Summary of findings 4. Inotersen compared to placebo for people with transthyretin‐familial amyloid polyneuropathy (TTR‐FAP).

Inotersen compared to placebo for people with transthyretin‐familial amyloid polyneuropathy (TTR‐FAP)
Patient or population: people with TTR‐FAP Setting: outpatient Intervention: inotersen Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with inotersen
Disability due to FAP progression Not measured	‐	‐	‐	‐	‐	Disability due to FAP progression was not measured.
Severity of peripheral neuropathy (expressed as the change in mNIS+7Ionis) Scale from: ‐22.3 (normal) to 346.3 (total impairment) Follow‐up: 66 weeksa	The mean baseline mNIS+7Ionis score in the placebo group was 74.8 points. The mean change from baseline in the placebo group was an increase (worsening) of 23.89 pointsb	The mean change in mNIS+7Ionis score in the inotersen group was 19.73 points lower (better) than in the placebo group (26.50 lower to 12.96 lower)b	‐	172 (1 RCT)	⊕⊕⊕⊝ Moderatec	The MCID detectable is 2 points. Inostersen probably reduces the worsening of peripheral neuropathy compared to placebo.
Quality of life (expressed as the change in 35‐Item Norfolk QOL‐DN total score) Scale from: ‐4 (best possible quality of life) to 136 (worst possible quality of life) Follow‐up: 66 weeksa	The mean baseline Norfolk QOL score in the placebo group was 48.7 points. The mean change from baseline in the placebo group was an increase (worsening) of 10.77 pointsb	The mean change in Norfolk QOL score in the inotersen group was 10.85 points lower (better) than in the placebo group (17.25 lower to 4.45 lower)b	‐	172 (1 RCT)	⊕⊕⊝⊝ Lowd	MICD not provided nor reported in the literature. Inotersen may have little effect on the change in QOL.
Number of participants who died during the trial Follow‐up: 66 weeksa	Study population		RR 5.94 (0.33 to 105.60)	172 (1 RCT)	⊕⊕⊝⊝ Lowe	The number of participants who died during the trial may be greater in the inotersen group than in the placebo group.
	0/60 deaths	5/112 deaths
Number of dropouts due to adverse events Follow‐up: 66 weeksa	Study population		RR 8.57 (1.16 to 63.07)	172 (1 RCT)	⊕⊕⊝⊝ Lowf	The number of dropouts due to adverse events may be greater in the inotersen group than the placebo group.
	2 per 100	14 per 100 (2 to 100)
Number of participants experiencing at least one severe adverse event Follow‐up: 66 weeksa	Study population		RR 1.48 (0.85 to 2.57)	172 (1 RCT)	⊕⊕⊝⊝ Lowe	The number of participants experiencing at least one severe adverse event may be greater in the inotersen group than in the placebo group.
	22 per 100	32 per 100 (18 to 56)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FAP: familial amyloid polyneuropathy; MCID: minimum clinically important difference; mNIS+7Ionis: modified Neuropathy Impairment Score plus 7 nerves test (Ionis version); QOL‐DN: Quality of Life‐Diabetic Neuropathy Questionnaire; RCT: randomised clinical trial; RR: risk ratio; TTR: transthyretin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^aEnd of the study.
 ^bMean change from baseline and mean differences between groups refer to least‐squares means and least‐squares mean differences, respectively.
 ^cWe downgraded the certainty of evidence by one level for serious imprecision.
 ^dWe downgraded the certainty of evidence by one level for serious imprecision and by one level for serious indirectness (mechanisms by which this intervention would affect QOL are not direct).
 ^eWe downgraded the certainty of evidence by two levels for very serious imprecision (small event numbers and CI includes the possibility of both harms and benefits).
 ^fWe downgraded the certainty of evidence by two levels for very serious imprecision (small event numbers and wide CI).