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

David P Nichols, Alex C Paynter, Sonya L Heltshe, Scott H Donaldson, Carla A Frederick, Steven D Freedman, Daniel Gelfond, Lucas R Hoffman, Andrea Kelly, Michael R Narkewicz, Jessica E Pittman, Felix Ratjen, Margaret Rosenfeld, Scott D Sagel, Sarah Jane Schwarzenberg, Pradeep K Singh, George M Solomon, Michael S Stalvey, John P Clancy, Shannon Kirby, Jill M Van Dalfsen, Margaret H Kloster, Steven M Rowe, PROMISE Study group, Richard Ahrens, Moira Aitken, Raouf Amin, Joanne Billings, Andrew Braun, Holly Carveth, Subramanyam Chittivelu, James Chmiel, Elliott Dasenbrook, Joan DeCelie-Germana, Daniel Dorgan, Henry Dorkin, Allen Dozor, Marie Egan, Deborah Froh, Ronald Gibson, Gavin Graff, Ann Granchelli, William Hunt, Sugeet Jagpal, Raksha Jain, Larry Johnson, Claire Keating, Kevin Kirchner, Dana Kissner, Kate Larson-Ode, Jorge Lascano, Kelvin MacDonald, Michelle Mann, Kimberly McBennett, Susanna McColley, Nighat Mehdi, Joel Mermis, Carlos Milla, Susan Millard, Peter Mogayzel, Samya Nasr, Julie Noe, Gregory Omlor, Krishna Pancham, Deepika Polineni, Christopher Richards, Dion Roberts, Iman Sami, Michael Schechter, Karen Schultz, Alvin Singh, Varsha Taskar, Jennifer Taylor-Cousar, Heather Thomas, Karen Voter, Patricia Walker, Daniel Weiner, Mark Wurth, Jennifer Arruda, Mary Bailey, Ryan Bethay, Mary Alice Blackwell, Jenna Bucher, Nadine Caci, James Cahill, Erin Canning, Akele Carter, Sophia Chiron Stevens, Mary Cross, Joy Dangerfield, Adrienne DeRicco, Erin Donnelly, Kim Farley, Jill Finto, Robert Fowler, Susan Galvin, Teresa Gambol, Alan Genatossio, Noni Graham, Catalina Guzman, Margot Hardcastle, Kelsey Haywood, Kathleen Hicks, Barb Johnson, Diane Kitch, Dawn Kruse, Anne Kukral, Margaret Lessard, Jean Malpass, Halina Malveaux, Tiffany McCrabb, Maria Mcleod, James Melson, Julia Meyer, Melissa Molter, Heather Mulroy, Margret Powell, Michelle Powers, Mya Pugh, Armando Ramirez, Rashika Rangaraj, Kira Rehn, Deanne Reyes, Christine Roach, Vicki Roberts, Tia Rone, Laura Roth, Sean Ryan, Ashley Sanders, Cindy Schaefer, Ashley Scott, Lawrence Scott, Charley Sellers, Molly Siegel, Heidi Stapp, Thomas Symington, Ashley Synger, Mary Teresi, Monica Ulles, Michel Veit, Jane Vroom, Justin Wade, Dave Weaver, Alix Wilson, Danielle Wolfe, Maria Ycaza, David P Nichols, Alex C Paynter, Sonya L Heltshe, Scott H Donaldson, Carla A Frederick, Steven D Freedman, Daniel Gelfond, Lucas R Hoffman, Andrea Kelly, Michael R Narkewicz, Jessica E Pittman, Felix Ratjen, Margaret Rosenfeld, Scott D Sagel, Sarah Jane Schwarzenberg, Pradeep K Singh, George M Solomon, Michael S Stalvey, John P Clancy, Shannon Kirby, Jill M Van Dalfsen, Margaret H Kloster, Steven M Rowe, PROMISE Study group, Richard Ahrens, Moira Aitken, Raouf Amin, Joanne Billings, Andrew Braun, Holly Carveth, Subramanyam Chittivelu, James Chmiel, Elliott Dasenbrook, Joan DeCelie-Germana, Daniel Dorgan, Henry Dorkin, Allen Dozor, Marie Egan, Deborah Froh, Ronald Gibson, Gavin Graff, Ann Granchelli, William Hunt, Sugeet Jagpal, Raksha Jain, Larry Johnson, Claire Keating, Kevin Kirchner, Dana Kissner, Kate Larson-Ode, Jorge Lascano, Kelvin MacDonald, Michelle Mann, Kimberly McBennett, Susanna McColley, Nighat Mehdi, Joel Mermis, Carlos Milla, Susan Millard, Peter Mogayzel, Samya Nasr, Julie Noe, Gregory Omlor, Krishna Pancham, Deepika Polineni, Christopher Richards, Dion Roberts, Iman Sami, Michael Schechter, Karen Schultz, Alvin Singh, Varsha Taskar, Jennifer Taylor-Cousar, Heather Thomas, Karen Voter, Patricia Walker, Daniel Weiner, Mark Wurth, Jennifer Arruda, Mary Bailey, Ryan Bethay, Mary Alice Blackwell, Jenna Bucher, Nadine Caci, James Cahill, Erin Canning, Akele Carter, Sophia Chiron Stevens, Mary Cross, Joy Dangerfield, Adrienne DeRicco, Erin Donnelly, Kim Farley, Jill Finto, Robert Fowler, Susan Galvin, Teresa Gambol, Alan Genatossio, Noni Graham, Catalina Guzman, Margot Hardcastle, Kelsey Haywood, Kathleen Hicks, Barb Johnson, Diane Kitch, Dawn Kruse, Anne Kukral, Margaret Lessard, Jean Malpass, Halina Malveaux, Tiffany McCrabb, Maria Mcleod, James Melson, Julia Meyer, Melissa Molter, Heather Mulroy, Margret Powell, Michelle Powers, Mya Pugh, Armando Ramirez, Rashika Rangaraj, Kira Rehn, Deanne Reyes, Christine Roach, Vicki Roberts, Tia Rone, Laura Roth, Sean Ryan, Ashley Sanders, Cindy Schaefer, Ashley Scott, Lawrence Scott, Charley Sellers, Molly Siegel, Heidi Stapp, Thomas Symington, Ashley Synger, Mary Teresi, Monica Ulles, Michel Veit, Jane Vroom, Justin Wade, Dave Weaver, Alix Wilson, Danielle Wolfe, Maria Ycaza

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.

Figures

Figure 1.
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 (seeTable 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.
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.
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.
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.

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