Study Design

A Phase 3, 24-week, randomized, double-blind, placebo-controlled, two-arm study evaluating efficacy and safety of SYMDEKO (N=504)1,2

24 weeks

SYMDEKO (n=248)
Placebo (n=256)
  • Patients were randomized to receive either tezacaftor/ivacaftor 100 mg/150 mg qd and ivacaftor 150 mg qd 12 hours apart or placebo q12h with fat-containing food, in addition to their currently prescribed CF therapies
Study Population
  • Selected inclusion criteria1,2

    • Confirmed CF diagnosis and clinically stable
    • Patients ≥12 years of age (mean age, 26.3 years) and homozygous for the F508del mutation
    • Percent predicted FEV1 (ppFEV1) ≥40% and ≤90% at screening (mean baseline ppFEV1, 60.0)
  • Selected exclusion criteria1

    • History of colonization with organisms associated with a more rapid decline in pulmonary status, such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus
    • Two or more abnormal liver function tests at screening (ALT, AST, AP, GGT ≥3 x ULN or total bilirubin ≥2 x ULN), or AST or ALT ≥5 x ULN
Endpoints
  • Primary endpoint1

    • Mean absolute change in ppFEV1 from baseline through Week 24
  • Key secondary endpoints1,2

    • Relative change in ppFEV1 from baseline through Week 24
    • Number of pulmonary exacerbations from baseline through Week 24*
    • Absolute change in BMI from baseline at Week 24
    • Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain score from baseline through Week 24
  • A hierarchical testing procedure was used for the primary and key secondary endpoints. For an endpoint to be significant, both it and all previous tests in the hierarchy had to achieve P<0.051,3

*A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre‑specified sino-pulmonary signs/symptoms.

ALT, alanine transaminase; AST, aspartate transaminase; AP, alkaline phosphatase; BMI, body mass index; GGT, gamma-glutamyl transferase; IV, intravenous; q12h, every 12 hours; qd, once a day; ULN, upper limit of normal.

Primary endpoint: Mean absolute change in ppFEV11,2

4.0 PERCENTAGE POINTS SIGNIFICANT IMPROVEMENT VS PLACEBO

in mean absolute change in ppFEV1 from baseline through Week 24 (95% CI: 3.1, 4.8; P<0.0001)1,2

EVOLVE (Trial 1)

Changes in ppFEV1 from baseline vs placebo through Week 241,3,4,a

Subgroups by baseline ppFEV1

Absolute change in ppFEV1 from baseline

(percentage points)
<40%
(SYMDEKO n=23; placebo n=24; range 27.8% to <40%)
+3.5
(95% CI: 1.0, 6.1)
≥40 to <70%
(SYMDEKO n=156; placebo n=152)
+4.2
(95% CI: 3.1, 5.2)
≥70%
(SYMDEKO n=66; placebo n=80; range ≥70% to 96.2%)
+3.7
(95% CI: 2.2, 5.2)
  1. In EVOLVE, while ppFEV1 at screening was 40-90%, changes may have occurred before baseline.1,2
  • Improvements in mean absolute change in ppFEV1 vs placebo across pre-specified subgroups were observed regardless of age, sex, baseline ppFEV1, colonization with Pseudomonas, and concomitant use of standard-of-care medications for CF1

Key secondary endpoint: Relative change in ppFEV11

6.8 Percent Significant Improvement VS Placebo

in relative change in ppFEV1 from baseline through Week 24 (95% CI: 5.3, 8.3; P<0.0001)1

Key secondary endpoint: Number of pulmonary exacerbations1,2

Annualized rate of pulmonary exacerbations through week 24

Pulmonary exacerbations: Additional analyses

  • 47% reduction in rate of pulmonary exacerbations requiring treatment with IV antibiotics vs placebo (RR: 0.53, 95% CI: 0.34, 0.82), not statistically significant5,b

  • The rate ratio for risk of pulmonary exacerbations requiring hospitalizations vs placebo was 0.78 (95% CI: 0.44, 1.36), not statistically significant5,b

bEstimated event rate per year calculated using 48 weeks per year.3

Key secondary endpoint: Absolute change in body mass index (BMI)

+0.06 kg/m2 in the SYMDEKO group vs placebo at Week 24 (95% CI: -0.08, 0.19) (not statistically significant)1,2,c

cPlacebo baseline BMI: 21.12 kg/m2; SYMDEKO baseline BMI: 20.96 kg/m2.2

Key secondary endpoint: Absolute change in CFQ-R Respiratory Domain score

5.1 point increase vs placebo

in absolute change from baseline through Week 24 (95% CI: 3.2, 7.0) (not statistically significant due to testing hierarchy)1,2,d

  • CFQ-R Respiratory Domain score evaluated respiratory symptoms including cough, sputum production, and difficulty breathing6

dThe MCID threshold for CFQ-R Respiratory Domain scores is 4 points in patients with CF with stable respiratory symptoms, which is the minimal change a patient can detect.7

CFQ-R, Cystic Fibrosis Questionnaire-Revised; CI, confidence interval; IV, intravenous; LS, least squares; MCID, minimal clinically important difference; ppFEV1, percent predicted forced expiratory volume in 1 second; RR, relative risk.