Clinical Trials for 6 Years or Older

6 Years to 11 Years (Trial 2)

6+ Years (Trial 4)

6+ Years (Trial 5)

Components

TRIAL 2 (ENVISION): Patients with CF age 6 to <12 with a G551D mutation. KALYDECO® (ivacaftor): Efficacy results include significant improvement in lung function1,2

ON THIS PAGE: Study Design | Summary of Results 

Mutation Eligible for Study1 (mutation in bold was enrolled)
G551D

 

STUDY DESIGN1

  • Trial 2 was a 48-week, Phase 3, randomized, double-blind, placebo-controlled trial (N=52) in patients with CF age 6 to 11 years (mean age: 9 years) and a G551D mutation 
  • Patients had to have FEV1 40%-105% predicted at screening [mean FEV1 84% predicted at baseline (range: 44%-134%)]
  • Patients received KALYDECO 150 mg or placebo every 12 hours with fat-containing food, in addition to their prescribed CF therapies. Use of hypertonic saline was not permitted 

Primary endpoint1: Improvement in lung function as determined by the mean absolute change from baseline in ppFEV1 through Week 24

Other efficacy endpoints1: Absolute change in ppFEV1 through Week 48, improvement from baseline in CFQ-R Respiratory Domain score through Weeks 24 and 48, absolute change from baseline in body weight at Weeks 24 and 48, and absolute change from baseline in sweat chloride concentration through Weeks 24 and 48


 

SUMMARY OF RESULTS1,2

Improvements in ppFEV1 vs placebo were seen at the first post-baseline visit and persisted through 48 weeks1,2

lungs

Treatment difference through:

First Column

24 weeks (primary endpoint)1,2,a

+12.5 points

(95% CI: 6.6, 18.3; P<0.0001)

Second Column

48 weeks (secondary endpoint)1,2,a 

+10.0 points

(95% CI: 4.5, 15.5; P<0.001)


 

chart

aTreatment difference = effect of KALYDECO – effect of placebo.1

Primary endpoint was assessed through 24 weeks for Trial 2 and was based on a mixed-effects model for repeated measures (MMRM).1,2 
CFQ-R, Cystic Fibrosis Questionnaire-Revised; SEM, standard error of the mean.


Other efficacy endpoints1 

score

CFQ-R RESPIRATORY DOMAIN SCORE
Treatment difference through:

First Column

24 weeksa 

+6.1 points (95% CI: -1.4, 13.5; not statistically significant)

Second Column

48 weeksa

+5.1 points (95% CI: -1.6, 11.8; not statistically significant)

  • CFQ-R Respiratory Domain score evaluated relevant CF respiratory symptoms including cough, sputum production, and difficulty breathing1
scale

BODY WEIGHT
Treatment difference at:

First Column

24 weeksa 

+1.9 kg (95% CI: 0.9, 2.9; P=.0004)

Second Column

48 weeksa

+2.8 kg (95% CI: 1.3, 4.2; P=.0002)
 

sweat

SWEAT CHLORIDE (pharmacodynamic measure)
Treatment difference through:

First Column

24 weeksa 

−54 mmol/L (95% CI: -62, -47; P<.0001)

Second Column

48 weeksa

−53 mmol/L (95% CI: -61, -46; P<.0001)

  • There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1)1 

aTreatment difference = effect of KALYDECO – effect of placebo.1
 

The risk of pulmonary exacerbations was not analyzed in Trial 2 due to low incidence of events.1

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Components

TRIAL 4 (KONNECTION): Patients with CF age 6 years and older. KALYDECO® (ivacaftor): Significant improvements demonstrated for the overall population with eligible mutations1,2 


Mutations Eligible for Study1 (mutations in bold were enrolled)
G1244E, G1349D, G178R, G551S, G970R*, S1251N, S1255P, S549N, or S549R

 

*KALYDECO is not indicated for use in patients with a G970R mutation

*Based on the clinical and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established.

 

STUDY DESIGN1

  • Trial 4 was a Phase 3, two-part, randomized, double-blind, placebo-controlled, crossover-design trial (two 8-week treatment periods separated by a 4- to 8-week washout period; N=39) in patients with CF age 6 years and older (mean age: 23 years)
    • Patients had either a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation
  • Patients had to have FEV1 ≥40% predicted at screening [mean FEV1 78% predicted at baseline (range: 43%-119%)]
  • Patients received KALYDECO 150 mg or placebo every 12 hours with fat-containing food, in addition to their prescribed CF therapies 

Primary endpoint1: Improvement in lung function as determined by the mean absolute change from baseline in ppFEV1 through 8 weeks

Other endpoints1: Absolute change from baseline in: BMI at 8 weeks, improvement in CFQ-R Respiratory Domain score through 8 weeks, and sweat chloride concentration through 8 weeks
 


 

SUMMARY OF RESULTS2

Significant improvements in ppFEV1 were maintained through 8 weeks of treatment2 
 

There was a high degree of variability of efficacy responses among the 9 mutations studied1

 

chart

 

Adapted with permission from De Boeck K et al. J Cyst Fibros. 2014;13:674-680.

  • For individual mutations, mean increases in ppFEV1 ranged from +3% points to +20% points at Week 81
  • Based on the clinical and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established1
     

 

There was a high degree of variability of responses among the 9 mutations studied1,2

scale
First Column

BMI

Treatment difference at 8 weeksa

+0.66 kg/m2 

(95% CI: 0.34, 0.99; P<.0001)

Second Column
  • Mean increases ranged from   
    +0.16 kg/m2 to +1.62 kg/m2 at Week 8
score
First Column

CFQ-R RESPIRATORY DOMAIN SCORE

Treatment difference through 8 weeksa 

+9.6 points 

(95% CI: 4.5, 14.7; P=.0004)

Second Column
  • CFQ-R Respiratory Domain score evaluated relevant CF respiratory symptoms including cough, sputum production, and difficulty breathing 
  • Mean increases ranged from +1.4 points to +23.3 points at Week 8 
sweat
First Column

SWEAT CHLORIDE1,2

Treatment difference through 8 weeksa

−49 mmol/L 

(95% CI: -57, -41; P<.0001)

Second Column
  • There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1)
  • Reductions ranged from -80 mmol/L to -6 mmol/L at Week 8

aTreatment difference = effect of KALYDECO – effect of placebo.1
*Reflects results from the 1 patient with the G551S mutation with data at the 8-week time point.

See the full Prescribing Information for complete results by mutation.

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Components

TRIAL 5 (KONDUCT): Patients with CF age 6 years and older. 
Results with KALYDECO® (ivacaftor) in patients with the R117H mutation1,2

 

Mutation Eligible for Study1 (mutation in bold was enrolled)
R117H
 

STUDY DESIGN1

  • Trial 5 was a 24-week, Phase 3, randomized, double-blind, placebo-controlled, parallel-group trial in patients with CF age 6 years and older (mean age: 31 years) who had an R117H mutation
  • Patients age 12 years and older had to have FEV1 40%-90% predicted at screening; patients age 6 to 11 years had to have FEV1 40%-105% predicted at screening; mean FEV1 73% predicted at baseline (range: 33%-106%)
  • Patients received KALYDECO 150 mg or placebo every 12 hours with fat-containing food, in addition to their prescribed CF therapies
  • Subgroups analyzed were based on age, lung function, and poly-T status

Primary endpoint1: Improvement in lung function as determined by the mean absolute change from baseline in ppFEV1 through 24 weeks

Other efficacy endpoints1Absolute change in BMI at Week 24, CFQ-R Respiratory Domain score through Week 24, time to first pulmonary exacerbation, and absolute change in sweat chloride from baseline through Week 24


SUMMARY OF RESULTS1

Overall change in ppFEV1 through Week 24, 2.1 percentage points (N=69), was not statistically significant1 
 

Absolute Change in ppFEV1 Through Week 241,a
SUBGROUP PARAMETER TREATMENT ARM n MEAN TREATMENT DIFFERENCE
(95% CI)
R117H
all patients
Placebo 35 0.5 2.1 (-1.1, 5.4)
KALYDECO 34 2.6
SUBGROUP BY AGE (YEARS)
6-11 Placebo 8 3.5 -6.3 (-12.0, -0.7)
KALYDECO 9 -2.8
2-17 Placebo 1 - -
KALYDECO 1 -
>18 Placebo 26 -0.5 5.0 (1.1, 8.8)
KALYDECO 24 4.5
SUBGROUP BY POLY-T STATUSb
5T Placebo 24 0.7 5.3 (1.3, 9.3)
KALYDECO 4 6.0
7T Placebo 5 -0.9 0.2 (-8.1, 8.5)
KALYDECO 11 -0.7
SUBGROUP BY BASELINE ppFEV1
<70% Placebo 15 0.4 4.0 (-2.1, 10.1)
KALYDECO 13 4.5
70%–90% Placebo 14 0.2 2.6 (-2.3, 7.5)
KALYDECO 14 2.8
>90% Placebo 6 2.2 -4.3 (-9.9, 1.3)
KALYDECO 7 -2.1

 

Absolute Change in ppFEV1 Through Week 241,a
Subgroup parameter R117H
all patients
Treatment arm Placebo KALYDECO
n 35 34
Mean 0.5 2.6
Treatment Difference
(95% Cl)
2.1 (-11, 5.4)
SUBGROUP BY AGE (YEARS)
Subgroup parameter 6-11
Treatment arm Placebo KALYDECO
n 8 9
Mean 3.5 -2.8
Treatment Difference
(95% Cl)
-6.3 (-12.0, -0.7)
Subgroup parameter 12-17
Treatment arm Placebo KALYDECO
n 1 1
Mean - -
Treatment Difference
(95% Cl)
-
Subgroup parameter >18
Treatment arm Placebo KALYDECO
n 26 1
Mean 24 4.5
Treatment Difference
(95% Cl)
5.0 (1.1, 8.8)
SUBGROUP BY POLY-T STATUSb
Subgroup parameter 5T
Treatment arm Placebo KALYDECO
n 24 14
Mean 0.7 6.0
Treatment Difference
(95% Cl)
5.3 (1.3, 9.3)
Subgroup parameter 7T
Treatment arm Placebo KALYDECO
n 5 11
Mean -0.9 -0.7
Treatment Difference
(95% Cl)
0.2 (8.1, 8.5)
SUBGROUP BY BASELINE ppFEV1
Subgroup parameter <70%
Treatment arm Placebo KALYDECO
n 15 13
Mean 0.4 4.5
Treatment Difference
(95% Cl)
4.0 (-2.1, 10.1)
Subgroup parameter 70%-90%
Treatment arm Placebo KALYDECO
n 14 14
Mean 0.2 2.8
Treatment Difference
(95% Cl)
2.6 (-2.3, 7.5)
Subgroup parameter >90%
Treatment arm Placebo KALYDECO
n 6 7
Mean 2.2 -2.1
Treatment Difference
(95% Cl)
-4.3 (-9.9, 1.3)

aMMRM analysis with fixed effects for treatment, age, week, baseline value, treatment by week, and subject as a random effect.
bPoly-T status confirmed by genotyping (n=54).


 

Results for other efficacy endpoints studied in Trial 51,2

weight

BODY WEIGHT

Treatment difference at 24 weeksc

+0.3 kg/m2

(95% CI: −1.57, 2.10; not statistically significant)

score
First Column

CFQ-R RESPIRATORY DOMAIN SCORE

Treatment difference through 24 weeksc

+8.4 points  

(95% CI: 2.2, 14.6; P=.009*)

*p-values are nominal

Second Column
  • CFQ-R Respiratory Domain score evaluated relevant CF respiratory symptoms, including cough, sputum production, and difficulty breathing
  • Results ranged from −6.1 to +15.3 points
exacerbations

RELATIVE RISK OF PULMONARY EXACERBATION

Treatment difference through 24 weeksc

7% reduction (HR, 0.93; not statistically significant)

sweat
First Column

SWEAT CHLORIDE (pharmacodynamic measure)

Treatment difference through 24 weeksc

−24 mmol/L

(95% CI: −28.0, -19.9; P<.0001*)

*p-values are nominal

Second Column
  • There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1)
  • Reductions in sweat chloride were seen in all subgroups, and ranged from −27.6 mmol/L to −20.0 mmol/L
     

HR, hazard ratio; BMI, body mass index.
cTreatment difference = effect of KALYDECO – effect of placebo.1  

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