RESUMEN
Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients. There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.
RESUMEN
BACKGROUND: Prescribers have an increasing range of inhaled antimicrobial formulations to choose from when prescribing both eradication and chronic suppression regimens in cystic fibrosis (CF). This study aimed to investigate the decision-making process behind prescribing of inhaled antimicrobials for Pseudomonas aeruginosa infections. METHODS: A questionnaire was developed using Microsoft Forms and then forwarded to 57 Principal Investigators (PIs), at each of the CF centres within the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN). Data collection occurred between November 2021 and February 2022. RESULTS: The response rate was 90 % (n = 51/57 PIs), with at least 50 % of CF centers in each of the 17 countries represented in the ECFS-CTN. Physicians used a median of eight factors in their decision-making process with delivery formulations (92.2 %), adherence history (84.3 %), and antibiotic side-effect profile (76.5 %) often selected. Nebulised tobramycin or colistin were frequently selected as the inhaled antimicrobial in first-line eradication (n = 45, 88.2 %) and chronic suppression regimens (n = 42, 82.4 %). Combination regimens were more often chosen in eradication (first-line: n = 35, 68.6 %, second-line: n = 34, 66.7 %) and later chronic suppression regimens (third-line: n = 27, 52.9 %) than monotherapy. For pwCF also prescribed CFTR modulator therapies, most PIs did not alter inhaled antimicrobial regimens (n = 40, 78.4 %), with few pwCF (n = 18, 35.3 %) or PIs (n = 10, 19.6 %) deciding to stop inhaled antimicrobials. CONCLUSIONS: The inhaled antimicrobial prescribing decision-making process is multifactorial. Nebulised tobramycin or colistin are often used in initial eradication and chronic suppression regimens. To date, CFTR modulator therapy has had a limited impact on the prescribing of inhaled antimicrobial regimens.
Asunto(s)
Antibacterianos , Fibrosis Quística , Pautas de la Práctica en Medicina , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Humanos , Infecciones por Pseudomonas/tratamiento farmacológico , Administración por Inhalación , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/microbiología , Europa (Continente) , Pautas de la Práctica en Medicina/estadística & datos numéricos , Antibacterianos/administración & dosificación , Pseudomonas aeruginosa/efectos de los fármacos , Encuestas y Cuestionarios , Toma de Decisiones Clínicas , Tobramicina/administración & dosificación , Colistina/administración & dosificación , Nebulizadores y VaporizadoresRESUMEN
Understanding the number of patients eligible to participate in research is important to design protocols and define research priorities. We reviewed the records of all patients with CF, age 12+, who receive care at our centre. We assessed their eligibility for trial participation based on common trial inclusion/exclusion criteria. 643 patients were included in the analysis, 31 were modulator ineligible(MI). Only 198(31 %) of the total cohort and 7(23 %) of the MI cohort were eligible for participation based on the hypothetical criteria. The most common reason for ineligibility was ppFEV1 ≥90 % followed by clinical instability, complex comorbidity and anticipated inability to adhere to the protocol. We suggest this would be a useful exercise for centres planning to either participate in, or refer subjects into, upcoming trials to undertake for their own cohort. We also make suggestions for protocol designs that optimise the number of patients who are eligible to participate.
Asunto(s)
Fibrosis Quística , Humanos , NiñoRESUMEN
There is considerable activity with respect to diagnosis in the field of cystic fibrosis (CF). This relates primarily to developments in newborn bloodspot screening (NBS), more extensive gene analysis and improved characterisation of CFTR-related disorder (CFTR-RD). This is particularly pertinent with respect to accessibility to variant-specific therapy (VST), a transformational intervention for people with CF with eligible CFTR gene variants. This advance reinforces the need for a timely and accurate diagnosis. In the future, there is potential for trials to assess effectiveness of variant-specific therapy for CFTR-RD. The guidance in this paper reaffirms previous standards, clarifies a number of issues, and integrates emerging evidence. Timely and accurate diagnosis has never been more important for people with CF.
Asunto(s)
Fibrosis Quística , Recién Nacido , Humanos , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Fibrosis Quística/terapia , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Tamizaje Neonatal/métodosRESUMEN
Bronchiectasis is often considered progressive and irreversible, so cases of regression or reversal are an important step in understanding the underlying pathophysiological mechanisms. Cystic fibrosis, (CF) caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been a success story in personalized medicine. The recent development of CFTR modulator therapies has revolutionized care. Dramatic improvements in lung function, sputum production, daytime functioning, and quality of life are seen within weeks. However, the effect of long-term exposure to elexacaftor + tezacaftor + ivacaftor (ETI) on the structural abnormalities is at present unknown. This case series outlines three adults with CF who have demonstrated progressive improvement in the cylindrical, varicose and importantly cystic changes of bronchiectasis with prolonged ETI treatment. This raises the exciting question of reversibility of bronchiectasis as well as the mechanisms involved in the maintenance and progression of bronchiectasis as it relates to CF.
RESUMEN
Diagnosing cystic fibrosis (CF) in adulthood is not a rare occurrence for CF centers despite the popular belief that the diagnosis is achieved almost universally in childhood by means of newborn screening or early clinical presentation. The purpose of this review article is to highlight specific considerations of adult diagnosis of CF. Obtaining a diagnosis of CF at any age is exceptionally important to ensure optimal treatment, monitoring, and support. In the new era of more personalized treatment with the advent of transformative therapies targeting the underlying protein defect, accurate diagnosis is of increasing importance. This review highlights the diagnostic algorithm leading to a new diagnosis of CF in adults. The diagnosis is usually confirmed in the presence of a compatible clinical presentation, evidence of cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction, and/or identification of variants in the CFTR gene believed to alter protein function. Achieving the diagnosis, however, is not always straightforward as CFTR protein function exists on a continuum with different organs displaying varying sensitivity to diminution in function. We highlight the current knowledge regarding the epidemiology of CF diagnosed in adults and outline the various clinical presentations, including pulmonary and extrapulmonary, which are more common in this population. We expand on the stepwise testing procedures that lead to diagnosis, paying particular attention to additional levels of testing which may be required to achieve an accurate diagnosis. There continues to be an important need for both pulmonary and other specialists to be aware of the potential for later presentation of CF, as the improvements in treatment over decades have had large positive impacts on prognosis for people with this condition.
Asunto(s)
Fibrosis Quística , Adulto , Humanos , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Pruebas Genéticas , Mutación , Tamizaje Neonatal , PronósticoRESUMEN
BACKGROUND: VOCAL was an observational study of the effect of long-term ivacaftor on real-world clinical outcomes and healthcare resource utilization (HCRU) in people with cystic fibrosis (pwCF) in Italy, the Netherlands, and the UK. METHODS: pwCF aged ≥6 years with non-G551D-CFTR gating mutations were eligible. Prospective data were collected up to 48 months after enrollment; retrospective data were collected to ensure that 12 months of pre-ivacaftor data were available. Endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and measures of nutritional status. Pulmonary exacerbation (PEx) rates, HCRU, and respiratory microbiology during ivacaftor treatment were compared with data from the 12-month period before initiation. RESULTS: Seventy-three eligible pwCF were enrolled and received ivacaftor; 65 (89.0%) completed the study (48 [65.8%] completed ≥48 months of ivacaftor). During the first 6 months of ivacaftor, ppFEV1, body mass index (BMI), and BMI-for-age z-score showed least-squares mean absolute improvements of 10.8 percentage points, 0.79 kg/m2, and 0.54, respectively; improvements were maintained through 48 months. Rates of PEx, antibiotic use due to PEx, and hospitalization decreased by >50% during ivacaftor treatment compared with before ivacaftor. The number of respiratory cultures and sputum was lower post-ivacaftor, as was the percentage of pwCF with positive respiratory cultures for 3 of 9 pathogens evaluated (Pseudomonas aeruginosa, Aspergillus fumigatus, Stenotrophomonas maltophilia). Reported safety results were consistent with CF and ivacaftor's known safety profile. CONCLUSIONS: These results demonstrate the positive long-term effectiveness of ivacaftor on clinical outcomes and HCRU in pwCF with non-G551D-CFTR gating mutations in real-world settings.
Asunto(s)
Fibrosis Quística , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Estudios Retrospectivos , Estudios Prospectivos , Aminofenoles/efectos adversos , Volumen Espiratorio Forzado , Mutación , Agonistas de los Canales de Cloruro/efectos adversosRESUMEN
BACKGROUND: Aspergillus fumigatus (Af) infection is associated with poor lung health in chronic suppurative lung diseases but often goes undetected. We hypothesised that inhibition of Af growth by Pseudomonas aeruginosa (Pa) increases the frequency of false-negative Af culture in co-infected people. Using a substantial group of cystic fibrosis (CF) airway samples, we assessed the relationship between Af and bacterial pathogens, additionally comparing fungal culture with next-generation sequencing. METHODS: Frequency of co-culture was assessed for 44,554 sputum/BAL cultures, from 1,367 CF patients between the years 2010-2020. In a subgroup, Internal Transcribed Spacer-2 (ITS2) fungal sequencing was used to determine sequencing-positive, culture-negative (S+/C-) rates. RESULTS: Pa+ samples were nearly 40% less likely (P<0.0001) than Pa- samples to culture Af, an effect that was also seen with some other Gram-negative isolates. This impact varied with Pa density and appeared to be moderated by Staphylococcus aureus co-infection. Sequencing identified Af-S+/C- for 40.1% of tested sputa. Samples with Pa had higher rates of Af-S+/C- (49.3%) than those without (35.7%; RR 1.38 [1.02-1.93], P<0.05). Af-S+/C- rate was not changed by other common bacterial infections. Pa did not affect the S+/C- rates of Candida, Exophiala or Scedosporium. CONCLUSIONS: Pa/ Af co-positive cultures are less common than expected in CF. Our findings suggest an Af-positive culture is less likely in the presence of Pa. Interpretation of negative cultures should be cautious, particularly in Pa-positive samples, and a companion molecular diagnostic could be useful. Further work investigating mechanisms, alternative detection techniques and other chronic suppurative lung diseases is needed.
Asunto(s)
Aspergilosis , Fibrosis Quística , Infecciones Estafilocócicas , Humanos , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/epidemiología , Aspergillus , Aspergilosis/microbiología , Pulmón , Infecciones Estafilocócicas/complicaciones , Bacterias , Pseudomonas aeruginosaRESUMEN
AIM: To explore the health risk of living near permitted composting sites (PCSs) on disease severity in children and adults with cystic fibrosis (CF) across the UK. METHODS: A semi-individual cross-sectional study was used to examine the risk of disease severity in people with CF (pwCF) within and beyond 4 km of PCSs in the UK in 2016. All pwCF registered in the UK CF Registry were eligible for this study. Linear and Poisson regressions, adjusted for age, gender, genotype, BMI, Pseudomonas aeruginosa and deprivation, were used to quantify associations between distance to a PCS and percent predicted forced expiratory volume in one second (ppFEV1), pulmonary exacerbations (#IVdays), and fungal and bacterial infections. RESULTS: The mean age of the 9,361 pwCF (3,931 children and 5,430 adults) studied was 20.1 (SD = 14.1) years; 53.3% were male; and 49.2% were homozygous F508del. Over 10% of pwCF (n = 1,015) lived within 4 km of a PCS. We found no statistically significant difference in ppFEV1 and #IVdays/year in children. However, in adults, ppFEV1 was -1.07% lower (95% confidence interval (CI): -2.29%, 0.16%) and #IVdays/year were 1.02 day higher (95%CI: 1.01, 1.04) within 4 km of a PCS. Furthermore, there were statistically significant differences in mean ppFEV1 in CF adults with Aspergillus fumigatus (58.2.% vs 62.0%, p = 0.005) and Candida spp. (56.9% vs 59.9%, p = 0.029) residing within 4 km of a PCS. No associations were identified for allergic bronchopulmonary aspergillosis, P. aeruginosa or Staphylococcus aureus. CONCLUSIONS: This novel national study provides evidence that adults with CF living near a PCS may experience small reductions in lung function, an increased risk of pulmonary exacerbations, and more frequent fungal infections. If confirmed by studies using refined exposure assessment methods accounting for bioaerosol dispersion, these results could have important implications for the living environment of pwCF.
Asunto(s)
Infecciones Bacterianas , Compostaje , Fibrosis Quística , Pulmón , Adulto , Niño , Femenino , Humanos , Masculino , Adulto Joven , Estudios Transversales , Fibrosis Quística/epidemiología , Fibrosis Quística/genética , Fibrosis Quística/microbiología , Pulmón/fisiopatología , Sistema de Registros , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy. OBJECTIVES: To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability, and reproducibility) within the context of ACT research in CF. DESIGN AND METHODS: A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required. RESULTS: No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified. DISCUSSION AND CONCLUSION: This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research; OMs which have been validated for this purpose are essential. REGISTRATION: This systematic review was registered on the PROSPERO database (CRD42020206033).
Asunto(s)
Fibrosis Quística , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/terapia , Humanos , Evaluación de Resultado en la Atención de SaludRESUMEN
AIM: To investigate whether the effect of cystic fibrosis-related diabetes (CFRD) on the composite outcome of mortality or transplant could act through lung function, pulmonary exacerbations and/or nutritional status. METHODS: A retrospective cohort of adult cystic fibrosis (CF) patients who had not been diagnosed with CFRD were identified from the UK Cystic Fibrosis Registry (n = 2750). Rate of death or transplant was compared between patients who did and did not develop CFRD (with insulin use) during follow-up using Poisson regression, separately by sex. Causal mediation methods were used to investigate whether lung function, pulmonary exacerbations and nutritional status lie on the causal pathway between insulin-treated CFRD and mortality/transplant. RESULTS: At all ages, the mortality/transplant rate was higher in both men and women diagnosed with CFRD. Pulmonary exacerbations were the strongest mediator of the effect of CFRD on mortality/transplant, with an estimated 15% [95% CI: 7%, 28%] of the effect at 2 years post-CFRD diagnosis attributed to exacerbations, growing to 24% [95% CI: 9%, 46%] at 4 years post-diagnosis. Neither lung function nor nutritional status were found to be significant mediators of this effect. Estimates were similar but with wider confidence intervals in a cohort that additionally included people with CFRD but not using insulin. CONCLUSION: There is evidence that pulmonary exacerbations mediate the effect of CFRD on mortality but, as they are estimated to mediate less than one-quarter of the total effect, the mechanism through which CFRD influences survival may involve other factors.
Asunto(s)
Fibrosis Quística , Diabetes Mellitus , Adulto , Estudios de Cohortes , Fibrosis Quística/complicaciones , Fibrosis Quística/epidemiología , Diabetes Mellitus/diagnóstico , Femenino , Humanos , Insulina/uso terapéutico , Masculino , Sistema de Registros , Estudios Retrospectivos , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: There is a growing consensus that the perspective of the patient should be considered in the evaluation of novel interventions. RESEARCH QUESTION: What treatment outcomes matter to people with cystic fibrosis (CF), and what trade-offs would they make to realize these outcomes? STUDY DESIGN AND METHODS: Adults attending a specialist CF center were invited to complete an online discrete choice experiment (DCE). The DCE required participants to evaluate hypothetical CF treatment profiles, defined by impact on lung function, pulmonary exacerbations, abdominal symptoms, life expectancy, quality of life, inhaled medicine usage, and physiotherapy requirement. Choice data were analyzed, using multinomial logit and latent class models. RESULTS: One hundred and three people with CF completed the survey (median age, 35 years; range, 18-76 years); 52% were female; mean FEV1 % predicted, 69% [SD, 22%]). On average, an improvement in life expectancy by 10 years or more had the greatest impact on treatment preference, followed by a 15% increase in lung function. However, it was shown that people would trade substantial reductions in these key outcomes to reduce treatment time or burden. Preference profiles were not uniform across the sample: three distinct subgroups were identified, each placing markedly different importance on the relative importance of both life expectancy and lung function compared with other attributes. INTERPRETATION: The relative importance of treatment burden to people with CF, compared with life expectancy and lung function, suggests it should be routinely captured in clinical trials as an important secondary outcome measure. When considering the patient perspective, it is important that decision-makers recognize that the values of people with CF are not homogeneous.
Asunto(s)
Fibrosis Quística , Adulto , Femenino , Humanos , Masculino , Fibrosis Quística/complicaciones , Calidad de Vida , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Pruebas de Función Respiratoria , PulmónRESUMEN
To assess cancer incidence in the UK cystic fibrosis (CF) population and determine the associated risk factors, we undertook a nested case-control study of patients with CF, registered with the UK CF Registry. Each case with a first reported cancer between 1999 and 2017 was matched with up to 4 controls: by age (±2-years) and year of cancer diagnosis. Conditional logistic regressions were adjusted for sex, lung function (FEV1%), CF related diabetes (CFRD), F508del status, transplant status, DIOS, gastro-oesophageal reflux disease, meconium ileus, Pseudomonas aeruginosa infection, pancreatic insufficiency, proton pump inhibitor (PPI) use, IV antibiotic days and BMI. Results: From 12,886 registered patients, 146 (1.1%) cases of malignancy were identified with 14.3% of cases occurring post solid organ transplant. Site of primary cancer was available for 98 patients: 22% were gastro-intestinal in origin (77% lower, 23% upper GI), 13% skin, 13% breast and 11% lymphomas/leukaemia. In univariable analysis, transplantation increased the odds of reporting any cancer by 2.46 times (95%CI: 1.3-4.6). CFRD also increased the odds of reporting any cancer (OR 2.35; CI: 1.37-4.0) and PPI use (OR 2.0; CI 1.28-3.19). In the multivariable models significant associations with CFRD and transplant remained, while PA infection, PPI use and being overweight showed increased, but statistically insignificant risks. The incidence of GI cancer was strongly associated with CFRD (OR=4.04; 1.47-11.1). Conclusions: We observed a high incidence of lower GI cancers in our cohort which was significantly affected by the presence of CFRD. Screening for gastrointestinal cancers could benefit patients at higher risk.
Asunto(s)
Fibrosis Quística , Neoplasias , Estudios de Casos y Controles , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/epidemiología , Humanos , Incidencia , Neoplasias/diagnóstico , Neoplasias/epidemiología , Neoplasias/etiología , Factores de Riesgo , Reino Unido/epidemiologíaRESUMEN
Background: Despite the importance of reducing treatment burden for people with cystic fibrosis (CF), it has not been fully understood as a concept. This study aims to quantify the treatment burden perceived by CF adults and explore the association between different validated treatment burden measures. Methods: This is a cross-sectional observational study of CF adults attending a single large UK adult center. Participants completed an online survey that contained three different treatment burden scales; CF Questionnaire-Revised (CFQ-R) subscale, CF Quality of Life (CFQoL) subscale, and the generic multimorbidity treatment burden questionnaire (MTBQ). Results: Among 101 participants, the median reported treatment burden by the CFQ-R subscale was 55.5 (IQR 33.3 - 66.6), the CFQoL subscale was 66.6 (IQR 46.6 - 86.6), and the MTBQ reversed global score was 84.6 (IQR 73.1 - 92.3). No correlation was found between respondents' demographic or clinical variables and treatment burden measured via any of the three measures. All treatment burden measures showed correlations against each other. More treatments were associated with high treatment burden as measured by the CFQ-R, CFQoL subscales, and the MTBQ. However, longer treatment time and more complex treatment plans were correlated with high treatment burden as measured by the CFQ-R and CFQoL subscales, but not with the MTBQ. Conclusions: Treatment burden is a substantial issue in CF. Currently, the only available way to evaluate it is with the CF-specific quality of life measure treatment burden subscales (CFQ-R and CFQoL); both indicated that treatment burden increases with more treatments, longer treatment time, and more complex treatments.
RESUMEN
The SARS-CoV-2 pandemic has disrupted clinical trials worldwide. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has tracked clinical trial disruption by surveying its 58 trial sites across 17 European countries and collated information on measures to mitigate the impact of the pandemic and ensure trial continuity. Here, we present recommendations on how to reduce the risk of SARS-CoV-2 exposure to patients and trial staff by implementing remote trial visits where possible, using home assessments, video and phone calls, electronic consent, and home delivery of study drugs. We discuss the practicalities of remote source data verification, protocol amendments, changing trial site location, and staff absences and home working. We outline recommendations on how to protect trial outcomes, including home assessments, safety reporting, protocol deviations, and recruitment challenges. Finally, we discuss the importance of continued access to study drugs via extension trials for some patients. This guidance was co-created from the shared knowledge and experience of sites in our network and was re-distributed directly to all ECFS-CTN sites to help mitigate the impact of further waves of the SARS-CoV-2 pandemic. We will also use this guidance to assist companies, academia, and consortia with future protocol design and risk mitigation plans. This guidance can be applied to clinical trials in other diseases and could help sites that are not supported by clinical trial networks.
Asunto(s)
COVID-19 , Fibrosis Quística , Fibrosis Quística/diagnóstico , Fibrosis Quística/epidemiología , Europa (Continente) , Humanos , Pandemias , SARS-CoV-2RESUMEN
Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer-term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual-agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA-based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizations, registries, and people with CF is something we are all rightly proud of, but innovative trial design and implementation will be needed if we are to continue to build on this progress and further develop drugs for people with CF.