Clinical Trials for Ages 4 Months to <2 Years
TRIAL 8 (ARRIVAL):
KALYDECO® (ivacaftor) in patients with CF age 4 months to less than 2 years.1-3

IN THIS SECTION:
ALSO IN THIS SECTION:

STUDY DESIGN

  • Trial 8 was a Phase 3, 24-week, open-label, 2-part study of KALYDECO that included the following cohorts of patients with CF: Patients age 4 to <6 months (n=6), patients age 6 to <12 months (n=11) and patients age 12 to <24 months (n=19)1-3
    •  Patients were eligible if they had a G551D, G1244E, G1349D, G178R, G551S, R117H,a S1251N, S1255P, S549N, or S549R mutation2-4
      • 4 to <6 months cohort: Patients had either a G551D mutation (n=5) or a R117H mutation (n=1)2
      • 6 to <12 months cohort: Patients had either a G551D mutation (n=10) or a G178R mutation (n=1)2
      • 12 to <24 months cohort: Patients had either a G551D mutation (n=16), a S549N mutation (n=2), or a G178R mutation (n=1)3
  • Patients in this trial received KALYDECO every 12 hours with fat-containing food, in addition to their prescribed CF therapies. In the 4 to <6 months cohort, patients received 25 mg of KALYDECO oral granules every 12 hours until reaching 6 months of age, after which they could receive 50 mg of KALYDECO oral granules if they weighed 7 kg or more. Patients 6 months and older received KALYDECO every 12 hours based on weight: 5 kg to <7 kg: one 25 mg packet of oral granules, 7 kg to <14 kg: one 50 mg packet of oral granules; ≥14 kg: one 75 mg packet of oral granules1
  • Instruction was provided to administer KALYDECO oral granules mixed with 5 mL of an age-appropriate soft food or liquid, either orally with a syringe or with a spoon, every 12 hours along with a fat-containing food. Bottle use was not recommended2,3

Primary endpoint2,3: Safety, assessed by adverse events (AEs) and clinical laboratory assessments

Select secondary endpoints2,3: Absolute change from baseline in sweat chloride concentration at Week 24

aPatients with the R117H mutation were only eligible to enroll in this study in the United States.

Trial 8 limitations2,3,5:

  • The study was open label and not placebo controlled; therefore, causality cannot be attributed to KALYDECO
  • All patients in the study knew they were on active drug, which may have introduced bias related to awareness of treatment

 

SAFETY PROFILE

Discontinuation and serious AEs

  • 4 to <6 months cohort2,5:
    - No treatment discontinuations
    - 1 serious AE included bronchiolitis
  • 6 to <12 months cohort2:
    - There was 1 treatment interruption and no permanent discontinuations due to AEs
    - Serious AEs included viral respiratory tract infection (n=1), viral rash (n=1), and cough (n=1)
  • 12 to <24 months cohort3:
    - 1 patient discontinued due to withdrawal of consent
    - 4 serious AEs occurred in 2 patients3
    • 1 patient had constipation, distal intestinal obstruction syndrome (DIOS), and eczema herpeticum
      • The serious adverse event of constipation was considered possibly related to ivacaftor by the investigator3
    • 1 patient had persistent cough3

All other serious AEs were considered unrelated or unlikely to be related to ivacaftor2,3

The safety profile of patients in this trial is similar
to that observed in patients age 2 years and older.1

Transaminase elevations1,2

INCIDENCE OF
TRANSAMINASE ELEVATIONS1,2
ELEVATED ALT OR AST 4 TO <6 MONTHS COHORT n/N (%) 6 TO <12 MONTHS COHORT n/N (%) 12 TO <24 MONTHS COHORT n/N (%)
>3x ULN 0/6 (0.0) 1/11 (9.1) 5/18 (27.8)
>5x ULN 0/6 (0.0) 0/11 (0.0) 2/18 (11.1)
>8x ULN 0/6 (0.0) 0/11 (0.0) 2/18 (11.1)

ALT, alanine aminotransferase. AST, aspartate aminotransferase. ULN, upper limit of normal.

  • No patients in any cohort had elevations in total bilirubin, or discontinued ivacaftor treatment due to transaminase elevations1

Please see Important Safety Information for more information about transaminase elevations reported in patients with CF receiving KALYDECO.

SUMMARY OF RESULTS

PHARMACODYNAMIC RESULTS1-3

Reduction in sweat chloride from baseline with KALYDECO in:

Patients age 4 to less than 6 months

-50.0 mmol/L

  • In the 4 to <6 months cohort (n=3), the mean absolute change from baseline in sweat chloride was -50.0 mmol/L (95% CI: -93.1, -6.9) at Week 24 (secondary endpoint)1

Patients age 6 to less than 12 months

-58.6 mmol/L

  • In the 6 to <12 months cohort (n=6), the mean absolute change from baseline in sweat chloride was -58.6 mmol/L (95% CI: -75.9, -41.3) at Week 24 (secondary endpoint)1,2

Patients age 12 to less than 24 months

-73.5 mmol/L

  • In the 12 to <24 months cohort (n=10), the mean absolute change from baseline in sweat chloride was −73.5 mmol/L (95% CI: −86.0, −61.0) at Week 24 (secondary endpoint)1,3

There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1).1

CI, confidence interval.

Back to top

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, Wainwright CE, Sawicki GS, et al. Ivacaftor in infants aged 4 to <12 months with cystic fibrosis and a gating mutation: results of a 2-part phase 3 clinical trial. Am J Respir Crit Care Med. 2020; doi: 10.1164. 3. Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med. 2018;6(7):545-553. 4. Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med. 2018;6(7)(suppl):553. 5. Rosenfeld M, Wainwright CE, Sawicki GS, et al. Ivacaftor in 4- to <6-month-old infants with cystic fibrosis and a gating mutation: results of a 2-part, single-arm, phase 3 study. Poster presented at: the 34th Annual North American Cystic Fibrosis Conference (virtual), October 7-23, 2020.