Table 2 Part B cohort with infantile-onset SMA: efficacy summary

From: High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial

Outcome

 

Hierarchical test order

50/28 mg (n = 50)

12/12 mg (n = 25)

ENDEAR matched sham (n = 20)

LSM difference (95% CI)

P

CHOP-INTENDa

LSM rankingb

1

42.9

NA

16.9

26.06 (17.9 to 34.2)

<0.0001c

LSM change from baseline at day 183b

 

+15.1

NA

−11.1

26.19 (20.7 to 31.7)

<0.0001d

LSM ranking

5

38.3

37.3

NA

1.0 (−9.3 to 11.3)

0.8484c

LSM change from baseline at day 302

 

+19.6

+21.6

NA

–1.94 (–7.77 to 3.88)

0.5132d

HINE-2e

LSM ranking

3

43.1

NA

16.5

26.67 (18.8 to 34.5)

<0.0001c

LSM change from baseline at day 183

 

+3.7

NA

−0.2

3.9 (2.5 to 5.4)

<0.0001d

LSM ranking

6

40.0

33.9

NA

6.1 (−2.7 to 14.9)

0.1734c

LSM change from baseline at day 302

 

+5.9

+5.3

NA

0.58 (−1.89 to 3.04)

0.6454d

Responders at day 183f

2

58%

NA

0%

NA

<0.0001

NfLg

LSM rank accounting for death (day 183)

4

44.0

NA

14.4

29.58 (22.1 to 37.0)

<0.0001c

LSM rank accounting for death (day 64)

7

42.2

29.5

NA

12.74 (3.8 to 21.6)

0.0050c,h

     

LSGM ratio (95% CI)

 

LSGM ratio to baseline at day 183

4

0.06

NA

0.70

0.08 (0.05 to 0.14)

NA

LSGM ratio to baseline at day 64

7

0.12

0.23

NA

0.51 (0.33 to 0.78)

NA

 

Comparison

 

HR (95% CI)i

P

EFS

OS

50/28 mg versus ENDEAR matched sham

8

0.322 (0.158 to 0.657)

0.0006h,j

50/28 mg versus 12/12 mg

10

0.701 (0.338 to 1.452)

0.2775j

50/28 mg versus ENDEAR matched sham

9

0.279 (0.112 to 0.696)

0.0012h,j

50/28 mg versus 12/12 mg

11

0.730 (0.264 to 2.015)

0.4821j

  1. Outcomes and time points reflect the prespecified hierarchical testing (Extended Data Table 2). All P values were obtained from comparing the two treatment groups indicated per row. In the treatment columns, rankings, changes from baseline in actual scores and ratios are shown; the corresponding LSM differences and LSGM ratios correspond to the differences between treatments. The comparisons of EFS and OS were all pairwise; adjustment for multiplicity was handled by the hierarchical testing—none of the comparisons were considered statistically significant and are denoted by h. All statistical tests were two-sided. aResults shown are from MI and an ANCOVA model with adjustment for participants’ disease duration and baseline CHOP-INTEND score. The primary analysis was performed using ranking based on the CHOP-INTEND score at day 183 or day of death and fitting an ANCOVA model to determine the difference in ranks. bPrimary endpoint. cThe statistical test was a joint-rank test. dThe statistical test was an ANCOVA + MI. eResults shown are from MI and an ANCOVA model with adjustment for participants’ disease duration, baseline HINE-2 score and baseline CHOP-INTEND score. fHINE-2 responders were defined as a participants who demonstrated at least a two-point increase in their ability to kick (or increase to the maximal score on that category (touching toes)), or a one-point increase in the motor milestones category of head control, rolling, sitting, crawling, standing or walking, and demonstrated improvement in more categories than worsening across the seven motor milestone categories (with the exclusion of voluntary grasp). gMI was performed based on log-transformed plasma NfL. The results in the chart are from an ANCOVA model with adjustment for participants’ disease duration, baseline log plasma NfL and baseline CHOP-INTEND score. The comparisons between 50/28 mg and 12/12 mg, and between 50/28 mg and matched sham, were performed as separate analyses. In the table, the LSGM ratio from the ANCOVA is shown; the P value from the joint-rank test is also shown. hP considered nominally significant. iHR determined using a Cox proportional hazards model adjusting for disease duration and baseline CHOP-INTEND score. jP is from a log-rank test stratified according to disease duration (≤12 weeks or >12 weeks). For CHOP-INTEND, see Fig. 2a for 50/28 mg versus the ENDEAR match sham, and Extended Data Fig. 2 for 50/28 mg versus 12/12 mg. For the HINE-2, NfL, EFS and OS, see Extended Data Fig. 1, Fig. 2b,c and Extended Data Fig. 3, respectively. NA, not applicable.
Back to article page