Clinical Trials for Ages 6 Through 11 Years
Patients age 6 through 11 years with CF homozygous for F508del or heterozygous for F508del and a mutation predicted to be responsive to tezacaftor/ivacaftor1
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 at the bottom of this page
STUDY DESIGN
Phase 3, 24-week, open-label, multicenter study evaluating pharmacokinetics, safety, and tolerability of SYMDEKO® (tezacaftor/ivacaftor and ivacaftor)1,2
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Patients (N=70) received tezacaftor/ivacaftor and ivacaftor. Dosage was based on weight1,2:
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<40 kg (n=62): tezacaftor/ivacaftor 50 mg/75 mg qd + ivacaftor 75 mg qd approximately 12 hours apart2
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≥40 kg (n=8): tezacaftor/ivacaftor 100 mg/150 mg qd + ivacaftor 150 mg qd approximately 12 hours apart2
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- Trial 4 was an open-label study with no placebo comparator arm2
Study Population
- Selected inclusion criteria
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Confirmed CF diagnosis and clinically stable3
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Patients were between 6 and 11 years of age (mean age 8.1 years)2,3
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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
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Percent predicted FEV₁ (ppFEV₁) ≥40% at screening (mean baseline ppFEV₁, 91.1, range: 63.4 to 118.0)3,4
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Body weight at screening ≥15 kg without shoes (mean baseline weight 30.7 kg, range: 19.1 kg to 58.0 kg)3,4
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- Selected exclusion criteria
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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
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History of colonization with organisms associated with a more rapid decline in pulmonary status, such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus3,4
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Endpoints
- Primary endpoint2
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Safety and tolerability of SYMDEKO through Week 24 as determined by adverse events and clinical and laboratory assessments
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- Select secondary endpoints2
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Absolute change in sweat chloride from baseline through Week 4 and Week 24
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Absolute change in ppFEV1 from baseline through Week 24
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Relative change in ppFEV1 from baseline through Week 24
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Absolute change in BMI and BMI-for-age z-score from baseline at Week 24
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Absolute change in CFQ-R Respiratory Domain (child version) score from baseline through Week 24
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CFQ-R Respiratory Domain score evaluated respiratory symptoms, including cough, sputum production, and difficulty breathing5
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Patients who completed the 24-week study were offered the opportunity to enroll in an extension study (Trial 661-116). Patients who prematurely discontinued study drug treatment were not eligible to roll over into the extension study2,4
Trial 4: Limitations and Disclosures
- 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 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:
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<30 kg: tezacaftor/ivacaftor (50 mg/75mg qd + ivacaftor 75 mg qd) approximately 12 hours apart
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≥30 kg: tezacaftor/ivacaftor (100 mg/150 mg qd + ivacafator 150 mg qd) approximately 12 hours apart
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SUMMARY OF RESULTS
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 not considered 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 adverse events that lead to treatment interruption, none were considered serious, and all resolved2,4
- 2 were considered related or possibly related to study drug (blood creatine phosphokinase increased; ALT, AST, AP, 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 ULN4
- 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.4
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) |
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Infective pulmonary exacerbation of CF |
16 (22.9) |
| Pyrexia | 13 (18.6) |
| Abdominal pain | 10 (14.3) |
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Nasal congestion |
10 (14.3) |
| Rhinorrhea | 7 (10) |
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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 discontinuation3
*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.4
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.1,2 See the FDA-approved dosing and administration page and limitations and disclosures
SECONDARY ENDPOINT: ABSOLUTE CHANGE IN SWEAT CHLORIDE2
-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)
Absolute Change in Sweat Chloride
Absolute Change in Sweat Chloride
Sweat chloride levels may not correlate with improvements in lung function (ppFEV1).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 PERCENTAGE POINTS
LS Mean relative change in ppFEV1 through Week 24 (Baseline 91.1%; 95% CI: -0.4, 3.1)
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)
SECONDARY ENDPOINT: LS MEAN 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)
ALT, alanine transaminase; AST, aspartate transaminase; AP, alkaline phosphatase; BMI, body mass index, CI, confidence interval; GGT, gamma-glutamyl transferase; IV, intravenous; qd, once a day; LS, least squares; ppFEV₁, percent predicted forced expiratory volume in 1 second; ULN, upper limit of normal.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Transaminase (ALT or AST) Elevations
- Elevated transaminases have been observed in patients with CF receiving SYMDEKO, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring should be considered
- Dosing should be interrupted in patients with significant elevations of transaminases (e.g., ALT or AST >5x upper limit of normal [ULN], or ALT or AST >3x ULN with bilirubin >2x ULN) and laboratory tests should be closely followed until abnormalities resolve. Following resolution of transaminase elevations, consider the benefits and risks of resuming treatment
INDICATIONS AND USAGE
SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
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.
Hypersensitivity Reactions, Including Anaphylaxis
- Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue SYMDEKO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with SYMDEKO
Concomitant Use With CYP3A Inducers
- Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness of SYMDEKO. Co-administration of SYMDEKO 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 have been reported in pediatric patients treated with SYMDEKO, as well as with ivacaftor monotherapy. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO
ADVERSE REACTIONS
Serious Adverse Reactions
- Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with SYMDEKO compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) patients treated with SYMDEKO vs. 0 placebo patients
Most Common Adverse Reactions
- The most common adverse reactions in Trials 1 and 3 occurring in ≥3% of patients treated with SYMDEKO (N=334) and at a higher rate than for placebo (N=343) were headache, nausea, sinus congestion, and dizziness
- The safety profile in patients age 6 to less than 12 years from an open-label Phase 3 trial (N=70) was similar to that observed in Trials 1 and 3
USE IN SPECIFIC POPULATIONS
Pediatric Use
- The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied
Click here to access full Prescribing Information for SYMDEKO.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Walker S, Flume P, McNamara J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 to 11 years with cystic fibrosis. J Cyst Fibros. 2019:1-6. doi: 10.1016/j.jcf.2019.06.009. 3. Walker S, Flume P, McNamara J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 to 11 years with cystic fibrosis. J Cyst Fibros. 2019:(suppl1-10). doi: 10.1016/j.jcf.2019.06.009. 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-2254; 2019. 5. CFQ-R Cystic Fibrosis Questionnaire- REVISED. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. CFQ-R—Parent, English Version 2.0.