A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation

Abstract

Background: The CFTR modulator tezacaftor/ivacaftor was efficacious and generally safe and well tolerated in Phase 3 studies in participants ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous with a residual function-CFTR mutation (F/F or F /RF respectively). We evaluated tezacaftor/ivacaftor's efficacy and safety over 8 weeks in participants 6 through 11 years of age with these mutations. Methods: Participants were randomized 4:1 to tezacaftor/ivacaftor or a blinding group (placebo for F/F , ivacaftor for F /RF). The primary endpoint was within-group change from baseline in the lung clearance index 2 •5 (LCI 2 •5) through Week 8. Secondary endpoints were change from baseline in sweat chloride (SwCl), cystic fibrosis questionnaire-revised (CFQ-R) respiratory domain score, and safety. Results: Sixty-seven participants received at least one study drug dose. Of those, 54 received tezacaftor/ivacaftor (F/F , 42; F /RF, 12), 10 placebo, and 3 ivacaftor; 66 completed the study. The within-group change in LCI 2 •5 was significantly reduced (improved) by −0 •51 (95% CI: −0 •74, −0 •29). SwCl concentration decreased (improved) by −12 •3 mmol/L and CFQ-R respiratory domain score increased (improved, nonsignificantly) by 2 •3 points. There were no serious adverse events (AEs) or AEs leading to tezacaftor/ivacaftor discontinuation or interruption. The most common AEs (≥10%) in participants receiving tezacaftor/ivacaftor were cough, headache, and productive cough. Conclusions: Tezacaftor/ivacaftor improved lung function (assessed using LCI) and CFTR function (measured by SwCl concentration) in participants 6 through 11 years of age with F/F or F /RF genotypes. Tezacaftor/ivacaftor was safe and well tolerated; no new safety concerns were identified.

Toward the Establishment of New Clinical Endpoints for Cystic Fibrosis: The Role of Lung Clearance Index and Cardiopulmonary Exercise Testing

“…The positive impact of inhalation of dornase alpha (66) and hypertonic Saline (67-69) has been demonstrated using LCI measurements. More recently LCI has been used as a primary outcome measure to assess the efficacy of CFTR potentiators (ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor) (70)(71)(72).…”

Review of CFTR Modulators 2020

“…Otherwise, adverse events were similar in iva versus placebo, sweat chloride difference was -9.2mmol/L (-12.4 to -5.9), and FEV1pp improvement was 2.7 (0.6-4.7) in iva versus placebo groups. A phase 3, double blind, parallel group, 8 week study of tez/iva in fifty-four 6-11 year olds with CF, homozygous for F508del or heterozygous for F508del/residual function mutations, showed a significant decrease in LCI 2.5 of 0.51 from baseline of 9.56 (95% CI, -0.74 to 0.29, p<0.0001) 15 . FEV1pp increased by 2.8 from baseline of 86.5 in the tez/iva group (95% CI, 1.0-4.6).…”

“…LCI is usually reported as LCI 2.5 , or washout until 1/40 th of the starting N 2 end tidal concentration is reached. Normal LCI is less than 7.5 "turnovers" 15 .…”

Correction of measurement error in a commercial multiple-breath washout device

“…The endorsement of the North American Cystic Fibrosis Foundation and the European Cystic Fibrosis Society Clinical Trials Network consolidated the LCI as an endpoint in clinical trials in children and adults with CF 3,9–12 . As recommended by different societies, most data on the efficacy of disease modifying therapies in CF 13,14 were obtained with the Exhalyzer D / Spiroware setup (Eco Medics AG, Duernten, Switzerland) and this is the device of choice in multiple ongoing studies with the LCI as a primary endpoint (www.clinicaltrials.gov: NCT04138589, NCT03320382, NCT04026360, NCT02657837). Consequently, the correct measurement of N 2 MBW is of critical importance, notably in studies that serve to guide drug approval.…”