Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial

Abstract

Rationale: The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF. Objectives: PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U.S. patient population with planned analyses after 6 months. Methods: Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV₁ (ppFEV₁), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms. Measurements and Main Results: Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV₁ improved 9.76 percentage points (95% confidence interval [CI], 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline. Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV₁ in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).

Keywords: PROMISE; clinical trial; cystic fibrosis; elexacaftor/tezacaftor/ivacaftor; modulators.

Figure 1.

Changes from baseline with 95% confidence intervals, stratified by cystic fibrosis transmembrane conductance regulator modulator use at baseline (iva = ivacaftor monotherapy). Times of observation are pre-elaxaftor/tezacaftor/ivacaftor baseline (B) and planned visit times. Participants who were pregnant at a visit were excluded from analyses of body mass index (BMI). Confidence intervals with five or fewer participants are not shown, and low follow-up at 3 months requires additional caution in interpretation (see Table 2). CFQ-R RD = Cystic Fibrosis Questionnaire–Revised, Respiratory Domain; Chg. = change; ETI = elaxaftor/tezacaftor/ivacaftor; Lum = lumacaftor; ppFEV₁ = percent predicted FEV₁; SwCl = sweat chloride; Tez = tezacaftor.

Figure 2.

Cross-sectional estimates and 95% confidence intervals of outcomes, stratified by cystic fibrosis transmembrane conductance regulator modulator use at baseline (iva = ivacaftor monotherapy). Times shown are baseline and the 6-month post-elaxaftor/tezacaftor/ivacaftor visit. Participants who were pregnant at a visit (n = 2 at baseline; n = 7 at 6 mo) were excluded from analyses of body mass index (BMI). Dotted lines show limits of the instrument (sweat chloride [SwCl] and Cystic Fibrosis Questionnaire–Revised, Respiratory Domain [CFQ-R RD]) or thresholds (BMI 25 for overweight, BMI 18 for underweight, and BMI z-score 0 for median). Lum = lumacaftor; ppFEV₁ = percent predicted FEV₁; Tez = tezacaftor.

Figure 3.

(A) Cystic Fibrosis Questionnaire–Revised, Respiratory Domain (CFQ-R RD) with participants grouped into categories at each visit. The top category (100, light green) represents the maximum achievable score, which a substantial number of participants obtained 6 months after elaxaftor/tezacaftor/ivacaftor initiation. Labels are omitted for categories with too few participants. (B) The same plot split into categories based on baseline percent predicted FEV₁ (ppFEV₁). The trend toward the maximum score was observed at each level of baseline lung function, with higher proportions in the high baseline lung function cohort reporting maximal CFQ-R RD at 6 months.

Figure 4.

Correlation between the change in percent predicted FEV₁ (ppFEV₁) and the change in sweat chloride (mmol/L) from baseline to 6 months (visit 4). Pearson correlation coefficient is −0.19 (P < 0.005). The dark line shows the equivalent linear regression fit, indicating that each additional 10-point decrease in sweat chloride (SwCl) is associated with a mean 0.89 greater change in ppFEV₁ from baseline to 6 months after elaxaftor/tezacaftor/ivacaftor initiation. This correlation remains significant if the influential points at (17, −31) and (−95, 35) are excluded, or if Spearman’s rank-based association statistic is substituted for the Pearson correlation statistic.