Rationale: Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for F508del-CFTR in a Phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index2.5 (LCI2.5), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment.
Objective: To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI).
Methods: This Phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for F508del-CFTR received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). The results from Part 1 are reported. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index–for-age z-scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the chest MRI global score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics.
Results: Fifty-one children were enrolled and received LUM/IVA (n = 35) or placebo (n = 16). For the change in chest MRI global score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference, <0; higher score indicates greater abnormality) was 76%; the mean treatment difference was −1.5 (95% credible interval, −5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI2.5, growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA.
Conclusions: This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years of age.
Clinical trial registered with www.clinicaltrials.gov (NCT 03625466).
Cystic fibrosis (CF) is a life-shortening, multisystemic genetic disease affecting more than 80,000 individuals worldwide (1). CF is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) that reduce the quantity and/or function of CFTR protein, resulting in reduced anion transport in many epithelial organs (1, 2). F508del-CFTR is the most common CFTR mutation, and approximately 40% of people with CF are homozygous for F508del (F/F genotype) (3).
CFTR modulators address the underlying cause of CF by restoring CFTR activity, modifying disease progression, and preventing or delaying organ damage (4–6). CFTR correctors (e.g., lumacaftor [LUM], tezacaftor [TEZ], and elexacaftor [ELX]) improve the processing and trafficking of CFTR protein to cell surfaces (1). CFTR potentiators (e.g., ivacaftor [IVA]) increase the open probability of CFTR channels on cell surfaces (1). LUM in combination with IVA (LUM/IVA) is currently the only CFTR modulator regimen approved for children as young as 2 years of age with CF and the F/F genotype (7). An open-label trial showed that treatment with LUM/IVA for 24 weeks in children 2 through 5 years of age was generally safe and well tolerated and showed within-group improvements in sweat chloride concentration, biomarkers of pancreatic function, and growth parameters (8).
Children with CF develop lung disease early in life, even in the absence of respiratory symptoms (9, 10). Airway infection, inflammation, and structural changes have been reported in infants as young as 3 months of age (9, 11, 12). However, it remains challenging to assess lung disease in children younger than 5 years of age (13).
Chest magnetic resonance imaging (MRI) allows for sensitive lung investigation without the radiation exposure associated with other forms of imaging (14–16). Chest MRI can detect abnormalities in lung structure and function, such as regional mucus plugging, and has been shown to correlate with measures of lung clearance index (LCI) (17). Additionally, chest MRI can detect abnormalities in lung structure and perfusion and progression of lung disease in preschool children with CF (18, 19) and is able to detect response to therapy for pulmonary exacerbations (PEx) in pediatric patients with CF (17, 18).
Here, we present the results from the first part of a two-part, 96-week study of LUM/IVA in children 2 through 5 years of age with CF and the F/F genotype. This is the first placebo-controlled study of LUM/IVA in this age population and the first to use chest MRI as an outcome measure.
Some of the results have been previously reported in the form of abstracts (20).
This Phase 2, two-part study of LUM/IVA enrolled children 2 through 5 years of age with CF and the F/F genotype. CFTR genotype was confirmed at screening. Additional inclusion and exclusion criteria are provided (see the data supplement).
Part 1 of the study evaluated the efficacy and impact of LUM/IVA on disease progression in a 48-week, multicenter, randomized, double-blind, placebo-controlled trial (Figure 1). A placebo control group was used in Part 1, as children were recruited for the trial before the commercial availability or approval of LUM/IVA for this age group in the region. Part 2 of the study evaluated the efficacy and safety of LUM/IVA in a 48-week open-label period. This study has been completed; only the results from Part 1 of the study are reported here.
LUM/IVA dosing in Part 1 was based on weight. Children were randomized (2:1) to receive either LUM/IVA (100 mg LUM/125 mg IVA [body weight, <14 kg] or 150 mg LUM/188 mg IVA [body weight, ⩾14 kg]) or matched placebo every 12 hours.
This trial was designed by Vertex Pharmaceuticals Incorporated in collaboration with the authors. The study protocol was reviewed and approved by the ethics committee of the University of Heidelberg and, subsequently, all participating institutions. Oversight of the safety of participating children was provided by an independent data monitoring committee. This study was conducted in accordance with the Declaration of Helsinki, local applicable laws and regulations, and current Good Clinical Practice Guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Written informed consent (and assent, if applicable) was obtained from parents or legal guardians before study participation. Data collection and analysis were performed by Vertex Pharmaceuticals in collaboration with the authors. All authors had full access to trial data after the final database lock, critically reviewed the manuscript, and approved the submission. Additional details regarding the chest MRI scoring system, statistical analyses, changes that were due to the coronavirus disease (COVID-19) pandemic, and full eligibility criteria are provided (see Table E1 in the data supplement).
The primary endpoint was absolute change from baseline in the MRI global score at Week 48. A semiquantitative scoring system was used to evaluate chest MRI data (14). Each participant had six lobes scored, with the lingula being treated as a separate lobe. The MRI global score indicates the level of lung abnormality (higher score indicates greater abnormality) across all parameters (bronchiectasis/wall thickening, mucus plugging, abscesses/sacculations, consolidation, special findings, and perfusion size), and morphology and perfusion scores indicate the level of abnormality across all morphological parameters and the functional parameter (14). Standardized sequence parameters were used for MRI image acquisition and are detailed (see Table E2). Secondary endpoints included absolute change in LCI2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index (BMI)–for-age z-scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, number of PEx requiring treatment with oral or intravenous antibiotics, time to first PEx, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48.
The proposed sample size of 50 children (2:1 randomization: 33 children receiving LUM/IVA and 17 children receiving placebo after adjusting for a dropout rate of 10%) was based on the number of potential children expected to be available for participation. Given that there was limited information on the primary endpoint of chest MRI global score in this patient population at the time of trial design and that the sample size was based on feasibility and was not powered for between-groups comparisons, Bayesian analysis and descriptive summaries of the primary endpoint were conducted. Descriptive summary statistics (n, mean, median, standard deviation [SD], and corresponding 95% confidence intervals [95% CIs]) were provided for both within-group change and between-group difference. The Bayesian posterior probability can be interpreted as the probability that one treatment group is better than the other (i.e., the probability that the difference between groups is less than 0). This posterior probability is calculated by updating prior information with new data. The actual Bayesian posterior probability of LUM/IVA being better than placebo in the chest MRI global score at Week 48 was calculated using a vague normal prior distribution. Bayesian summary statistics, including the Bayesian posterior mean difference and corresponding 95% credible intervals, were determined. Secondary efficacy endpoints were analyzed on the basis of descriptive summary statistics (n, mean, median, SD, and corresponding 95% CIs) for within–treatment group changes. For secondary efficacy endpoints, if either the LUM/IVA group or the placebo group demonstrated a within–treatment group change with a 95% CI excluding 0, and the variability of this variable was within expectation, an analysis of between–treatment group differences was also performed on the basis of descriptive summary statistics, with corresponding 95% CIs. Additional endpoints were analyzed on the basis of descriptive summary statistics for within–treatment group changes.
Part 1 of the study was conducted at five hospitals in Germany between August 10, 2018, and October 9, 2020. Overall, 51 children were enrolled and received at least one dose of study drug, 35 in the LUM/IVA group and 16 in the placebo group (Figure 2). Mean exposure (and SD) was 47.0 (8.5) weeks in the LUM/IVA group and 48.7 (2.3) weeks in the placebo group. Two children (5.7%) discontinued LUM/IVA, 1 because of an adverse event (AE) that began before the first dose of study drug and 1 because the child started treatment with commercially available LUM/IVA. There were no treatment discontinuations in the placebo group. Demographics and baseline characteristics were similar between treatment groups (Table 1).
|Lumacaftor/Ivacaftor Group (n = 35)||Placebo Group (n = 16)|
|Sex, n (%)|
|Male||24 (68.6)||9 (56.3)|
|Female||11 (31.4)||7 (43.8)|
|Age, in yr, mean (SD)||4.2 (1.0)||4.2 (1.0)|
|<3, n (%)||4 (11.4)||1 (6.3)|
|⩾3, n (%)||31 (88.6)||15 (93.8)|
|White, n (%)||35 (100.0)||16 (100.0)|
|MRI score, mean (SD)|
|Global||17.6 (9.7)*||21.4 (9.3)†|
|Morphology||13.6 (7.3)*||17.0 (7.6)†|
|Perfusion||4.0 (2.8)*||4.3 (2.4)|
|LCI2.5, mean (SD)||8.86 (2.01)||8.97 (2.42)|
|LCI5.0, mean (SD)||5.90 (0.94)||5.94 (1.06)|
|z-score, mean (SD)|
|BMI for age||−0.25 (1.14)||0.06 (1.03)|
|Stature for age||0.36 (1.06)||0.08 (1.24)|
|Weight for age||0.06 (0.92)||0.02 (1.19)|
|Concentrations, mean (SD)|
|Sweat chloride, mmol/L||104.0 (16.7)*||100.6 (7.9)|
|Fecal elastase-1, μg/g||26.6 (77.1)‡||8.7 (4.9)|
|Immunoreactive trypsinogen, ng/ml||173.0 (316.6)§||155.7 (184.7)†|
|Fecal calprotectin, μg/g||258.79 (281.57)*||215.37 (255.42)|
As a result of travel restrictions because of the COVID-19 pandemic, 6 children missed the Week 24 visit (LUM/IVA, n = 6), 5 children missed the Week 36 visit (LUM/IVA, n = 2; placebo, n = 3), and 1 child missed the Week 48 visit (LUM/IVA, n = 1).
Treatment with LUM/IVA led to a mean absolute change in the MRI global score primary endpoint (a negative value indicates improvement) of −1.7 (SD = 6.6) compared with −0.3 (SD = 6.1) for the placebo group from baseline at Week 48 (treatment difference, −1.5; 95% credibility interval, −5.5 to 2.6), with a Bayesian posterior probability of LUM/IVA being better than placebo of 76% (Figures 3A and 3B and Table 2). The MRI global score is defined as the sum of the seven scoring parameters for each of the six lobes (i.e., bronchiectasis/wall thickening, mucus plugging, abscesses/sacculations, consolidations, special findings, mosaic pattern, and perfusion abnormalities) (see Table E3). Participants who were treated with LUM/IVA had numerically greater decreases versus placebo in consolidations (difference, −0.2 [95% CI, −0.7 to 0.3]), mosaic pattern (difference, −0.3 [95% CI, −1.7 to 1.1]), mucus plugging (difference, −0.2 [95% CI, −1.4 to 1.0]), and perfusion abnormalities (difference, −1.2 [95% CI, −2.7 to 0.4]); there were no numerical differences after 48 weeks of LUM/IVA treatment in abscesses/sacculations, bronchiectasis/wall thickening, or special findings MRI subscores versus those for placebo (see Table E4).
|Lumacaftor/Ivacaftor Group (n = 35)||Placebo Group (n = 16)|
|Mean score (SD)||17.6 (9.7)||21.4 (9.3)|
|Week 48, n||32||15|
|Mean score (SD)||16.0 (9.4)||21.1 (11.1)|
|Change from baseline at Week 48, mean (SD)||−1.7 (6.6)||−0.3 (6.1)|
|95% CI of mean||−4.1, 0.7||−3.7, 3.1|
|Bayesian posterior probability for a between-treatment difference <0, lumacaftor/ivacaftor vs. placebo, %||76||—|
|Mean treatment difference, lumacaftor/ivacaftor vs. placebo, 95% credible interval||−1.5 (−5.5, 2.6)||—|
Results for secondary and additional efficacy endpoints are provided in Table 3. The mean absolute change from baseline in LCI2.5 through Week 48 was −0.37 (95% CI, −0.85 to 0.10) in the LUM/IVA group and 0.32 (95% CI, −0.20 to 0.84) in the placebo group (Figure 4A and Table 3). The mean absolute changes in weight-for-age, stature-for-age, and BMI-for-age z-scores were 0.13 (95% CI, −0.01 to 0.27), 0.09 (95% CI, −0.05 to 0.22), and 0.20 (95% CI, −0.20 to 0.41), respectively, in the LUM/IVA treatment group and −0.07 (95% CI, −0.24 to 0.11), 0.10 (95% CI, −0.04 to 0.24), and −0.24 (95% CI, −0.55 to 0.07) in the placebo group from baseline at Week 48 (Table 3). The mean absolute change from baseline in sweat chloride concentration through Week 48 was −25.4 mmol/L (95% CI, −32.0 to −18.8) in the LUM/IVA group and 1.0 mmol/L (95% CI, −4.5 to 6.6) in the placebo group (treatment difference, −26.4 mmol/L; 95% CI, −36.5 to −16.3) (Figure 4B and Table 3). The mean absolute change from baseline in fecal elastase-1 concentration through Week 48 was 37.1 μg/g (95% CI, 7.2 to 67.0) in the LUM/IVA group and 2.6 μg/g (95% CI, −3.0 to 8.2) in the placebo group. The mean absolute change from baseline in serum immunoreactive trypsinogen concentration through Week 48 was −85.5 ng/ml (95% CI, −177.9 to 6.8) in the LUM/IVA group and −37.9 ng/ml (95% CI, −75.5 to −0.2) in the placebo group (Table 3). The mean absolute change from baseline in fecal calprotectin concentration through Week 48 was −133.90 μg/g (95% CI, −213.94 to −35.86) in the LUM/IVA group and 26.14 μg/g (95% CI, −139.85 to 192.12) in the placebo group.
|Lumacaftor/Ivacaftor Group (n = 35)||Placebo Group (n = 16)|
|Absolute change from baseline through Week 48, mean (95% CI)|
|LCI2.5*||−0.37 (−0.85 to 0.10)||0.32 (−0.20 to 0.84)|
|Absolute change from baseline at Week 48, mean (95% CI)|
|Weight-for-age z-score||0.13 (−0.01 to 0.27)†||−0.07 (−0.24 to 0.11)|
|Stature-for-age z-score||0.09 (−0.05 to 0.22)†||0.10 (−0.04 to 0.24)|
|BMI-for-age z-score||0.20 (−0.02 to 0.41)†||−0.24 (−0.55 to 0.07)|
|Absolute change from baseline through Week 48, mean (95% CI)|
|Sweat chloride concentration, mmol/L‡||−25.4 (−32.0 to −18.8)§||1.0 (−4.5 to 6.6)|
|Lumacaftor/ivacaftor compared with placebo, mean (95% CI)ǁ||−26.4 (−36.5 to −16.3)|
|Fecal elastase-1 concentration, μg/g*||37.1 (7.2 to 67.0)§||2.6 (−3.0 to 8.2)|
|Immunoreactive trypsinogen concentration, ng/ml*||−85.5 (−177.9 to 6.8)†||−37.9 (−75.5 to −0.20)¶|
|Fecal calprotectin concentration, μg/g*||−133.90 (−231.94 to −35.86)**||26.14 (−135.85 to 192.12)|
|LCI5.0*||−0.20 (−0.41 to 0.02)||0.07 (−0.20 to 0.33)|
|Absolute change from baseline at Week 48, mean (95% CI)|
|Chest MRI morphology score||−1.1 (−2.7 to 0.6)†||−0.9 (−3.5 to 1.7)¶|
|Chest MRI perfusion score||−0.7 (−1.6 to 0.3)†||0.5 (−0.9 to 1.9)|
|Weight, kg||2.4 (2.1 to 2.8)†||1.9 (1.6 to 2.1)|
|Stature, cm||6.9 (6.3 to 7.6)†||6.9 (6.1 to 7.6)|
|BMI||0.07 (−0.17 to 0.30)†||−0.36 (−0.68 to −0.03)|
|PEx requiring oral, inhaled, or intravenous antibiotics|
|Total number of patient-years||34.7||16.3|
|Number of children with events, n (%)||15 (42.9)||10 (62.5)|
|Number of events||26||19|
|Observed event rate per year||0.75||1.17|
|PEx requiring intravenous antibiotics|
|Number of children with events, n (%)||4 (11.4)||1 (6.3)|
|Number of events||4||1|
|Observed event rate per year in study||0.12||0.06|
|PEx requiring hospitalization|
|Number of children with events, n (%)||5 (14.3)||1 (6.3)|
|Number of events||5||1|
|Observed event rate per year in study||0.14||0.06|
The annualized rate of PEx events requiring treatment with oral, inhaled, or intravenous antibiotics was 0.75 in the LUM/IVA group and 1.17 in the placebo group. The annualized rate of PEx requiring treatment with intravenous antibiotics was 0.12 in the LUM/IVA group and 0.06 in the placebo group. The annualized rate of PEx requiring hospitalizations was 0.14 in the LUM/IVA group and 0.06 in the placebo group. The median time to first PEx requiring treatment with oral, inhaled, or intravenous antibiotics was 38.4 weeks in the placebo group; median time could not be estimated in the LUM/IVA group because less than 50% of the children experienced events (Figure 4C). Microbiology culture results at baseline and at Week 48 are available (see Table E5).
All children had at least one treatment-emergent AE (TEAE), which in most were mild or moderate in severity and considered by study investigators to be unlikely or not related to the study drug (Table 4). The most common AEs (in ⩾15% of children) in the LUM/IVA group were nasopharyngitis, infective PEx of CF, cough, rhinitis, abdominal pain, and pyrexia. Serious AEs (SAEs) occurred in 20.0% of children in the LUM/IVA group and 12.5% of children in the placebo group. SAEs were consistent with the background events of CF in this young age group and were considered by study investigators to be not related or unlikely to be related to study drug. The only SAE that occurred in more than 1 child in the LUM/IVA group was infective PEx of CF (3 children [8.6%]). There were no AEs that led to treatment discontinuation in either treatment group.
|Lumacaftor/Ivacaftor Group (n = 35)||Placebo Group (n = 16)|
|Any TEAEs, n (%)||35 (100.0)||16 (100.0)|
|TEAEs by preferred term (⩾15% of children), n (%)|
|Nasopharyngitis||22 (62.9)||8 (50.0)|
|Infective PEx of CF||16 (45.7)||9 (56.3)|
|Cough||10 (28.6)||5 (31.3)|
|Rhinitis||9 (25.7)||6 (37.5)|
|Abdominal pain||7 (20.0)||2 (12.5)|
|Pyrexia||6 (17.1)||3 (18.8)|
|Upper respiratory tract infection||1 (2.9)||3 (18.8)|
|Nasal congestion||0 (0)||4 (25.0)|
|TEAEs by maximum severity, n (%)|
|Mild||10 (28.6)||6 (37.5)|
|Moderate||24 (68.6)||10 (62.5)|
|Severe||1 (2.9)||0 (0)|
|Life-threatening||0 (0)||0 (0)|
|TEAEs by strongest relationship to study drug, n (%)|
|Related||0 (0)||0 (0)|
|Possibly related||13 (37.1)||8 (50.0)|
|Unlikely related||9 (25.7)||4 (25.0)|
|Not related||13 (37.1)||4 (25.0)|
|Serious TEAEs, n (%)||7 (20.0)||2 (12.5)|
|Serious TEAEs (⩾1% of children), n (%)|
|Infective PEx of CF||3 (8.6)||1 (6.3)|
|Pneumonia||1 (2.9)||0 (0)|
|Constipation||1 (2.9)||0 (0)|
|Hematemesis||1 (2.9)||0 (0)|
|Intussusception||1 (2.9)||0 (0)|
|Lung infiltration||0 (0)||1 (6.3)|
|Related serious TEAEs, n (%)||0 (0)||0 (0)|
|TEAEs leading to treatment interruption, n (%)||3 (8.6)||0 (0)|
|Intussusception||1 (2.9)||0 (0)|
|Autoimmune hepatitis||1 (2.9)||0 (0)|
|Aspartate aminotransferase increase||1 (2.9)||0 (0)|
|TEAEs leading to treatment discontinuation, n (%)||0 (0)||0 (0)|
|TEAEs leading to death, n (%)||0 (0)||0 (0)|
On the basis of prior experience with LUM/IVA (8, 21, 22), respiratory events and elevated transaminase levels were predefined as AEs of interest. Treatment-emergent respiratory events (defined as chest discomfort, dyspnea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing) were reported in 2 children (5.7%) in the LUM/IVA group and 3 children (18.8%) in the placebo group; no child had a respiratory event that was considered serious or that led to treatment discontinuation (see Table E6). Treatment-emergent events of elevated transaminase levels were reported in 3 children (8.6%) in the LUM/IVA group and no children in the placebo group (see Table E7); no child had an event of elevated transaminases that was considered serious or that led to treatment discontinuation. Four children (11.4%) in the LUM/IVA group had alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal to eight or fewer times the upper limit of normal, and 1 child (2.9%) had alanine aminotransferase or aspartate aminotransferase levels more than eight times the upper limit of normal. No children in the placebo group had elevated transaminase levels more than three times the upper limit of normal. There were no clinically meaningful trends in other laboratory or vital sign measurements and no cataracts. Overall, these safety data were consistent with the established safety profile of LUM/IVA.
Here, we report the use of chest MRI as an outcome measure in the first randomized placebo-controlled study to evaluate the efficacy and safety of LUM/IVA in children 2 through 5 years of age with CF and the F/F genotype. Chest MRI has been previously shown to detect early lung structure and perfusion abnormalities and response to therapy for exacerbations in people with CF (17–19, 23), with MRI global scores shown to decrease in children with CF after treatment for PEx (17, 18). These reports suggested that chest MRI is an appropriate method to assess lung structure and function in young children for whom spirometry might not be feasible.
Several recent studies have also shown that chest MRI can be used to detect responses to CFTR modulator treatment in patients with CF and established CF lung disease. A prospective, observational study in patients with CF 12 years of age and older who were treated with LUM/IVA showed statistically significant improvements from baseline in both MRI morphology and MRI perfusion scores, along with improved ventilation homogeneity, lung morphology, and perfusion (24). Chest MRI was also used in several prospective, observational studies of adolescent and adult patients with CF who were taking the triple-combination regimen ELX/TEZ/IVA in a real-world, postapproval setting (25–27). After 3 months of ELX/TEZ/IVA therapy, MRI results showed reductions in mucus plugging and bronchial wall thickening, along with improvements in spirometry parameters, nutritional status, and sweat chloride concentration. Taken together, these studies strongly suggest that chest MRI is a useful tool in assessing lung perfusion change and disease progression in adolescents and adults taking CFTR modulators.
In the present study, the primary efficacy endpoint was absolute change in chest MRI global score. The MRI global score is the sum of MRI morphology (defined as the aggregation of subscores for bronchiectasis/wall thickening, mucus plugging, abscesses/sacculations, consolidations, special findings, and mosaic pattern) and MRI perfusion scores (24). Children 2 through 5 years of age who were given LUM/IVA had numerical decreases in both MRI morphology score and MRI perfusion score over the 48-week treatment period. A previous study suggested that air trapping and perfusion abnormalities could be the earliest signs of detectable CF lung disease by MRI, even before morphological changes become evident, reflecting reversible disease (28). The decrease in the MRI perfusion score seen in children 2 through 5 years of age in this study could indicate reductions in the amount of mucus in small airways with a diameter below the resolution of MRI causing hypoxic pulmonary vasoconstriction (15, 18). Overall, for the primary endpoint, there was a larger numerical decrease in the mean chest MRI global score with LUM/IVA treatment than placebo (−1.7 vs. −0.3). Because the sample size for this Phase 2 study was expected to be small and there was limited information with which to predict the size of a treatment effect in this age group, a Bayesian analysis of the primary endpoint was prespecified in the study protocol to provide a measure of the likelihood of a treatment difference between LUM/IVA and placebo. The calculated Bayesian posterior probability of the mean treatment difference (−1.5; 95% credible interval, −5.5 to 2.6) being <0 (indicating that LUM/IVA treatment is better than placebo) was 76%. Taken together, these results suggest that chest MRI can be used safely in children 2 through 5 years of age to identify changes or improvements in lung structure and perfusion, strongly supporting the potential of using chest MRI as an endpoint in pediatric clinical trials of CFTR modulators to assess CF lung disease progression.
The preservation of lung function and lung structure are important goals in the management of CF, and lung disease begins early in life in people with this disease (29). The utility of the LCI, derived from multiple-breath washout testing, has been demonstrated in several studies (17, 29, 30). The LCI has been shown to be a more sensitive measure of lung function than forced expiratory volume in 1 second (FEV1) in children with CF (31, 32), and it can be performed at most ages because it relies only on tidal breathing and is, therefore, less dependent on effort than FEV1 (31). The LCI reflects the level of ventilation inhomogeneity in the lungs, with higher values indicating a need for more lung turnovers (i.e., cycles of inhalation and exhalation) to clear a tracer gas from the lungs (32). Children in this study had mean baseline LCI2.5 of 8.86 and 8.97 in the LUM/IVA and placebo groups, respectively, indicating established airway disease at baseline (33). The within-group numerical improvement in LCI2.5 observed with LUM/IVA treatment in this study was consistent with the previous Phase 3, open-label study of LUM/IVA in this pediatric population (8), whereas the LCI2.5 numerically worsened over time in the placebo group. These results, along with the changes seen in the MRI global score, add to the growing body of evidence demonstrating that subclinical lung disease develops early in children with CF and that intervention with CFTR modulators in children 2 through 5 years of age may improve lung function and offer the opportunity to slow lung function decline over time (8, 29, 34).
Maintaining or improving nutritional status is associated with better lung function and longer survival in patients with CF (35). During this 48-week study, within-group numerical increases in both weight-for-age z-score and BMI-for-age z-score were observed. It is noteworthy that the BMI-for-age z-score in the LUM/IVA group improved at Week 48. Overall, these findings are consistent with improvements in nutritional parameters that have previously been reported in open-label studies with LUM/IVA in this age group (8).
Beyond respiratory and nutritional outcomes, changes in sweat chloride concentration provide a direct indicator of systemic CFTR function (36). The improvement in sweat chloride concentration observed in this study (reduction of 25.4 mmol/L from a mean baseline value of 104.0 mmol/L) demonstrates the robust effect of LUM/IVA on CFTR function in these children; this improvement is consistent with the previous reports of LUM/IVA treatment in this age group (8) and is substantially greater than the improvement seen in previous studies of adolescents and adults with CF (37).
Across all CFTR genotypes, approximately 85% of infants with CF develop exocrine pancreatic insufficiency within the first year of life and require lifelong pancreatic enzyme replacement therapy (38). At baseline, children in this randomized, controlled study had pancreatic insufficiency (fecal elastase-1 concentration, <200 μg/g). Within-group mean fecal elastase-1 concentration numerically improved with LUM/IVA treatment. Many children in this study had elevated serum concentrations of immunoreactive trypsinogen, a nonspecific marker of pancreatic injury (35), at baseline that numerically decreased with LUM/IVA treatment. Although these results are consistent with results detected in a previous open-label LUM/IVA study in this age group (8), additional studies in larger and younger patient populations, as well as with more efficacious next-generation CFTR modulator regimens (25, 39–43), will be needed to determine the impact of CFTR modulator therapy on rescue of pancreatic function.
The present study has several limitations. Although the chest MRI score is a validated measure for assessing CF-related lung disease (14), it does not have a documented minimal clinically important difference. The small number of children with CF in this study limits the ability to definitively document improvements relative to placebo and to perform subgroup analyses (44). The number of CF treatment centers that are currently equipped to perform chest MRI in multicenter studies is small (45); additional studies with larger numbers of CF treatment centers equipped to perform chest MRI are needed. A study with a larger sample size may better determine the correlation between abnormalities in lung morphology and perfusion detected by chest MRI, ventilation inhomogeneity detected by LCI, and other measures of early CF lung disease and extrapulmonary manifestations. It should also be noted that the software for the EcoMedics Exhalyzer-D multiple-breath washout device used for LCI2.5 assessment in this study was recently updated to correct for cross-sensitivity in the oxygen and carbon dioxide sensors that would otherwise overestimate the nitrogen concentration (46). A reanalysis of datasets from six previous studies involving 1,036 multiple-breath washout tests found that, although use of this correction algorithm did result in slightly lower LCI values, the reanalysis did not change the interpretation of the results or the significance of any observed treatment effects (47). Finally, it should be noted that, as this study overlapped with the first year of the COVID-19 pandemic, a global protocol addendum was implemented that enabled in-home assessments. The safety results reported here were based on both in-clinic and in-home safety assessments; however, the efficacy results presented here were based solely on in-clinic assessments.
In conclusion, this study suggests that LUM/IVA may modify CF disease progression when administered early in life. These findings also add to our knowledge of the usefulness of chest MRI in evaluating treatment benefit in preschool children with CF, and they support the potential of chest MRI as an outcome measure in early-intervention clinical trials. Furthermore, the abnormal LCI2.5 at baseline and the numerical improvements in LCI2.5 observed with LUM/IVA add to the growing body of evidence demonstrating the presence of subclinical lung disease in young children with CF and the potential of LUM/IVA to improve subclinical lung disease (29). Taken together, our results support the clinical benefit of early treatment intervention with LUM/IVA in children 2 years of age and older with CF and the F/F genotype.
The authors thank the children and their families for participating in this trial and the trial investigators and coordinators for their contributions to the trial. Medical writing and editorial support were provided by Nathan Blow, Ph.D., of Vertex Pharmaceuticals Incorporated, under the direction of the authors. Editorial coordination and support were provided by Thomas Pickette, Pharm.D., M.B.A., and Emily Poulin, Ph.D., of Vertex Pharmaceuticals Incorporated and by Linda Gorman, Ph.D., of the Envision Pharma Group, contracted by Vertex Pharmaceuticals Incorporated. Nathan Blow, Thomas Pickette, and Emily Poulin may own stock or stock options in Vertex Pharmaceuticals Incorporated. Linda Gorman may own stock or stock options in Envision Pharma Group. The authors acknowledge the contributions of Anita Maniktala, M.D., of ICON plc Global Strategic Solutions and Vertex Pharmaceuticals Incorporated, who served as medical monitor for this study. Anita Maniktala may own stock or stock options in those companies. Christopher Edwards, Ph.D., C.M.P.P., and Karen Kaluza Smith, Ph.D., C.M.P.P., provided medical writing and editorial support on an early draft of the manuscript under the direction of the authors. Christopher Edwards and Karen Kaluza Smith are employees of ArticulateScience, LLC, which received funding from Vertex Pharmaceuticals Incorporated.
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Supported by Vertex Pharmaceuticals Incorporated.
Author Contributions: All authors contributed to data interpretation, conception, drafting, and/or revisions to the manuscript, and all approved the final version that was submitted for publication. M.S. contributed to study design, central quality control and evaluation of multiple-breath washout measurements (performed all multiple-breath washout analysis [central overreading]), data analysis and interpretation, and writing and editing of the manuscript. J.R. contributed to patient acquisition, conduct of the study, data acquisition, and writing and revision of the manuscript. M.E. contributed to data collection, examinations and evaluations, and manuscript editing; and performed evaluation of all magnetic resonance imaging data sets. F.D. contributed to investigations (magnetic resonance imaging), resources, and writing – reviewing and editing. L.N. contributed to investigations, data acquisition, and writing – reviewing and editing. M.V.K. contributed to investigations and writing – reviewing and editing. A.-M.D. contributed to investigations, funding acquisition, data acquisition, resources, and writing – reviewing and editing. C.L. contributed to the analysis of safety data; conclusions; and writing, reviewing, and editing of the manuscript. O.S. contributed to study design, data collection, and statistical analysis. S.T. contributed to investigations, data evaluation, interpretation, and writing and reviewing of the manuscript. T.X. contributed to study design, data collection, and statistical analysis. P.W. contributed to the study design, data collection, and statistical analysis. A.J. was the clinical imaging lead on the study and, in that capacity, contributed to project administration of data collection. P.R. contributed to project administration; analysis and interpretation of study data; and drafting, critical revisions, and final approval of the manuscript. M.E.D. contributed to study design, data collection and analysis, writing of the draft manuscript, and reviewing and editing. M.O.W. contributed to literature research, study design, data collection, data analysis, data interpretation, writing of the manuscript, and approval of the final manuscript; and performed all magnetic resonance imaging data evaluation. M.A.M. contributed to study design, data collection, data interpretation, writing – original draft, and reviewing and editing.
Data sharing statement: Vertex Pharmaceuticals Incorporated is committed to advancing medical science and improving the health of people with cystic fibrosis. This includes the responsible sharing of clinical trial data with qualified researchers. Proposals for the use of these data will be reviewed by a scientific board. Approvals are at the discretion of Vertex Pharmaceuticals Incorporated and will be dependent on the nature of the request, the merit of the research proposed, and the intended use of the data. Please contact [email protected] if you would like to submit a proposal or need more information.
This article has a data supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.