Cystic Fibrosis Clinical Trials Research Articles

Levelling the playing field through the London Network of the UK clinical trials accelerator platform

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.

Transduction of Ferret Surface and Basal Cells of Airways, Lung, Liver, and Pancreas via Intratracheal or Intravenous Delivery of Adeno-Associated Virus 1 or 6.

Cystic fibrosis (CF) is potentially treatable by gene therapy. Since the identification of the CF gene, preclinical and clinical trials have concentrated on achieving effective gene therapy targeting the lung. However, the lung has proven to be a formidable barrier to successful gene therapy especially for CF, and many clinical trials failed to achieve efficacy. Recent advances in vector design and adeno-associated virus (AAV) serotypes have increased the chances of success. Given that CF is a multi-organ disease, the goal of this study was to test whether a gene therapy approach involving AAV1 or AAV6 vector delivery via the systemic circulation would at the same time overcome the barrier of lung delivery and transduce organs commonly affected by CF. To accomplish this, we sprayed AAV1 containing green fluorescent protein (GFP) into the trachea or injected it intravenously (IV). We also tested AAV6 injected IV. No adverse events were noted. Ferrets were necropsied 30 days after vector delivery. AAV1 or AAV6 vector genomes, messenger RNA (mRNA) expression, and GFP were detected in all the tracheal and lung samples from the treated animals, whether AAV1 was sprayed into the trachea or injected IV or AAV6 was injected IV. Importantly, both surface epithelial and basal cells of the trachea and lung airways were successfully transduced, regardless of which route of delivery or vector serotype used for transduction. We detected also AAV1 and AAV6 vector genomes, mRNA expression, and GFP in the livers and pancreases, particularly in the acinar cells of the pancreatic duct. These data suggest that gene transfer is attainable in the airways, liver, and pancreas using either serotype, AAV1 or AAV6. Given that these same organs are affected in CF, systemic delivery of AAV may be the preferred route of delivery for a gene therapy for CF.

Potential implicit bias in attribution of adverse events in randomized controlled trials in cystic fibrosis

IntroductionAlthough work to date in cystic fibrosis (CF) has elucidated frequencies and characteristics of adverse events, the accuracy of attribution of relatedness to study drug by investigators has not been assessed. We aimed to determine whether there was an association of attribution by group allocation in CF clinical trials. MethodsWe conducted a secondary analysis from 4 CF trials of all persons who experienced an AE. Our primary outcome was the odds of an AE related to active study drug and predictor of interest was the treatment allocation. We constructed a multivariable generalized estimating equation model allowing for repeated measures. ResultsA total of 785 subjects (47.5% female, mean age 12 years) had 11,974 AEs, of which 430 were serious. AE attribution was greater with receipt of active study drug as compared to placebo but did not reach statistical significance (OR 1.38, 95% CI 0.98–1.82). Significantly associated factors included female sex (OR 0.58, 95% 0.39–0.87), age (OR 1.24, 95% CI 1.06–1.46) and baseline lung function (per 10%, OR 1.16, 95% CI 1.05–1.28). ConclusionIn our large study, there was a non-significant but greater odds of AE attribution (a key element of clinical trial reporting) to active study drug based on assigned treatment to study drug or control which suggests that there is a trend in physicians to attribute blinded safety data to the active drug. Interestingly, females were less likely to have AE attribution to study drug and warrants further work in development and validation of monitoring guidelines and processes.

P088 A systematic review on all efficacy endpoints used in cystic fibrosis clinical trials in the past 5 years

P088 A systematic review on all efficacy endpoints used in cystic fibrosis clinical trials in the past 5 years

Center-level self-study identifies opportunities to advance equity in cystic fibrosis clinical trial participation

Clinical trials are a necessary tool for evaluating the effectiveness of newly developed treatments and interventions for cystic fibrosis (CF). Prior work demonstrated a proportional underrepresentation of people with CF (pwCF) identifying as part of a minoritized racial or ethnic group in clinical trials. In order to establish a baseline for improvement efforts, we undertook a center-level self-study to evaluate if the racial and ethnic backgrounds of pwCF participating in clinical trials at our CF Center in New York City reflect our overall patient diversity (N = 200; 55 pwCF identifying as part of a minoritized racial or ethnic group and 145 pwCF identifying as non-Hispanic White). A smaller proportion of pwCF identifying as part of a minoritized racial or ethnic group participated in a clinical trial as compared to pwCF identifying as non-Hispanic White (21.8% vs. 35.9%, P = 0.06). A similar trend was present for pharmaceutical clinical trials (9.1% vs. 16.6%, P = 0.3). When limiting the study population to the pwCF most likely to be eligible for a CF pharmaceutical clinical trial, a larger proportion of pwCF identifying as part of a minoritized racial or ethnic group participated in a pharmaceutical clinical trial as compared to pwCF identifying as non-Hispanic White (36.4% vs. 19.6%, P = 0.2). No pwCF identifying as part of a minoritized racial or ethnic group participated in an offsite clinical trial. Efforts to improve the racial and ethnic diversity of pwCF in clinical trials, both onsite and offsite, will require a shift in how recruitment opportunities are identified and communicated to pwCF.

35 Approaches that use historical controls to meet modern needs in cystic fibrosis clinical trials

35 Approaches that use historical controls to meet modern needs in cystic fibrosis clinical trials

355 Investigating disparities in cystic fibrosis clinical trial participation: One cystic fibrosis center's self-study

355 Investigating disparities in cystic fibrosis clinical trial participation: One cystic fibrosis center's self-study

EPS6.09 A discrete choice experiment to quantify the influence of trial features on patients’ decisions to join cystic fibrosis clinical trials

ePS6.09 A discrete choice experiment to quantify the influence of trial features on patients’ decisions to join cystic fibrosis clinical trials

Application of gap time analysis with flexible hazards to pulmonary exacerbations in the EPIC observational study.

Cystic fibrosis and other chronic lung disease clinical trials often use time to first pulmonary exacerbation (PEx) or total PEx count as endpoints. The use of these outcomes may fail to capture patterns or timing of multiple exacerbations and how covariates influence the risk of future exacerbations. Analysis of gap times between PEx provides a useful framework to understand risks of subsequent events, particularly to assess if there is a temporary increase in a hazard of a subsequent PEx following the occurrence of a PEx. This may be useful for estimating the amount of time needed to follow patients after a PEx and predicting which patients are more likely to have multiple PEx. We propose a smoothed hazard for gap times to account for elevated hazards after exacerbations. A simulation study was conducted to explore model performance and was able to appropriately estimate parameters in all situations with an underlying change point with independent or correlated recurrent events. Models with different change-point structures and trends are compared using Early Pseudomonas Infection Control (EPIC) observational study data, using a quasi-likelihood modification of the Akaike information criterion; a model with a change-point provided a better fit than a model without one. The analysis suggests that the change point may be 1.8 years (SE 0.09) after the end of a PEx. Models including covariates in the hazard function revealed that having one or two copies of the F508 mutation, female sex, and higher numbers of previous PEx were significantly associated with increased risk of anotherPEx.

Inflammation biomarkers in sputum for clinical trials in cystic fibrosis: current understanding and gaps in knowledge

RationaleSputum biomarkers hold promise as a direct measure of inflammation within the cystic fibrosis (CF) lung, but variability in study design and sampling methodology have limited their use. A full evaluation of the reliability, validity and clinical relevance of individual biomarkers is required to optimise their use within CF clinical research. ObjectivesA biomarker Special Interest Working Group was established within the European Cystic Fibrosis Society-Clinical Trials Network Standardisation Committee, to perform a review of the evidence regarding sputum biomarkers in CF. MethodsFrom the 139 included articles, we identified 71 sputum biomarkers to undergo evaluation of their clinimetric properties, responsiveness, discriminant, concurrent and convergent validity. ResultsCurrent evidence confirms the potential of sputum biomarkers as outcome measures in clinical trials. Inconsistency in responsiveness, concurrent and convergent validity require further research into these markers and processing standardisation before translation into wider use. Of the 71 biomarkers identified, Neutrophil Elastase (NE), IL-8, TNF-α and IL-1β, demonstrated validity and responsiveness to be currently considered for use in clinical trials. Other biomarkers show future promise, including IL-6, calprotectin, HMGB-1 and YKL-40. ConclusionA concerted international effort across the cystic fibrosis community is needed to promote high quality biomarker trial design, establish large population-based biomarker studies, and work together to create standards for collection, storage and analysis of sputum biomarkers.

The Association between IgG and Disease Severity Parameters in CF Patients.

Assessing disease severity in patients with cystic fibrosis (CF) is essential when directing therapies. Serum immunoglobulin G (IgG) levels increase with disease severity. Lung clearance index (LCI) is recognized as an outcome measure for CF clinical trials. Our aim was to evaluate the correlations between IgG and disease severity markers. This was a single-center retrospective study, evaluating association between IgG and markers of severity in CF patients (including clinical characteristics, lung spirometry, LCI, clinical scores and computed tomography (CT) scores) during stable conditions. There were 69 patients, age 20.5 ± 11.6 years. Nineteen (27.5%) patients had elevated IgG. IgG correlated positively with LCI (r = 0.342, p = 0.005). IgG was higher in pancreatic insufficient (PI) and patients with liver disease (1504.3 ± 625.5 vs. 1229 ± 276.1 mg/dL in PI vs. PS, p = 0.023, and 1702.6 ± 720.3 vs. 1256.2 ± 345.5 mg/dL with vs. without liver disease, p = 0.001, respectively). IgG also correlated positively with CRP, CT score, and days with antibiotics in the previous year (r = 0.38, p = 0.003; r = 0.435, p = 0.001; and r = 0.361, p = 0.002, respectively), and negatively with FEV1% and SK score (r = −0.527, p < 0.001 and r = −0.613, p < 0.001, respectively). IgG correlated with clinical parameters, pulmonary functions, and imaging. However, this is still an auxiliary test, complementing other tests, including lung function and imaging tests. Larger multi-center longitudinal studies are warranted.

NIH and National Foundation Expenditures For Sickle Cell Disease and Cystic Fibrosis Are Associated With Pubmed Publications and FDA Approvals

Sickle cell disease (SCD) and cystic fibrosis are both rare inherited diseases most often diagnosed in the United States by newborn screening. Early diagnosis and treatment have led to substantial improvements in survival, but adult mortality remains high with median survival of 40 to 45 years for sickle cell anemia and 35 to 40 years for cystic fibrosis. Disparities in funding between these two diseases of similar severity have been long recognized, but the relationship between funding and research productivity has not been rigorously evaluated. We hypothesized that expenditures by the NIH and the national foundations for these diseases would be associated with the number of publications indexed in PubMed, active clinical trials, and FDA approvals.We estimated disease-specific funding and number of career development awards using NIH RePORT (http://www.report.nih.gov/categorical_spending.aspx) and the Form 990 financial reports for expenditures by year for the Sickle Cell Disease Association of America and the Cystic Fibrosis Foundation and Cystic Fibrosis Foundation Therapeutics, Inc. We calculated expenditures per individual using published estimates of the number of people with SCD (89,079) and cystic fibrosis (30,000) in the United States. We developed a comprehensive search strategy with a medical informationist to identify relevant publications in PubMed and new postings of clinical trials (clinicaltrials.gov) by disease. We reviewed FDA approvals from 2009 to July 2013 to identify indications for SCD or cystic fibrosis.Funding per affected individual was 7.6 (2010) to 11.4 fold (2011) greater for cystic fibrosis than SCD and included a 3.5-fold higher NIH funding and 370 (2010) to 440 fold (2011) higher national foundation funding. NIH career development awards were similar for the two diseases despite nearly 3-fold more individuals affected by SCD. There were nearly twice as many publications and slightly more new listings of clinical trials for cystic fibrosis. No drugs were approved between 2010 and July 2013 for the treatment of SCD compared with 5 for cystic fibrosis.We confirmed widely disparate NIH and national foundation funding per individual affected by SCD and cystic fibrosis. Research productivity as measured by articles indexed in PubMed, new clinical trials, and new drug approvals were substantially higher for cystic fibrosis, despite similar severity to SCD and many fewer affected individuals in the United States. This likely reflects the increased financial resources available for research and quality improvement efforts.TableFunding and Research Productivity for Sickle Cell Disease and Cystic Fibrosis by Year.Sickle Cell DiseaseCystic FibrosisNIH Funding 2010$85,023,144$99,201,078NIH Funding 2011$65,094,922$78,861,688NIH Career Development Awards 20101514NIH Career Development Awards 20111618Foundation Funding 2010$1,399,062$122,135,426Foundation Funding 2011$1,185,023$176,209,849Per Person Funding 2010$970$7,378Per Person Funding 2011$744$8,502PubMed Publication 20108011553PubMed Publication 20118671556Clinical Trials 20102437Clinical Trials 20112625 Disclosures:Strouse:NIH: Research Funding; Doris Duke Charitable Foundation: Research Funding; Masimo Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lanzkron:NIH: Research Funding. Haywood:NIH: Research Funding.

Pulmonary Function Testing in the Coronavirus Disease Era: Lessons and Opportunities.

Pulmonary Function Testing in the Coronavirus Disease Era: Lessons and Opportunities.

Guiding the rational design of patient-centred drug trials in Cystic Fibrosis: A Delphi study

BackgroundMaking trials more patient-centred improves recruitment and retention, patient satisfaction and makes research accessible to a more representative population. We aimed to understand the factors that influence participation and engagement in clinical trials in cystic fibrosis (CF) trials to guide the rational design and delivery of patient-centred trials. MethodsWe used a Delphi process, supported by extensive literature review and 3 workshops, to determine which factors stakeholders think exert significant influence in participation and engagement in CF trials. Panellists were recruited from across the UK and the study was administered online. ResultsWe had representation from 19 CF centres; 28 people with CF (pwCF), 26 parents and 30 healthcare professionals (HCPs). Panels were presented with a shortlist of 104 factors and asked which they thought influence participation and engagement in CF trials. After 3 iterations, 43 statements met consensus for pwCF, 48 for the parents and 69 for the HCPs. ConclusionsWe identified many targets to make trials more patient-centred. Whilst some require an overhaul of trial delivery, many are relatively easy to implement. We outline a list of ‘dos and don'ts’ for sponsors and research teams including: focus on good communication; recognise that lack of time is the greatest barrier to trial participation so minimise the frequency and length of visits; help participants fit trials around busy lives; remember trial participation can be a major life-event and support participants accordingly; and don't underestimate the impact of simple strategies e.g. on-site access to Wifi and cups of tea.

P063 Community involvement in shaping cystic fibrosis clinical trials

P063 Community involvement in shaping cystic fibrosis clinical trials

P061 The UK Clinical Trials Accelerator Platform - a national cystic fibrosis clinical trials network increasing access to clinical trials for the UK cystic fibrosis community

P061 The UK Clinical Trials Accelerator Platform - a national cystic fibrosis clinical trials network increasing access to clinical trials for the UK cystic fibrosis community

Novel Lung Tropic Adeno-Associated Virus Capsids for Therapeutic Gene Delivery.

Efforts to identify mutations that underlie inherited genetic diseases combined with strides in the development of gene therapy vectors over the last three decades have culminated in the approval of several adeno-associated virus (AAV)-based gene therapies. Genetic diseases that manifest in the lung such as cystic fibrosis (CF) and surfactant deficiencies, however, have so far proven to be elusive targets. Early clinical trials in CF using AAV serotype 2 (AAV2) achieved safety, but not efficacy endpoints; however, importantly, these studies provided critical information on barriers that need to be surmounted to translate AAV lung gene therapy toward clinical success. Bolstered with an improved understanding of AAV biology and more clinically relevant lung models, next-generation molecular biology and bioinformatics approaches have given rise to novel AAV capsid variants that offer improvements in transduction efficiency, immunological profile, and the ability to circumvent physical barriers in the lung such as mucus. This review discusses the principal limiting barriers to clinical success in lung gene therapy and focuses on novel engineered AAV capsid variants that have been developed to overcome those challenges.

Evaluating assumptions of definition-based pulmonary exacerbation endpoints in cystic fibrosis clinical trials

BackgroundCystic fibrosis (CF) pulmonary exacerbations can be serious respiratory events and reduction in exacerbation rate or risk are important efficacy endpoints for CF therapeutic trials. Variability in exacerbation diagnoses and treatment have led drug developers to employ “objective” exacerbation definitions combining antimicrobial treatment (AT) and the presence of ≥4 of 12 respiratory criteria (first published by Fuchs et al. [NEJM 1994;331(10):637–42]). Assumptions underlying this approach have yet to be formally evaluated. MethodsRespiratory events (RE) observed during a 48-week trial of ataluren (NCT02139306), a read-through agent for premature nonsense codons, were compared across six exacerbation definitions: any AT, intravenous AT (IVAT), ≥4 Fuchs criteria present, AT plus ≥4 Fuchs criteria, IVAT plus ≥4 Fuchs criteria, and investigator assessment. Fuchs definitions were evaluated by assessing missingness of individual criteria and associations between criteria presence and clinician exacerbation assessment. ResultsAmong 751 RE, more than one third had ≥4 Fuchs criteria present but were not assessed as exacerbations by investigators. Data for ≥1 and for 4 Fuchs criteria, respectively, were missing for ~ 90% and >30% of RE. Only 6/12 Fuchs criteria were present more often when investigators assessed RE as exacerbations than when they did not. Conclusions“Objective” definitions have shortcomings inconsistent with their purpose of optimizing exacerbation capture in clinical trials : 1) they capture events clinicians do not consider exacerbations, 2) are prone to data missingness which can bias the likelihood of meeting the definition, and 3) employ criteria that are not associated with investigator assessment of exacerbation.

Cystic fibrosis drug trial design in the era of CFTR modulators associated with substantial clinical benefit: stakeholders’ consensus view

CFTR modulators associated with substantial clinical benefit are expected to rapidly improve the baseline condition of people with cystic fibrosis (PWCF) as well as decrease the rate of lung function decline, the occurrence of pulmonary exacerbations and likely even other disease complications. These changes in clinical status of PWCF introduced by clinically effective modulator therapy will have major repercussions on modalities of future CF drug development.As part of its ‘Strategic Plan to speed up Access to new Drugs’, the European Cystic Fibrosis Society (ECFS) convened a meeting in Brussels on November 27th 2019 with relevant stakeholders (CF researchers and clinicians, patient organization and pharmaceutical company representatives, regulators, health technology assessors; see Acknowledgments for list of attendees) to discuss the future of clinical trials in cystic fibrosis (CF) in the context of HEMT entering the clinical arena. The following is the conclusion of the presentations and discussions. It is hoped that these concepts will be considered in future regulatory guidelines and may provide rationale and support for alternative trial designs.

My Pathway to Adeno-Associated Virus and Adeno-Associated Virus Gene Therapy: A Personal Perspective.

My Pathway to Adeno-Associated Virus and Adeno-Associated Virus Gene Therapy: A Personal Perspective.