism in humans

Grade D: Acts on a biological mechanism but it is not clear that this mechanism is relevant in ALS

Grade F: Implausible; would violate known principles or laws of biology

Grade U: No useful information was found for this category

Grade A: Two or more peer-reviewed publications reporting benefits in well-designed studies.

Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.

Grade B: One peer-reviewed publication reporting benefits in a well-designed study.

Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.

Grade C: One or more peer-reviewed publication(s) reporting benefits in flawed studies.

Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.

Grade D: One or more non-peer reviewed studies reporting benefits (published on a website or in an abstract)

Grade F: The only studies available show no benefit

Grade U: No useful information was found for this category

Grade A: One or more peer-reviewed publications reporting benefits with validated diagnosis and benefits

Grade B: More than one unpublished report of benefit with validated diagnosis and benefits

Grade C: One unpublished report of benefit with validated diagnosis and benefits

Grade D: Subjective report(s) of benefit without validated diagnoses and/or benefits

Grade F: The only reports available show no benefit

Grade U: No useful information was found for this category

Two or more peer-reviewed publications describing benefits in well-designed randomized, blinded placebo-controlled phase III trials

Grade C: One or more peer-reviewed publications reporting benefits in a well-designed randomized, blinded, placebo-controlled phase I or II trial

Grade D: One or more peer-reviewed publications reporting benefits in a flawed trial.

Flawed trials means those in which there are identifiable problems with patient selection, randomization, blinding, controls or follow-up. These have ‘high or unclear risk of bias’ according to published criteria. Well-designed trials are those that have ‘low risk of bias’.

Grade F: The only trials available show no benefit

Grade U: No useful information was found for this category

Grade A: No exposed patients appear to have experienced harms

Grade B: More than 0% but less than 10% of exposed patients experienced harms (no hospitalizations or deaths)

Grade B (oral): More than 0% but less than10% of exposed patients experienced harms (no hospitalizations or deaths)

Grade D (intravenous): More than 0% but less than 5% of exposed patients experienced death or hospitalizations

Grade C: At least 10% of exposed patients experienced harms (no hospitalizations or deaths)

Grade D: More than 0% but less than 5% of exposed patients experienced death or hospitalizations

Grade D: More than 0% but less than 5% of exposed patients experienced death or hospitalizations

Grade F: At least 5% of exposed patients experienced death or hospitalization

Grade F: At least 5% of exposed patients experienced death or hospitalization

Grade U: No useful information was found for this category