Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials

Mayer-Hamblett, Nicole; Ratjen, Félix; Russell, Renee; Riekert, Kristin A.; Sawicki, Gregory S.; Odem‐Davis, Katherine; Young, J.; Goss, Christopher H.; Retsch‐Bogart, George; Clancy, John; Nichols, David P.; Gifford, Alex H.; Kloster, Margaret; Weaver, Katie; Chapdu, Claire; Xie, Jun; Skalland, M.; Romasco, Melita; Heltshe, Sonya L.; Simon, Noah; VanDalfsen, Jill M; Mead, Anna; Buckingham, Rachael; Seidel, Kathy; Midamba, Nikita; Couture, Laurel; Case, Brooke Zappone; Au, Wendy; Rockers, Elsie; Cooke, Diane; Olander, Amber; Bondick, Irene; Johnson, Miya; VanHousen, Lisya; Nicholson, Boris; Omlor, Gregory J.; Parrish, Michelle; Roberts, Dion; Head, Jillian; Carey, Jessica; Caverly, Lindsay J.; Dangerfield, Joy; Linnemann, Rachel W.; Fullmer, Jason J.; Roman, Chelsea; Mogayzel, Peter J.; Reyes, Deanne; Harmala, Amy; Lysinger, Jerimiah; Bergeron, Jonathan; Virella‐Lowell, Isabel; Brown, Perry; Godusevic, Lejla; Casey, Alicia; Paquette, Lauren; Lahiri, Thomas; Sweet, Julie G.; Donaldson, Scott H.; Harris, Joshua D.; Parnell, Shelia; Szentpetery, Sylvia; Froh, D.; Tharrington, Erica; Jain, Manu; Nelson, Andrew; Kadon, Sharon; McPhail, Gary L.; McBennett, Kimberly; Rone, Tia; Dasenbrook, Elliott C.; Weaver, D. J.; Johnson, Terri; McCoy, Karen; Jain, Raksha; Mcleod, Maria; Klosterman, Mary; Sharma, Preeti; Jones, A. S.; Mueller, Gary A.; Janney, Rachel; Taylor‐Cousar, Jennifer L.; Cross, Mary; Hoppe, Jordana E.; Cahill, James; Mukadam, Zubin; Finto, Jill; Schultz, Karen D.; Villalta, Silvia Delgado; Smith, Alexa; Millard, Susan L.; Symington, T.; Graff, Gavin R.; Kitch, Diane; Sanders, Don B.; Thompson, Misty; Peña, Tahuanty; Teresi, Mary E.; Gafford, Jennifer; Schaeffer, David F.; Mermis, Joel; Scott, Lawrence T.; Escobar, Hugo Murua; Williams, Kristen M.; Dorman, Dana B.; O’Sullivan, Brian; Bethay, Ryan; Danov, Zoran; Berlinski, Ariel; Turbeville, Kat; Johannes, Jimmy; Rodriguez, Angelica; Marra, Bridget; Zanni, Robert; Morton, Ronald A.; Simeon, Terri; Braun, Andrew T.; Dondlinger, Nicole; Biller, Julie; Hubertz, Erin; Antos, Nicholas; Roth, Laura; Billings, Joanne; Larson, Catherine; Balaji, Priya; McNamara, John J.; Clark, Tammy J.; Moffett, Kathryn; Griffith, Rebecca; Martinez, Nancy E.; Hussain, Sabiha; Malveaux, Halina; Egan, Marie E.; Guzman, Catalina; DeCelie-Germana, Joan; Galvin, Susan; Savant, Adrienne P.; Falgout, Nicole; Walker, Patricia; DeMarco, Teresa; DiMango, Emily; Ycaza, Maria; Ballo, Julie; Tirakitsoontorn, Pornchai; Layish, Daniel T.; Serr, Desiree; Livingston, F. R.; Wooldridge, Sherry; Milla, Carlos; Spano, Jacquelyn; Davis, Rebecca L.; Elidemir, Okan; Chittivelu, Subramanyam; Ashley, Scott; Alam, Sarah; Dorgan, Daniel; Butoryak, Matt; Weiner, Daniel J.; Renna, Harmony; Wyatt, Colby; Klein, Brendan; Stone, Anne J.; Lessard, Meg; Schechter, Michael S.; Johnson, Barbara; Scofield, Steven R.; Liou, Theodore G.; Vroom, J.B.; Akong, Kathryn; Gil, Marissa; Betancourt, Legna; Singer, Jonathan P.; Ly, Ngoc P.; Moreno, Courtney C.; Aitken, Moira L.; Gambol, Teresa E; Genatossio, Alan; Gibson, Ronald L.; Lambert, Allison; Milton, Joan; Rosenbluth, Daniel; Smith, Sarah; Green, Deanna; Hodge, Diana; Fortner, Christopher N.; Forell, Mary; Karlnoski, Rachel; Patel, Kapil; Daines, Cori; Ryan, Elizabeth P.; Amaro-Galvez, Rodolfo; Dohanich, Elizabeth; Lennox, Alison; Messer, Zachary R.; Hanes, Holly; Powell, Kay; Polineni, Deepika

doi:10.1016/s2213-2600(22)00434-9

Cited by 74 publications

(23 citation statements)

References 48 publications

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“…As health improves, particularly after initiation of elexacaftor-tezacaftor-ivacaftor, people with cystic fibrosis have expressed interest in reducing the number of treatments . Randomized clinical trials and observational studies are underway to identify therapies that can be reduced or eliminated in patients receiving CFTR modulator therapies.…”

Section: Discussion and Observationsmentioning

confidence: 99%

Cystic Fibrosis

Ong

Ramsey

2023

JAMA

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ImportanceCystic fibrosis, a genetic disorder defined by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects more than 30 000 individuals in the US and approximately 89 000 worldwide. Absent or decreased function of the CFTR protein is associated with multiorgan dysfunction and shortened life expectancy.ObservationsCFTR is an anion channel in the apical membrane of epithelial cells. Loss of function leads to obstructed exocrine glands. Of people with cystic fibrosis in the US, approximately 85.5% have the gene variant F508del. Manifestations of cystic fibrosis in patients with the F508del gene variant begin in infancy with steatorrhea, poor weight gain, and respiratory symptoms (coughing, wheezing). As people with cystic fibrosis age, chronic respiratory bacterial infections cause loss of lung function and bronchiectasis. With the availability of universal newborn screening in multiple countries including the US, many people with cystic fibrosis are asymptomatic at diagnosis. With multidisciplinary care teams that included dietitians, respiratory therapists, and social workers, treatment of cystic fibrosis can slow disease progression. Median survival has improved from 36.3 years (95% CI, 35.1-37.9) in 2006 to 53.1 years (95% CI, 51.6-54.7) in 2021. Pulmonary therapies for patients with cystic fibrosis consist of mucolytics (eg, dornase alfa), anti-inflammatories (eg, azithromycin), and antibiotics (such as tobramycin delivered by a nebulizer). Four small molecular therapies, termed CFTR modulators, that facilitate CFTR production and/or function have received regulatory approval. Examples are ivacaftor and elexacaftor-tezacaftor-ivacaftor. For example, in patients with 1 F508del variant, the combination of ivacaftor, tezacaftor, and elexacaftor improved lung function from −0.2% in the placebo group to 13.6% (difference, 13.8%; 95% CI, 12.1%-15.4%) and decreased the annualized estimated rate of pulmonary exacerbations from 0.98 to 0.37 (rate ratio, 0.37; 95% CI, 0.25-0.55). Improved respiratory function and symptoms have lasted up to 144 weeks in postapproval observational studies. An additional 177 variants are eligible for treatment with the elexacaftor-tezacaftor-ivacaftor combination.ConclusionCystic fibrosis affects approximately 89 000 people worldwide and is associated with a spectrum of disease related to exocrine dysfunction, including chronic respiratory bacterial infections and reduced life expectancy. First-line pulmonary therapies consist of mucolytics, anti-inflammatories, and antibiotics, and approximately 90% of people with cystic fibrosis who are 2 years or older may benefit from a combination of ivacaftor, tezacaftor, and elexacaftor.

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Section: Discussion and Observationsmentioning

confidence: 99%

Cystic Fibrosis

Ong

Ramsey

2023

JAMA

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“…This is the foundation for the CF STORM (www. cfstorm.org.uk) and SIMPLIFY (clinicaltrials.gov NCT04378153) trials which aim to assess the real-world effects of stopping mucoactive agents; the latter has recently been published confirming noninferiority of stopping either nebulised hypertonic saline or DNase over the short-term 98 . The CF community has also identified airway clearance techniques as the most burdensome of treatments; 99 the question 'Can exercise replace chest physiotherapy for people with CF?'…”

Section: Future Directions and Research Prioritiesmentioning

confidence: 99%

Future therapies for cystic fibrosis

et al. 2023

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We are currently witnessing transformative change for people with cystic fibrosis with the introduction of small molecule, mutation-specific drugs capable of restoring function of the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there are multiple cystic fibrosis-causing genetic variants; mutation-specific drugs are not suitable for all genetic variants and also do not correct all the multisystem clinical manifestations of the disease. For many, there will remain a need for improved treatments. Those patients with gene variants responsive to CFTR modulators may have found these therapies to be transformational; research is now focusing on safely reducing the burden of symptom-directed treatment. However, modulators are not available in all parts of the globe, an issue which is further widening existing health inequalities. For patients who are not suitable for- or do not have access to- modulator drugs, alternative approaches are progressing through the trials pipeline. There will be challenges encountered in design and implementation of these trials, for which the established global CF infrastructure is a major advantage. Here, the Cystic Fibrosis National Research Strategy Group of the UK NIHR Respiratory Translational Research Collaboration looks to the future of cystic fibrosis therapies and consider priorities for future research and development.

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“…In a recent multicenter, open-label, randomized, controlled clinical study, Mayer-Hamblett and collaborators assessed the possibility of reducing the therapeutic burden in PwCF receiving ETI therapy by removing hypertonic saline or dornase alpha [ 41 ]. All participants were receiving ETI therapy and should have received mucoactive therapies (i.e., more than 3% hypertonic saline or dornase alpha) for at least 90 days before the start of this study.…”

Section: Clinical Trials: From Monotherapy To Triple Combination Therapymentioning

confidence: 99%

“…The main adverse effects reported were cough, nasal congestion, chest discomfort, increased sputum production, myalgia, and headache. Despite the significant clinical outcomes observed in this study, it should be kept in mind that these findings were observed in PwCF with relatively well-preserved lung function (ppFEV 1 ≥60%) and in a short-term (6 weeks) [ 41 ].…”

Section: Clinical Trials: From Monotherapy To Triple Combination Therapymentioning

confidence: 99%

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

et al. 2023

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Cystic fibrosis (CF) is a potentially fatal monogenic disease that causes a progressive multisystemic pathology. Over the last decade, the introduction of CF transmembrane conductance regulator (CFTR) modulator drugs into clinical practice has profoundly modified the lives of many people with CF (PwCF) by targeting the fundamental cause of the disease. These drugs consist of the potentiator ivacaftor (VX-770) and the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). In particular, the triple combination of CFTR modulators composed of elexacaftor, tezacaftor, and ivacaftor (ETI) represents a life-changing therapy for the majority of PwCF worldwide. A growing number of clinical studies have demonstrated the safety and efficacy of ETI therapy in both short- and long-term (up to two years of follow-up to date) and its ability to significantly reduce pulmonary and gastrointestinal manifestations, sweat chloride concentration, exocrine pancreatic dysfunction, and infertility/subfertility, among other disease signs and symptoms. Nevertheless, ETI therapy-related adverse effects have also been reported, and close monitoring by a multidisciplinary healthcare team remains vital. This review aims to address and discuss the major therapeutic benefits and adverse effects reported by the clinical use of ETI therapy for PwCF.

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Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials

Cited by 74 publications

References 48 publications

Cystic Fibrosis

Cystic Fibrosis

Future therapies for cystic fibrosis

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

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