TRIAL 1: A double-blind, placebo-controlled, Phase 3 trial in patients heterozygous for F508del and a specific mutation1,2

Study Design

RANDOMIZED

1:1

BASELINE

WEEK 24a

TRIKAFTATM
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)
200 mg/100 mg/150 mg qam and 150 mg qpm with fat-containing food (N=200)

Placebo
q12h with fat-containing food (N=203)

WEEK 4
(primary endpoint)

All patients remained on their standard-of-care CF therapies.1

aAll patients who completed the study were eligible to roll over into a 96-week, open-label extension study.1

 

Key inclusion criteria1,2b

  • Confirmed CF diagnosis, clinically stable, at least 12 years of age
  • Heterozygous for F508del and one of ~200 other mutations in the CFTR gene that resulted in either:
    • No CFTR protein
    • A CFTR protein that lacks baseline activity and is not responsive to ivacaftor and tezacaftor/ivacaftor
  • ppFEV1 between 40% and 90% at screening

bKey exclusion criteria included clinically significant cirrhosis with or without portal hypertension, a history of colonization with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus), and solid organ or hematologic transplantation.1,2

 

Primary endpoint1

  • Absolute change in ppFEV1 at Week 4
    • Preplanned interim analysis was conducted after ≥140 patients completed the Week 4 visit and ≥ 100 patients completed the Week 12 visit
    • There were 403 patients included in the preplanned interim analysis at Week 4

SELECTED KEY SECONDARY ENDPOINTS1c

FROM BASELINE THROUGH WEEK 24:

  • Absolute change in ppFEV1
  • Number of pulmonary exacerbationsd
  • Absolute change in sweat chloride
  • Absolute change in CFQ-R Respiratory Domain score

FROM BASELINE AT WEEK 24:

  • Absolute change in BMI

FROM BASELINE AT WEEK 24:

  • Absolute change in CFQ-R Respiratory Domain score

ᶜA hierarchical testing procedure was performed for key secondary endpoints. For an endpoint to be significant, both it and all previous tests in the hierarchy had to achieve P<0.05.2 
ᵈIn the trial, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 prespecified sinopulmonary signs/symptoms.1

 

Baseline characteristics in Trial 13
TRIKAFTA
Placebo
Sex, female, %
48.0
48.3
Mean age, years (range)
25.6 (12.1-59.9)
26.8 (12.3-64.0)
Mean BMI, kg/m2 (range)
21.49 (15.01-30.86)
21.31 (14.42-33.80)
Mean ppFEV1 (range)
61.6 (33.8-97.1)
61.3 (32.3-93.7)
Mean SwCI, mmol/L (range)
102.3 (22.5-156.0)
102.9 (68.5-137.0)
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Summary of Efficacy Results

Significant improvement in lung function at Week 4, sustained through Week 241

PRIMARY ENDPOINT

ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE AT WEEK 4

13.8

Percentage
Points

SIGNIFICANT IMPROVEMENT VS PLACEBO

in mean absolute change in ppFEV1 from baseline at Week 4 based on preplanned interim analysis (95% CI: 12.1, 15.4; P<0.0001)

SECONDARY ENDPOINT

Absolute Change in ppFEV1 from Baseline Through Week 241 

Increase

14.3

Percentage
Points

IMPROVEMENT VS PLACEBO
based on the average of Weeks 4, 8, 12, 16, and 24 
(95% CI: 12.7, 15.8; P<0.0001)

  • Improvements in ppFEV1 were seen regardless of age, ppFEV1 at baseline, geographic region, and sex1 

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Reduction in rate of pulmonary exacerbations through Week 241 

SECONDARY ENDPOINT

Annualized Rate of Pulmonary Exacerbationse

Decrease

63%

REDUCTION THROUGH WEEK 24
(Rate ratio: 0.29, [95% CI: 0.25, 0.55]; P<0.0001)

The number of pulmonary exacerbations is expressed as a rate over 48 weeks based on 24 weeks of observation.

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ADDITIONAL ENDPOINTS4,5

71%

REDUCTION in event Rate leading to HOSPITALIZATION (32 events for placebo vs 9 events for TRIKAFTA [Rate ratio: 0.29, 95% CI: 0.14, 0.61])

78%

REDUCTION in event RATE leading to IV ANTIBIOTIC USE (51 events for placebo vs 11 events for TRIKAFTA [Rate ratio: 0.22, 95% CI: 0.11, 0.43])

  • Power for additional endpoints was limited. Analysis of additional endpoints was not adjusted for multiplicity. These additional endpoints are not included in the TRIKAFTA full Prescribing Information
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Significant reduction in sweat chloride through Week 241,4 

SECONDARY ENDPOINT

Mean Absolute Change in Sweat Chloride

Decrease

41.8

mmol/L REDUCTION
vs placebo through Week 24 (95% CI: -44.4, -39.3; P<0.0001)

vs placebo through Week 24 (95% CI: -44.4, -39.3; P<0.0001)

Sweat chloride levels may not correlate with improvements in lung function (ppFEV1).

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Significant improvement in CFQ-R Respiratory Domain score at Week 4, maintained through Week 241,4

SECONDARY ENDPOINT

ABSOLUTE CHANGE FROM BASELINE IN CFQ-R RESPIRATORY DOMAIN SCORE THROUGH WEEK 24

Increase

20.2

POINTS IMPROVEMENT
vs placebo through Week 24 (95% CI: 17.5, 23.0; P<0.0001)

vs placebo through Week 24 (95% CI: 17.5, 23.0; P<0.0001)

  • Significant improvement in CFQ-R Respiratory Domain score was seen as early as Week 4
    •  20.1-point improvement vs placebo (95% CI: 16.9, 23.2; P<0.0001)

The MCID threshold for CFQ-R Respiratory Domain score is 4 points in patients with CF with stable respiratory symptoms and represents the minimal change a patient can detect.6

CFQ-R Respiratory Domain score measured composite patient-reported outcomes in the following respiratory symptoms7: 

  • Waking up from coughing
  • Wheezing
  • Coughing
  • Congestion
  • Difficulty breathing
  • Mucus production

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Significant increase in BMI at Week 241,4

SECONDARY ENDPOINT

ABSOLUTE CHANGE FROM BASELINE IN BMI

Increase

1.0

kg/m2 INCREASE VS PLACEBO AT WEEK 24
(95% CI: 0.85, 1.23; P<0.0001)

(95% CI: 0.85, 1.23; P<0.0001)

  • For example, if a patient weighs 130 lbs and is 5'5" tall, then a 1.0-kg/m2 absolute change in BMI is equivalent to a 6-lb increase in weight.

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BMI, body mass index; CF, cystic fibrosis; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CFTR, cystic fibrosis transmembrane conductance regulator; CI, confidence interval; IV, intravenous; LS, least squares; MCID, minimal clinically important difference; ppFEV1, percent predicted forced expiratory volume in 1 second; q12h, every 12 hours; qam, every morning; qpm, every evening; RR, rate ratio, SE, standard error; SwCl, sweat chloride; WK, week.