Summary of findings for the main comparison. Intrathecal injected nusinersen compared to sham procedure for infants with SMA and 2 SMN2 copies.
| Intrathecal injected nusinersen compared to sham procedure for infants with SMA and 2 SMN2 copies | ||||||
| Patient or population: infants with SMA and 2 SMN2 copies Setting: in‐hospital treatment for outpatient clinic Intervention: intrathecal injected nusinersen Comparison: sham procedure | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with sham procedure | Risk with intrathecal injected nusinersen | |||||
| Time from birth until death or full‐time ventilationa Follow‐up: range 6 months to 13 monthsc | Study population | HR 0.53 (0.32 to 0.89) | 121 (1 RCT) | ⊕⊕⊕⊝ Moderateb | This represents a 47% lower risk of death or full‐time ventilation with nusinersen than with the sham procedure | |
| 68 per 100 | 46 per 100 (31 to 64) | |||||
| Acquisition of head control within one year after the onset of treatment Follow‐up: range 6 months to 13 monthsc | 0 of 37 participants | 16 of 73 participants in the nusinersen‐treated group achieved head control | RR 16.95 (1.04 to 274.84) | 110 (1 RCT) | ⊕⊕⊝⊝ Moderated | |
| Acquisition of the ability to sit within one year after the onset of treatment Follow‐up: range 6 months to 13 monthsc | 0 of 37 participants | 6 of 73 participants in the nusinersen‐treated group achieved the ability to sit independently |
RR 6.68 (0.39 to 115.38) |
110 (1 RCT) | ⊕⊕⊝⊝ Moderated | |
| Acquisition of the ability to stand within one year after the onset of treatment Follow‐up: range 6 months to 13 monthsc | 0 of 37 participants in the sham procedure group | 1 of 73 participants in the nusinersen‐treated group achieved the ability to stand |
RR 1.54 (0.06 to 36.92) |
110 (1 RCT) | ⊕⊕⊝⊝ Moderated | |
| Change in motor disability score ‐ response on HINE‐2 within one year after the onset of treatmente Follow‐up: range 6 months to 13 months | 0 of 37 participants in the sham procedure group | 37 of 73 participants in the nusinersen‐treated group showed a motor milestone response on the HINE‐2 | RR 38.51 (2.43 to 610.14) | 110 (1 RCT) | ⊕⊕⊝⊝ Moderated | |
|
Adverse events attributable to treatment Measured as adverse events (all) Follow‐up: range 6 months to 13 months |
Study population |
RR 0.99 (0.92 to 1.05) |
121 (1 RCT) | ⊕⊕⊕⊝ Moderatef | Including bleeding risk from thrombocytopenia, renal toxicity, hyponatraemia, reduced growth, rash and possible (cerebral) vasculitis, hepatotoxicity, QTc interval prolongation on electrocardiogram, aspiration, infections, gastrointestinal problems | |
| 976 per 1000 |
966 per 1000 (898 to 1000) |
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|
Severe adverse events attributable to treatment Measured as severe adverse events (all) Follow‐up: range 6 months to 13 months |
Study population |
RR 0.70 (0.55 to 0.89) |
121 (1 RCT) | ⊕⊕⊕⊝ Moderatef | Including respiratory problems, cardiorespiratory arrest, death, brain injury, hypoxic ischaemic encephalopathy | |
| 805 per 1000 |
563 per 1000 (443 to 716) |
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| *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). CHOP INTEND: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE‐2: Hammersmith Infant Neurological Examination‐Section 2; CI: confidence interval; HR: hazard ratio; RCT: randomised controlled trial; RR: risk ratio; SMA: spinal muscular atrophy | ||||||
| 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. | ||||||
aDefined as a requirement for 16 hours of ventilation per day regardless of whether via tracheostomy, tube or mask. bWe downgraded the certainty of the evidence once for risk of bias and imprecision (not sufficient to downgrade once for each). A slight baseline imbalance meant that children in the nusinersen‐treated group had an earlier onset and were more severely affected by respiratory and bulbar problems. This baseline imbalance in factors related to respiratory decline would tend to favour the control intervention for this outcome. Although the effect of nusinersen is large, there is some degree of uncertainty in the effect estimate arising from imprecision in a single study of this size. cBased on the final analysis. An interim analysis of motor milestones (HINE‐2) was performed on all participants who had a day 183 visit. The study was then stopped for significant benefit from nusinersen. Final analysis was performed on data including participants fulfilling at least six months of trial enrolment. dWe downgraded the certainty of the evidence once for risk of bias and imprecision (not sufficient to downgrade once for each). There was slight baseline imbalance and there is some degree of uncertainty in the effect estimate arising from imprecision in a single study of this size. We did not downgrade the motor milestone outcome results further for imprecision, in spite of wide CI. The absence of events in the control group is consistent with the natural history of SMA type 1 and a response represents a large treatment effect. eResponse was defined according to scores on the HINE‐2, which assesses the development of motor function through the achievement of motor milestones; in this trial, the scores accounted for 7 of the 8 motor milestone categories, excluding voluntary grasp. Infants were considered to have a motor milestone response if they met the following two criteria: improvement in at least one category (i.e. an increase in the score for head control, rolling, sitting, crawling, standing, or walking of ≥ 1 point, an increase in the score for kicking of ≥ 2 points, or achievement of the maximal score for kicking) and more categories with improvement than categories with worsening (i.e. a decrease was defined as ≥ 1 point decrease in the score for head control, rolling, sitting, crawling, standing, or walking and a decrease in the score for kicking was defined as a decrease of ≥ 2 points). fWe downgraded one level for imprecision because the small sample size and shortened study duration mean that the study is unlikely to have captured uncommon adverse events.