Study Design

Phase 3, 24-week, open-label, multicenter study evaluating pharmacokinetics, safety, and tolerability of SYMDEKO® (tezacaftor/ivacaftor and ivacaftor)1,2

  • Patients (N=70) received tezacaftor/ivacaftor and ivacaftor. Dosage was based on weight1,2:

    • <40 kg (n=62): tezacaftor/ivacaftor 50 mg/75 mg qd + ivacaftor 75 mg qd approximately 12 hours apart2

    • ≥40 kg (n=8): tezacaftor/ivacaftor 100 mg/150 mg qd + ivacaftor 150 mg qd approximately 12 hours apart 2
  • Trial 4 was an open-label study with no placebo comparator arm2

  • Trial 4 was conducted using a weight-based dosing regimen that differs from the FDA-approved dosing regimen for patients age 6 through 11 years. See Limitations and Disclosures at the bottom of the page for FDA-approved dosing and administration details

Study Population
  • Selected inclusion criteria

    • Confirmed CF diagnosis and clinically stable3
    • Patients were between 6 and 11 years of age (mean age 8.1 years)2,3
    • Patients homozygous for F508del (n=61) or with one copy of the F508del mutation and one copy of a mutation predicted to be responsive to tezacaftor/ivacaftor (n=9). Indicated mutations that were enrolled included F508del plus the following: F508del, 3849+10kbC→T, R352Q, 3272-26A→G, 2789+5G→A, D1152H, L206W, and D579G2,3
    • Percent predicted FEV1 (ppFEV1) ≥40% at screening (mean baseline ppFEV1, 91.1, range: 63.4 to 118.0)3,4
    • Body weight at screening ≥15 kg without shoes (mean baseline weight 30.7 kg, range: 19.1 kg to 58.0 kg)3,4
  • Selected exclusion criteria

    • 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 ULN3
    • History of colonization with organisms associated with a more rapid decline in pulmonary status, such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus3,4
Endpoints
  • Primary endpoint2

    • Safety and tolerability of SYMDEKO through Week 24 as determined by adverse events and clinical and laboratory assessments
  • Select secondary endpoints2

    • Absolute change in sweat chloride from baseline through Week 4 and Week 24
    • Absolute change in ppFEV1 from baseline through Week 24
    • Relative change in ppFEV1 from baseline through Week 24
    • Absolute change in BMI and BMI-for-age z-score from baseline at week 24
    • Absolute change in CFQ-R Respiratory Domain (child version) score from baseline through Week 24
  • Patients who completed the 24-week study were offered the opportunity to enroll in an extension study. Patients who prematurely discontinued study drug treatment were not eligible to roll over into the extension study.2,4

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

Trial 4: LIMITATIONS AND DISCLOSURES

  • Enrollment was limited to only those patients who met strict inclusion criteria and elected to enroll
  • The study was open label and not placebo controlled; therefore, causality cannot be attributed to SYMDEKO
  • Trial 4 was conducted using a weight-based dosing regimen that differs from the FDA-approved dosing regimen for patients age 6 through 11 years1,2
  • The dosing regimen studied in Trial 4 had a 40 kg weight-based dosing cutoff2
  • The FDA-approved dosing regimen for patients age 6 through 11 years is1:
    • <30 kg: tezcaftor/ivacaftor (50 mg/75 mg qd + ivacaftor 75 mg qd) approximately 12 hours apart
    • 30 kg: tezacaftor/ivacaftor (100 mg/150 mg qd + ivacaftor 150 mg qd) approximately 12 hours apart

Please see more information on dosing and administration

Primary Endpoint: Safety and tolerability through Week 24

Discontinuations2

  • The proportion of patients who discontinued study drug due to adverse events (AE) was:

    1.4 % OF PATIENTS TREATED WITH SYMDEKO® (tezacaftor/ivacaftor and ivacaftor) (n=1)
    • The 1 discontinuation was due to constipation, which was considered unlikely related to the study drug
  • No deaths occurred in patients taking SYMDEKO
  • There were no treatment discontinuations due to respiratory adverse events or transaminase elevations
  • 4 patients had AEs that lead to treatment interruption, none were considered serious, and all resolved without any treatment2,3
    • 2 were considered related or possibly related to study drug (blood creatine phosphokinase increased; ALT, AST, ALP, and GGT increased)

Transaminase elevations1,2

Incidence of maximum transaminases

Elevated ALT or AST

SYMDEKO (N=70)
n (%)

>3 x ULN
7 (10.0)a
>5 x ULN
3 (4.3)b
>8 x ULN
1 (1.4)

  • 1 patient experienced liver enzyme elevations that led to study drug interruption2

  • 4 patients experienced total bilirubin >1 to ≤1.5 x ULN3

  • No patients experienced total bilirubin >1.5 x ULN2

aIncludes all patients who experienced transaminase elevations >3 x ULN, including those who experienced >5 and >8 x ULN.1

bIncludes all patients who experienced transaminase elevations >5 x ULN, including those who experienced >8 x ULN.1

Serious adverse events2*

  • Serious adverse events occurred in 6 patients (8.6%) on SYMDEKO

  • Serious adverse events, which were not considered drug-related by the investigators, that occurred in patients treated with SYMDEKO included infective pulmonary exacerbation of CF, 2 (2.9%); breath odor, 1 (1.4%); snoring, 1 (1.4%); failure to thrive, 1 (1.4%); sinusitis, 1 (1.4%); and constipation, 1 (1.4%)

*Serious adverse events included any adverse event that was fatal or life-threatening or resulted in hospitalization or prolonged hospitalization, disability/incapacity, congenital anomaly or birth defect, or an important medical event that required professional medical intervention.3

Most common adverse events2

Incidence of adverse reactions in ≥10% of patients taking SYMDEKO

Adverse Reactions
(Preferred Term)

SYMDEKO (N=70)
n (%)

Cough
25 (35.7)
Infective pulmonary exacerbation of CF
16 (22.9)
Pyrexia
13 (18.6)
Abdominal pain
10 (14.3)
Nasal congestion
10 (14.3)
Rhinorrhea
7 (10)
Vomiting
7 (10)

  • 92.9% of patients (n=65) experienced at least 1 adverse event

Respiratory adverse events2*

  • 2 patients (2.9%) experienced abnormal respiration (eg, chest tightness) after respiration, which did not result in treatment discontinuation2

*Serious adverse events included any adverse event that was fatal or life-threatening or resulted in hospitalization or prolonged hospitalization, disability/incapacity, congenital anomaly or birth defect, or an important medical event that required professional medical intervention.3

Secondary Endpoints

  • Trial 4 was open label and not placebo controlled; therefore, causality cannot be attributed to SYMDEKO

  • Trial 4 was conducted using a weight-based dosing regimen that differs from the FDA-approved dosing regimen for patients age 6 through 11 years. See the FDA-approved dosing and administration page and limitations and disclosures

Secondary Endpoint: Absolute change in sweat chloride2,3

-14.5 mmol/L DECREASE IN THE LS MEAN absolute change in sweat chloride from baseline through Week 24 (Baseline 99.1 mmol/L; 95% CI: -17.4, -11.6)

There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (ppFEV1).

Click here for limitations and disclosures for Trial 4

Secondary Endpoints: Absolute and relative change in ppFEV12

0.9 PERCENTAGE POINTS

LS Mean absolute change in ppFEV1 from baseline through Week 24 (Baseline 91.1%; 95% CI: -0.6, 2.3)

1.4 PERCENT

LS Mean relative change in ppFEV1 through Week 24 (Baseline 91.1%; 95% CI: -0.4, 3.1)

Click here for limitations and disclosures for Trial 4

Secondary Endpoint: Absolute change in BMI2

+0.23 kg/m2 LS MEAN ABSOLUTE CHANGE IN BMI from baseline at Week 24 (Baseline 17.44; 95% CI: 0.06, 0.40)

-0.03 LS MEAN ABSOLUTE CHANGE IN BMI-FOR-AGE Z-SCORE from baseline at Week 24 (Baseline 0.37; 95% CI: -0.10, 0.04)

Click here for limitations and disclosures for Trial 4

Secondary Endpoint: Absolute change in CFQ-R Respiratory Domain score (child version)2

+3.4 POINT LS MEAN ABSOLUTE CHANGE in CFQ-R Respiratory Domain score from baseline through Week 24 (95% CI: 1.4, 5.5)

Click here for limitations and disclosures for Trial 4

CI, confidence interval; LS, least squares.