IN THIS SECTION: ALSO In this section:

CLINICAL TRIALS FOR AGE 12 YEARS AND OLDER:

IN THIS SECTION: ALSO In this section:

    Trial 1
    (Heterozygous F508del/Other Specific)

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

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

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

    Study Design

    RANDOMIZED

    1:1

    BASELINE

    WEEK 24a

    TRIKAFTA®
    (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 192-week, open-label extension study.1,3

     

    Key inclusion criteria1,2b

    • Confirmed CF diagnosis, clinically stable, and at least 12 years of age
    • Heterozygous for the F508del mutation 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 from baseline 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 4:

    • 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 14

    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)

    TRIKAFTA

    Sex, female, %

    48.0

    Mean age, years (range)

    25.6 (12.1-59.9)

    Mean BMI, kg/m2 (range)

    21.49 (15.01-30.86)

    Mean ppFEV1 (range)

    61.6 (33.8-97.1)

    Mean SwCI, mmol/L (range)

    102.3 (22.5-156.0)

    Placebo

    Sex, female, %

    48.3

    Mean age, years (range)

    26.8 (12.3-64.0)

    Mean BMI, kg/m2 (range)

    21.31 (14.42-33.80)

    Mean ppFEV1 (range)

    61.3 (32.3-93.7)

    Mean SwCI, mmol/L (range)

    102.9 (68.5-137.0)

    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

    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 sex

    In Trial 1, mean baseline ppFEV₁ was 61.6 percentage points (range: 33.8, 97.1) for patients receiving TRIKAFTA and 61.3 percentage points (range: 32.3, 93.7) for patients receiving placebo.4

    Reduction in rate of pulmonary exacerbations through Week 241,5

    Secondary Endpoint  

    ANNUALIZED RATE OF PULMONARY
    EXACERBATIONSe,f

    63%

    REDUCTION THROUGH WEEK 24

    (RR: 0.37, [95% CI: 0.25, 0.55]; P<0.0001)

    ᵉIn Trial 1, the number of pulmonary exacerbation events was 113 (0.98) for placebo vs 41 (0.37) for TRIKAFTA.1
    f
    In Trial 1, the number of pulmonary exacerbations is expressed as a rate over 48 weeks based on 24 weeks of observation.1

    ADDITIONAL ENDPOINTS IN TRIAL 15,6

    IV Icon
    down arrow

    71%

    REDUCTION IN EVENT RATE leading to HOSPITALIZATION (32 events for placebo vs 9 events for TRIKAFTA [RR: 0.29, 95% CI: 0.14, 0.61])

    Hospital Reduction Icon
    down arrow

    78%

    REDUCTION IN EVENT RATE leading to IV ANTIBIOTIC USE (51 events for placebo vs 11 events for TRIKAFTA [RR: 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

    Significant reduction in sweat chloride through Week 241,5

    Secondary Endpoint  

    MEAN ABSOLUTE CHANGE IN SWEAT CHLORIDE

    41.8

    mmol/L REDUCTION

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

    In Trial 1, mean baseline sweat chloride was 102.3 mmol/L (range: 22.5, 156.0) for patients receiving TRIKAFTA and 102.9 mmol/L (range: 68.5, 137.0) for those receiving placebo.4

    Significant improvement in CFQ-R Respiratory Domain score at Week 4, maintained through Week 241,5

    Secondary Endpoint  

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

    20.2

    POINTS IMPROVEMENT

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

    • In Trial 1, 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.7

    In Trial 1, mean baseline CFQ-R Respiratory Domain score was 68.3 for patients receiving TRIKAFTA and 70.0 for those receiving placebo.5

    CFQ-R Respiratory Domain score measured composite patient-reported outcomes in the following respiratory symptoms8: 

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

    Significant increase in BMI at Week 241,2

    Secondary endpoint

    ABSOLUTE CHANGE FROM BASELINE IN BMI

    1.0

     

    kg/m2 INCREASE VS PLACEBO AT WEEK 24

    (95% CI: 0.85, 1.23; P<0.0001)

    For example a patient who began TRIKAFTA in the trial at 130 lb and is 5'5" tall with a BMI of 22, may have completed the trial with a 6-lb increase in weight.9

    In Trial 1, mean baseline BMI was 21.49 kg/m² (range: 15.01, 30.86) for patients receiving TRIKAFTA and 21.31 kg/m² (range: 14.42, 33.80) for patients receiving placebo.4
     

    BMI, body mass index; CF, cystic fibrosis; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CFTR, cystic fibrosis transmembrane conductance regulator; CI, confidence interval; IV, intravenous; lb, pounds; 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.

    BMI, body mass index; CF, cystic fibrosis; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CFTR, cystic fibrosis transmembrane conductance regulator; CI, confidence interval; IV, intravenous; lb, pounds; 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.

    BMI, body mass index; CF, cystic fibrosis; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CFTR, cystic fibrosis transmembrane conductance regulator; CI, confidence interval; IV, intravenous; lb, pounds; 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.

    Trial 2
    (Homozygous F508del Mutation)

    TRIAL 2: A double-blind, active-controlled, head-to-head Phase 3 trial in patients homozygous for the F508del mutation1,2

    TRIAL 2: A double-blind, active-controlled, head-to-head Phase 3 trial in patients homozygous for the F508del mutation1,2

    TRIAL 2: A double-blind, active-controlled, head-to-head Phase 3 trial in patients homozygous for the F508del mutation1,2

    Study Design

    Study Image Study Image

    Prior to the run-in period, all patients in this study discontinued previous CFTR modulator therapies, but remained on their standard-of-care CF therapies.1

     

     

    aAll patients who completed the study were eligible to roll over into a 192-week, open-label extension study.1,3

     

    Key inclusion criteria1,2b

    • Confirmed CF diagnosis, clinically stable, and at least 12 years of age
    • Homozygous for the F508del mutation
    • 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 cenocepaciaBurkholderia dolosa, and Mycobacterium abscessus), and solid organ or hematologic transplantation.1,4

    PRIMARY ENDPOINT1

    • Absolute change in ppFEV1 from baseline at Week 4

    KEY SECONDARY ENDPOINTS1c

    FROM BASELINE AT WEEK 4:

    • Absolute change in sweat chloride
    • 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 a hierarchy of P<0.05.5

    Baseline characteristics in Trial 26

    TRIKAFTA

    Tezacaftor /ivacaftor and ivacaftor

    Sex, female, %

    56.4

    53.8

    Mean age, years (range)

    28.8 (12.7-54.1)

    27.9 (12.4-60.5)

    Mean BMI, kg/m2 (range)

    21.8 (16.0-28.4)

    21.9 (15.6-34.6)

    Mean ppFEV1 (range)

    61.6 (35.0-87.4)

    60.2 (35.0-89.0)

    Mean SwCI, mmol/L (range)

    91.4 (67.0-114.0)

    90 (60.5-112.0)

    TRIKAFTA

    Sex, female, %

    56.4

    Mean age, years (range)

    28.8 (12.7-54.1)

    Mean BMI, kg/m2 (range)

    21.8 (16.0-28.4)

    Mean ppFEV1 (range)

    61.6 (35.0-87.4)

    Mean SwCI, mmol/L (range)

    91.4 (67.0-114.0)

    Tezacaftor /ivacaftor and ivacaftor

    Sex, female, %

    53.8

    Mean age, years (range)

    27.9 (12.4-60.5)

    Mean BMI, kg/m2 (range)

    21.9 (15.6-34.6)

    Mean ppFEV1 (range)

    60.2 (35.0-89.0)

    Mean SwCI, mmol/L (range)

    90 (60.5-112.0)

    Summary of Efficacy Results

    Significant improvements in lung function and sweat chloride vs active comparator1,2

    primary endpoint

    ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE

    10.0

    Percentage Points

    IMPROVEMENT vs tezacaftor/ivacaftor and ivacaftor at Week 4 (95% CI: 7.4, 12.6; P<0.0001)

    In Trial 2, mean baseline ppFEV₁ was 61.6 percentage points (range: 35.0, 87.4) for patients receiving TRIKAFTA and 60.2 percentage points (range: 35.0, 89.0) for patients receiving the active comparator.6

    SECONDARY ENDPOINT1

    -45.1

    mmol/L

    SIGNIFICANT REDUCTION IN SWEAT CHLORIDE

    Compared with tezacaftor/ ivacaftor and ivacaftor at Week 4 (95% CI: -50.1, -40.1; P<0.0001)

    In Trial 2, mean baseline sweat chloride was 91.4 mmol/L (range: 67.0, 114.0) for patients receiving TRIKAFTA and 90.0 mmol/L (range: 60.5, 112.0) for patients receiving the active comparator.6

     

    Significantly improved CFQ-R Respiratory Domain score vs active comparator1,2

    SECONDARY ENDPOINT

    MEAN ABSOLUTE CHANGE FROM BASELINE IN CFQ-R RESPIRATORY DOMAIN SCORE

    17.4

    POINTS IMPROVEMENT

    vs tezacaftor/ivacaftor and ivacaftor at Week 4 
    (95% CI: 11.8, 23.0; P<0.0001)

    vs tezacaftor/ivacaftor and ivacaftor at Week 4 (95% CI: 11.8, 23.0; 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.7

    In Trial 2, mean baseline CFQ-R Respiratory Domain score was 70.6 points for patients receiving TRIKAFTA and 72.6 points for those receiving the active comparator.6

     

    CFQ-R Respiratory Domain score measured composite patient-reported outcomes in the following respiratory symptoms8: 

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

    BMI, body mass index; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CI, confidence interval; IV, intravenous; LS, least square; 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.

    Important Safety Information

    Elevated Transaminases and Hepatic Injury

    • Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment
    • Isolated elevations of transaminases or bilirubin have been observed in patients with CF treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease
    • Assessments of liver function tests (ALT, AST, and bilirubin) are recommended prior to initiating TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter
    • In the event of significant elevations in liver function tests, e.g. ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of liver function test elevations, consider the benefits and risks of resuming treatment
    • For patients with a history of hepatobiliary disease or liver function test elevations, more frequent monitoring should be considered

    Indications and Usage

    TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on in vitro data.

    If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data.

    Concomitant Use With CYP3A Inducers

    • Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness of TRIKAFTA. Co‑administration with strong CYP3A inducers is not recommended

    Concomitant Use With CYP3A Inhibitors

    • Exposure to elexacaftor, tezacaftor, and ivacaftor are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors

    Cataracts

    • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow up ophthalmological examinations are recommended in pediatric patients initiating treatment with TRIKAFTA

    Pediatric Use

    • The safety and effectiveness of TRIKAFTA in patients with CF younger than 6 years of age have not been established

    Serious Adverse Reactions

    • Serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs <1%) and influenza (1% vs 0)

    Most Common Adverse Reactions

    • The most common adverse reactions occurring in ≥5% of patients treated with TRIKAFTA (N=202) and higher than placebo (N=201) by ≥1% in the 24-week placebo-controlled, parallel-group Phase 3 trial (Trial 1) were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis, and blood bilirubin increased
       
    • The safety profile for the patients with CF receiving TRIKAFTA (N=55) enrolled in the 4-week, randomized, double-blind, active-controlled Phase 3 trial (Trial 2) was similar to that observed in Trial 1
       
    • The safety profile in patients age 6 to less than 12 years from an open-label Phase 3 trial (N=66) was similar to that observed in trials of patients age 12 years and older

    Click here to access full Prescribing Information for TRIKAFTA.