Table 3 Summary of prespecified primary and key secondary end points for (a) period 1 and (b) period 2

From: Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial

a, Period 1 results

End point

Order of hierarchy

Population

Modela

Garetosmab LS mean (s.e.m.)

Placebo LS mean (s.e.m.)

LS mean difference (95% CI)

P valueb

Primary: TWA of percent change from baseline in TLA by 18F-NaF PET over 28 weeks

1

AHO

ANCOVA

−8.1 (9.93)

16.6 (9.11)

−24.6 (−51.8, 2.5)

0.0741

Primary: percent change from baseline in total volume of HO lesions by CT at week 28

2

AHO

MMRM

7.1 (20.43)

32.0 (18.66)

−24.9 (−80.8, 30.9)

-

Primary: TWA of percent change from baseline in TLA by 18F-NaF PET over 28 weeks

3

AHOC

ANCOVA

−8.0 (10.14)

17.6 (9.73)

−25.6 (−53.9, 2.8)

-

Primary: percent change from baseline in total volume of HO lesions by CT at week 28

4

AHOC

MMRM

7.0 (20.87)

34.9 (19.90)

−27.8 (−86.1, 30.5)

-

Key secondary: TWA of change from baseline in daily average pain over 28 weeks

5

AHO

ANCOVA

−0.51 (0.231)

−0.17 (0.21)

−0.34 (−0.96, 0.27)

-

6

AHOC

ANCOVA

−0.48 (0.237)

−0.12 (0.22)

−0.36 (−1.01, 0.29)

-

b, Period 2 results (COVID-19 mITT analysis set)

End point

Order of hierarchy

Armc

n

Model

Period 1

Period 2

Comparison of period 1 versus period 2

P valued

Number of new HO lesions as assessed by CT at week 56 relative to week 28 scan

1

Placebo/garetosmab

22

Descriptive + Wilcoxon

Observed rate = 1

Total no. of lesions = 22

Observed rate = 0

Total no. of lesions = 0

Observed rate reduction = 100%

0.0039

–

Garetosmab/garetosmab

18

Descriptive

Observed rate = 0.11

Total no. of lesions = 2

Observed rate = 0

Total no. of lesions = 0

  

Total volume of new HO lesions as assessed by CT at week 56 relative to week 28 scan

2

Placebo/garetosmab

22

MMRM + Wilcoxon

LS mean 9.29 cm3

LS mean 0.05 cm3

LS mean difference, −9.24 (95% CI −17.96, −0.52)

0.0039

–

Garetosmab/garetosmab

18

Descriptive

Mean 1 cm3

Mean 0 cm3

  

Number of new HO lesions as assessed by 18F-NaF PET at week 56 relative to week 28 scan

3

Placebo/garetosmab

22

GEE + Wilcoxon

Adjusted rate 0.93 (95% CI 0.54, 1.62)

Total no. of lesions = 23

Adjusted rate 0.04 (95% CI 0.01, 0.31)

Total no. of lesions = 1

Adjusted rate ratio, 0.05 (95% CI 0.01, 0.33)

Rate reduction = 95%

0.0039

–

Garetosmab/garetosmab

18

Descriptive

Observed rate = 0.06

Total no. of lesions = 1

Observed rate = 0

Total no. of lesions = 1

  

TLA by 18F-NaF PET in new lesions at week 56 relative to week 28 scan

4

Placebo/garetosmab

22

MMRM + Wilcoxon

LS mean 204.45

LS mean 13.20

LS mean difference, −191.25 (95% CI −390.80, 8.29)

0.0273

–

Garetosmab/garetosmab

18

Descriptive

Mean 4.7

Mean 0

  

Percent of patients with new HO lesions as assessed by CT at week 56 relative to week 28

5

Placebo/garetosmab

22

Descriptive + McNemar

40.9 (9 of 22)

0 (0 of 22)

Observed relative risk reduction = 100%

0.0027

–

Garetosmab/garetosmab

18

Descriptive

11.1 (2 of 18)

0 (0 of 18)

  

Percent of patients with new HO lesions as assessed by PET at week 56 relative to week 28

6

Placebo/garetosmab

22

GEE + McNemar

40.9 (9 of 22)

4.5 (1 of 22)

Adjusted relative risk reduction = 89%

Adjusted odds ratio, 0.07 (95% CI 0.01, 0.48)

0.0047

–

Garetosmab/garetosmab

18

Descriptive

5.6 (1 of 18)

0 (0 of 18)

  
  1. aFor ANCOVA and MMRM, LS mean (s.e.m.) and LS mean differences (95% CI) are shown.
  2. bTesting of the primary and key secondary efficacy end points followed a hierarchical testing sequence only if statistical significance was established for all primary end points (P value < 0.05). The first primary end point was not statistically significant therefore only effect sizes and 95% CI were given for the other end points.
  3. cThe key statistical comparisons were based on within-group comparisons for the patients who were randomized to placebo in the double-blind period and crossed over to the garetosmab group in the open-label period (period 2). Those who received garetosmab for both periods are included in this table; however, they were not in the period 2 hierarchy.
  4. dTo control for the type I error rate at 0.10 for the primary and key secondary null hypotheses in period 2, a hierarchical testing procedure was applied at a two-sided 10% significant level (P values < 0.1 are considered statistically significant).
  5. 18F-NaF, fluorine-18-labeled sodium fluoride; AHO, patients with at least one active HO lesion at baseline; AHOC, patients with at least one active HO lesion at baseline and with classic ACVR1R206H mutation; ANCOVA, analysis of covariance; COVID-19 mITT, coronavirus disease 2019 modified intention to treat analysis set; GEE, general estimating equation; LS, least squares; MMRM, mixed model with repeated measures.
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