Population

Table 1. Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.

The trial was conducted at 115 sites in 13 countries from June 2018 to April 2019. Overall, 405 patients underwent randomization, and 403 received at least one dose of the trial regimen (200 in the elexacaftor–tezacaftor–ivacaftor group and 203 in the placebo group) (Fig. S2). At baseline, the trial groups were well matched (Table 1 and Table S2). The mean adherence to the trial regimen was more than 98% in both trial groups. All 400 patients who completed the intervention period were enrolled in the open-label extension study.

Efficacy

Table 2. Table 2. Primary and Key Secondary Efficacy End Points.

Figure 1. Figure 1. Absolute Change from Baseline in Percentage of Predicted FEV 1 , and Rate of Pulmonary Exacerbations. Panel A shows the absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV 1 ), based on a mixed-effects model for repeated measures. Data are least-squares means, and 𝙸 bars indicate standard error of the mean; the dashed line indicates no change from baseline. Panel B shows a histogram of absolute change from baseline in percentage of predicted FEV 1 through week 24, according to trial group. Panel C shows the overall estimated annualized rate of pulmonary exacerbations, the estimated annualized rate of pulmonary exacerbations leading to hospitalization, and the estimated annualized rate of pulmonary exacerbations treated with intravenous antibiotics. CI denotes confidence interval.

Treatment with elexacaftor–tezacaftor–ivacaftor resulted in significant improvement in the primary end point of absolute change in percentage of predicted FEV 1 at week 4, assessed at the interim analysis, with a mean treatment difference of 13.8 points relative to placebo (P<0.001) (Table 2 and Figure 1A). Sustained improvement in percentage of predicted FEV 1 was seen through week 24 (final analysis), with a mean treatment difference of 14.3 points relative to placebo (P<0.001) (Table 2 and Figure 1A). The histogram of absolute change in percentage of predicted FEV 1 through week 24 showed marked separation of the two trial groups (Figure 1B).

Subgroup analysis for absolute change in percentage of predicted FEV 1 at week 4 showed that the mean treatment difference was consistent across all prespecified subgroups (Fig. S3). This difference was also consistent in the subgroup of patients in whom the minimal-function mutation caused an absence of CFTR protein production (78.0% of the trial population) and those with missense or in-frame deletion mutations (Table S3). Patients with a percentage of predicted FEV 1 of less than 40% at baseline (8.4% of the trial population) had a similar magnitude change in percentage of predicted FEV 1 at week 4 as the overall population (Table S4).

Treatment with elexacaftor–tezacaftor–ivacaftor resulted in a 63% lower annualized rate of pulmonary exacerbations than placebo (rate ratio, 0.37; 95% confidence interval, 0.25 to 0.55; P<0.001) (Table 2). A similar benefit was seen with respect to the rate of exacerbations that led to hospitalization or that were treated with intravenous antibiotics (Figure 1C). A higher percentage of patients in the elexacaftor–tezacaftor–ivacaftor group than in the placebo group remained free of pulmonary exacerbations (Fig. S4).

Figure 2. Figure 2. Absolute Change from Baseline in Sweat Chloride Concentration and CFQ-R Respiratory Domain Score. Panel A shows the absolute change from baseline in sweat chloride concentration, based on a mixed-effects model for repeated measures; a reduction over time indicates improvement in CFTR function. Panel B shows a histogram of absolute change from baseline in sweat chloride concentration through week 24, according to trial group. Panel C shows the absolute change from baseline in the respiratory domain score on the Cystic Fibrosis Questionnaire–Revised (CFQ-R), based on a mixed-effects model for repeated measures. Scores are normalized to range from 0 to 100 points, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; the minimum clinically important difference is 4 points. In Panels A and C, least-squares means at each visit are shown, and the 𝙸 bars indicate the corresponding standard error; the dashed line indicates no change from baseline.

Sweat chloride concentrations improved significantly through week 24, with a mean treatment difference of −41.8 mmol per liter relative to placebo (P<0.001) (Table 2 and Figure 2A). The histogram of absolute change in sweat chloride concentration through week 24 showed separation of the two groups (Figure 2B). The mean sweat chloride concentration in the elexacaftor–tezacaftor–ivacaftor group at week 24 was 57.9 mmol per liter, as compared with 102.4 mmol per liter in the placebo group (Fig. S5).

The CFQ-R respiratory domain score improved significantly through week 24 in the elexacaftor–tezacaftor–ivacaftor group, with a mean treatment difference of 20.2 points relative to placebo (P<0.001) (Table 2 and Figure 2C). BMI also improved significantly at week 24, with a mean treatment difference of 1.04 relative to placebo (P<0.001) (Table 2 and Fig. S6). All additional secondary efficacy end points showed improvement (Table 2 and Table S5).

Safety

Table 3. Table 3. Adverse Events.

Table 3 provides an overview of adverse events. The percentage of patients with at least one adverse event was 93.1% in the elexacaftor–tezacaftor–ivacaftor group and 96.0% in the placebo group; excluding adverse events of pulmonary exacerbation, the percentage was 92.6% in the elexacaftor–tezacaftor–ivacaftor group and 93.0% in the placebo group. Adverse events occurring in at least 10% of patients in either trial group were consistent with common manifestations and complications of cystic fibrosis. The majority of patients in the elexacaftor–tezacaftor–ivacaftor group had adverse events that were mild (33.2%) or moderate (50.5%) in severity. The large majority of adverse events resolved during the trial.

Serious adverse events occurred in 28 patients (13.9%) in the elexacaftor–tezacaftor–ivacaftor group and 42 patients (20.9%) in the placebo group (Table 3 and Table S6); excluding serious adverse events of pulmonary exacerbation, serious adverse events occurred in 20 patients (9.9%) in the elexacaftor–tezacaftor–ivacaftor group and 16 patients (8.0%) in the placebo group. There were no deaths in either trial group. Two patients (1.0%) in the elexacaftor–tezacaftor–ivacaftor group discontinued the trial regimen because of adverse events: rash in 1 patient and portal hypertension in a patient with preexisting cirrhosis. No patients in the placebo group discontinued the trial regimen because of an adverse event.

On the basis of previous experience with CFTR modulator therapy,9-12 including the phase 2 trial of elexacaftor–tezacaftor–ivacaftor,18 data related to aminotransferase levels and rash were reviewed. Adverse events of elevated aminotransferase levels occurred in 22 patients (10.9%) in the elexacaftor–tezacaftor–ivacaftor group and 8 patients (4.0%) in the placebo group. In the elexacaftor–tezacaftor–ivacaftor group, elevated levels of alanine aminotransferase or aspartate aminotransferase that were greater than three times, greater than five times, and greater than eight times the upper limit of the normal range occurred in 16 patients (7.9%), 5 patients (2.5%), and 3 patients (1.5%), respectively, as compared with 11 patients (5.5%), 3 patients (1.5%), and 2 patients (1.0%) in the placebo group. No patient had an elevated aminotransferase level greater than three times the upper limit of the normal range concurrent with an elevated bilirubin level greater than two times the upper limit of the normal range that emerged during the intervention period. Rash occurred in 22 patients (10.9%) in the elexacaftor–tezacaftor–ivacaftor group and 13 patients (6.5%) in the placebo group. In both trial groups, rash was more common in female patients than in male patients and more common in female patients who used hormonal contraceptives than in those who did not (Table S7).

Additional observations included elevated levels of creatine kinase and blood-pressure changes in the elexacaftor–tezacaftor–ivacaftor group. Elevated levels of creatine kinase were often associated with exercise, and no elevations of creatine kinase led to discontinuation of the trial regimen (Table S8). The baseline mean systolic and diastolic blood pressures in the elexacaftor–tezacaftor–ivacaftor group were 113.4 mm Hg and 69.4 mm Hg, and they increased by 3.1 mm Hg and 1.9 mm Hg, respectively, at week 24 (Table S9). There were no relevant safety findings in other clinical or laboratory assessments.