Clinical Trials for 6 Years or Older

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    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 endpoints2: 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

    Treatment difference through:

    24 weeks (primary endpoint)1,2,a

    +12.5 points

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

    48 weeks (secondary endpoint)1,2,a 

    +10.0 points

    (95% CI: 4.5, 15.5; P<0.001)

    Summary chart for trial 2 Summary chart for trial 2

    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 

    CFQ-R RESPIRATORY DOMAIN SCORE
    Treatment difference through:

    24 weeksa 

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

    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

    BODY WEIGHT
    Treatment difference at:

    24 weeksa 

    +1.9 kg (95% CI: 0.9, 2.9; P=0.0004)

    48 weeksa

    +2.8 kg (95% CI: 1.3, 4.2; P=0.0002)
     

    SWEAT CHLORIDE (pharmacodynamic measure)
    Treatment difference through:

    24 weeksa 

    −54 mmol/L (95% CI: -62, -47; P<0.0001)

    48 weeksa

    −53 mmol/L (95% CI: -61, -46; P<0.0001)

    • 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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    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
     

    Summary chart for trial 4 Summary chart for trial 4

    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

    BMI

    Treatment difference at 8 weeksa

    +0.66 kg/m2 

    (95% CI: 0.34, 0.99; P<0.0001)

    • Mean increases ranged from   
      +0.16 kg/m2 to +1.62 kg/m2 at Week 8

    CFQ-R RESPIRATORY DOMAIN SCORE

    Treatment difference through 8 weeksa 

    +9.6 points 

    (95% CI: 4.5, 14.7; P=0.0004)

    • 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 CHLORIDE1,2

    Treatment difference through 8 weeksa

    −49 mmol/L 

    (95% CI: -57, -41; P<0.0001)

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

    ON THIS PAGE: Study Design | Summary of Results 

    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

    BODY WEIGHT

    Treatment difference at 24 weeksc

    +0.3 kg/m2

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

    CFQ-R RESPIRATORY DOMAIN SCORE
    Treatment difference through 24 weeksc

    +8.4 points

    (95% CI: 2.2, 14.6; P=0.009*)

    *p-values are nominal

    • 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

    RELATIVE RISK OF PULMONARY EXACERBATION

    Treatment difference through 24 weeksc

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

    SWEAT CHLORIDE (pharmacodynamic measure)

    Treatment difference through 24 weeksc

    −24 mmol/L

    (95% CI: −28.0, -19.9; P<0.0001*)

    *p-values are nominal

    • 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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    Important Safety Information

    Transaminase (ALT or AST) Elevations

    • Elevated transaminases have been reported in patients with CF receiving KALYDECO. Transaminase elevations were more common in patients with a history of transaminase elevations or in patients who had abnormal transaminases at baseline. ALT and AST should be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, consider more frequent monitoring of liver function tests
    • Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO

    Indications and Usage

    KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 4 months and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

    If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

    Indications and Usage

    KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 4 months and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

    If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

    Important Safety Information

    Transaminase (ALT or AST) Elevations

    • Elevated transaminases have been reported in patients with CF receiving KALYDECO. Transaminase elevations were more common in patients with a history of transaminase elevations or in patients who had abnormal transaminases at baseline. ALT and AST should be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, consider more frequent monitoring of liver function tests
    • Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO

    Concomitant Use With CYP3A Inducers

    • Use of KALYDECO with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of KALYDECO. Co-administration of KALYDECO with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended

    Cataracts

    • Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating KALYDECO treatment

    Pediatric Use

    • The safety and effectiveness of KALYDECO in patients with CF younger than 4 months of age have not been studied. The use of KALYDECO in children under the age of 4 months is not recommended

    Serious Adverse Reactions

    • Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in patients treated with KALYDECO included abdominal pain, increased hepatic enzymes, and hypoglycemia

    Most Common Adverse Reactions

    • The most common adverse reactions in patients with a G551D mutation in the CFTR gene (Trials 1 and 2) with an incidence of ≥8% and at a higher incidence for patients treated with KALYDECO (N=109) than for placebo (N=104) were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness
    • The safety profiles for patients with additional approved mutations enrolled in Trials 4, 5, and 7; and for patients aged 2 to less than 6 years enrolled in Trial 6; and for patients aged 4 months to less than 24 months enrolled in Trial 8; were similar to that observed in Trials 1 and 2

    Click here to access full Prescribing Information.

    References:
    1
    . KALYDECO (ivacaftor) [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with G551D mutation. Am J Respir Crit Care Med. 2013;187(11):1219–1225.

    References:
    1.
    KALYDECO (ivacaftor) [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014;(6)13:674-680.

    References:
    1. KALYDECO (ivacaftor) [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Moss RB, Flume PA, Elborn JS, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomized controlled trial. Lancet Respir Med. 2015;3(7):524-533.