Clinical Trials for Ages 2 to <6 Years
TRIAL 6 (KIWI): Patients with CF age 2 to less than 6 years. KALYDECO® (ivacaftor): Safety consistent with patients age 6 years and older1,2
ON THIS PAGE: Study Design | Summary of Results
Mutations Eligible for Study2 (mutations in bold were enrolled)
G551D, G1244E, G1349D, G178R, G551S, G970R*, S1251N, S1255P, S549N, or S549R
*KALYDECO is not indicated for use in patients with a G970R mutation1
STUDY DESIGN1,2
- Trial 6 was a 24-week, open-label trial (N=34) evaluating safety, pharmacokinetics, and pharmacodynamics in patients with CF age 2 to less than 6 years (mean age: 3 years)1
- Patients were eligible if they had either a G551D, G1244E, G1349D, G178R, G551S, G970R*, S1251N, S1255P, S549N, or S549R mutation2
- Of the 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation2
- Patients received KALYDECO every 12 hours with fat-containing food, in addition to their prescribed CF therapies, based on weight; 7 kg to <14 kg: One 50-mg packet of oral granules; ≥14 kg: One 75-mg packet of oral granules2
Primary outcome2: Safety, assessed by adverse events and clinical laboratory assessments
Select secondary outcome measure2: Absolute change from baseline in sweat chloride concentration at 24 weeks
Trial 6 limitations2
- The study was open label and not placebo controlled; therefore, causality cannot be attributed
- All patients in the study knew they were on active drug, which may have introduced a treatment bias
SUMMARY OF RESULTS1
Safety results and pharmacokinetics were similar to older patients1
- The safety profile for patients in Trial 6, including type and frequency of adverse reactions, was similar to that observed in Trials 1 and 2
- Transaminase elevations were more common in patients who had abnormal transaminases at baseline
- The incidence of patients experiencing transaminase elevations (ALT or AST) >3x ULN was 14.7% (5/34). All 5 patients had maximum ALT or AST levels >8x ULN, which returned to baseline levels following interruption of KALYDECO dosing. KALYDECO was permanently discontinued in 1 patient
- Ivacaftor exposure in patients age 2 to less than 6 years administered either 50 mg or 75 mg of KALYDECO oral granules every 12 hours was similar to that observed in older patients administered KALYDECO tablets
- KALYDECO oral granules (2 x 75 mg) had similar bioavailability as the 150-mg tablet when given with fat-containing food
The efficacy of KALYDECO in patients age 2 to less than 6 years
was extrapolated from patients age 6 years and older with support from
population pharmacokinetic analyses showing similar drug exposure levels in adults and
children age 2 to less than 6 years.1
Reduction in sweat chloride from baseline (pharmacodynamic measure) with KALYDECO1,†
†SD 24.3, P=0.002 for patients who received 50 mg; SD 27.6, P<0.0001 for patients who received 75 mg.2
- The mean absolute change from baseline in sweat chloride for patients age 2 to less than 6 years (n=34) was −45 mmol/L (95% CI: −53, −38) through Week 24 (secondary endpoint)1,2
- There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1)1
CI, confidence interval; SD, standard deviation.
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 [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med. 2016;4(2):107-115. 3. Data on File. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0084 (v1.0); 2018.