CI = confidence interval; COMPASS 31 = Composite Autonomic Symptom Score 31; HRQoL = health-related quality of life; LS = least squares; mNIS+7 = modified Neuropathy Impairment Score +7; NA = not applicable; Norfolk QoL-DN = Norfolk Quality of Life–Diabetic Neuropathy; NR = not reported; PND = polyneuropathy disability; RCT = randomized controlled trial; R-ODS = Rasch-built Overall Disability Score; SD = standard deviation; SE = standard error; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the following footnotes.

There was a risk of bias due to the open-label study design and the subjective nature of the outcome. The open-label study design may have biased measurement scores due to knowledge of assigned treatment, although the direction of the potential bias is unclear. The HELIOS-A study implemented integrity strategies for the mNIS+7 and Norfolk QoL-DN measures to mitigate any potential bias. The CADTH review team did not rate down for risk of bias, as, according to the CADTH review team’s judgment, the potential risk of bias arising from the open-label study design did not warrant rating down to “very low” certainty.

Imprecision was not rated down. No known threshold was identified but according to the clinical expert consulted by CADTH for the review, a 4-point difference between groups in the R-ODS score could be considered clinically meaningful. The CADTH review team judged that the effect estimate as well as both lower and upper boundaries of the 95%CI of the between-group difference exceeded the threshold and suggested a benefit. Despite the small sample size, the clinical expert consulted by CADTH judged the observed benefit with vutrisiran against placebo to be plausible and in line with what is observed with the comparator patisiran, with whom vutrisiran shares the same mechanism of action.

Imprecision was not rated down. There is no known threshold and the clinical expert consulted by CADTH could not provide a threshold of important difference, so the null was used. The CADTH team judged that the point estimate and both the lower and upper boundaries of the 95% CI of the between-group comparison suggested a possibility of benefit. The treatment effect estimates observed in a small study sample may not be replicable in a larger study sample. However, the clinical expert consulted by CADTH judged the observed benefit with vutrisiran against placebo to be plausible and in line with what is observed with the comparator patisiran, with whom vutrisiran shares the same mechanism of action.

Imprecision was not rated down. A threshold of 8.8 was identified in the literature. The CADTH review team judged that the effect estimate as well as both lower and upper boundaries of the 95%CI of the between-group difference exceeded the threshold and suggested a benefit. Despite the small sample size, the clinical expert consulted by CADTH judged the observed benefit with vutrisiran against placebo to be plausible and in line with what is observed with the comparator patisiran, with whom vutrisiran shares the same mechanism of action.

Rated down 1 level for serious imprecision. There is no known threshold and the clinical expert consulted by CADTH could not provide a threshold of important difference. In the absence of a known threshold, the null was used. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the lower bound of the 95% CI for the difference between groups suggested a possibility of little to no difference.

The HELIOS-A study used an external control (placebo group in the APOLLO trial) in comparison to the vutrisiran group in the HELIOS-A trial. This observational comparison introduced the potential for bias resulting from confounding and selection bias and the certainty of evidence was started at low.

This analysis was not part of the sponsor's statistical analysis plan and was requested by CADTH to facilitate a certainty of evidence appraisal.

Rated down 1 level for serious indirectness due to insufficient duration of follow-up for the outcome according to clinical expert input.