TY - THES ID - 136790530 TI - Optimization of outcome parameters for use in studies with disease modifying drugs in cystic fibrosis AU - Vermeulen, François. AU - De Boeck, Christiane. AU - Proesmans, Marijke. AU - Dupont, Lieven. AU - KU Leuven. Faculty of medicine. Department of development and regeneration. PY - 2018 PB - Leuven KU Leuven. Faculty of Medicine DB - UniCat UR - https://www.unicat.be/uniCat?func=search&query=sysid:136790530 AB - Cystic Fibrosis (CF) is the most common severe hereditary disease in Caucasian populations, affecting approximately 1 in 3500 births. Mutations in the CFTR gene cause abnormal production and/or function of the CFTR protein, an anion channel in the apical membrane with a high expression in most cells lining the airways and the ducts of exocrine glands as the sweat gland, the pancreas or the vas deferens. The abnormal CFTR function results in defective ion and water transport, leading to abnormal viscous respiratory secretions and eventually progressive respiratory insufficiency, high chloride levels in sweat, pancreatic insufficiency, and male infertility. Even with optimal therapy, CF is a life shortening disease with a predicted median survival of around 50 years.^ Although CF is a multisystem disease, more than 90% of patients die from lung disease.(1)Complex genetics necessitate a personalized medicine approach with genotype-specific disease modifying therapiesMore than 2000 different mutations in the CFTR gene have been reported in the CFTR1 database.(2) The most frequent mutation is F508del, for which around half of the patients are homozygous. The other patients carry at least one of the numerous other mutations, which are almost all very rare. In each country, only 5 or 6 mutations apart from F508del are found in more than 1% of the patients.(3)The current treatment for CF is mainly symptomatic: improving mucociliary clearance with mucolytics and physiotherapy, treating lung infection with antibiotics and lung transplantation in end stage lung disease. Eventually, more than 20 years after the discovery of the CFTR gene, treatments that aim at correcting the basic CFTR defect are emerging.^ New ‘disease modifying therapies’ were recently developed to target the basic defect, thereby directly improving or restoring the function of the CFTR protein.(4) Two of these are already on the market, and many more are at varying stages of development. Ivacaftor is a ‘potentiator’ and restores the chloride transport in patients with gating mutations, in which CFTR protein is present at the apical membrane but are not activated. Ivacaftor improves sweat chloride, lung function and weight in patients with gating mutations. Lumacaftor is a ‘corrector’, allowing a proportion of the misfolded F508del protein to traffic to the cell membrane.^ The combination of lumacaftor and ivacaftor resulted in improvement of the sweat chloride value and of the lung function in patients homozygote for the F508del mutation.The diversity of genetic abnormalities in CF results in the need for different compounds targeting each type of mutation, so-called ‘genotype specific personalized medicine’. Clinical trials in patients homozygous for F508del are feasible because sufficient patient numbers are available. Performing clinical trials to prove the effect of a disease modifying therapy becomes much more challenging in patients carrying rare mutations.^ And even in patients with less rare mutations, reliable and precise outcome measures give more robust evidence and allow more efficient use of patients and financial means.With the advent of these disease-modifying treatments the need for outcome parameters that accurately quantify the improvement in the underlying disease defect are more than ever important.Clinical trials and the need for sensitive and accurate outcome measuresClinical trials assess the risk/benefit profile of a compound. Phase 1 trials establish the safety and the tolerability of the new drug in healthy volunteers and allow dose finding. Phase 2 trials assess compound safety in patients, and evaluate ‘proof of concept’ of the effect of the drug on the disease process. At this stage, biomarkers are often used. Given the low number of participants in such trials and the short observation period, a significant effect on clinical or surrogate endpoints is often not achievable.^ In larger-scale phase 3 trials, the beneficial effect of the drug should be demonstrated as a substantial improvement in clinical or surrogate endpoints. Sensitive endpoints, applicable in the population studied, responsive to intervention and adapted to the phase of the trial are thus required. Endpoints or outcome measures can be classified in three categories:- Clinical outcome measures measure how patients feel, function or survive. Increased survival is the result of improvement in the treatment of patients with cystic fibrosis. With a median survival of 35 years, survival is an impossible endpoint to use in clinical trials. Other clinical endpoints are the frequency of respiratory exacerbations and quality of life questionnaires such as the respiratory part of the Cystic Fibrosis Questionnaire-Revised (CFQ-R).- Surrogate outcome measures are lab measurements used as substitutes for clinical end-points.^ To qualify as surrogate outcome, the link between the measurement and eventual clinical disease outcome such as survival must be established. At present, forced expiratory volume in 1 sec (FEV1) is the only FDA approved surrogate endpoint for clinical trials in CF.- Biomarkers are an objective measure of a normal or pathogenic biologic process, or of a pharmacologic response to a therapeutic intervention. In CF, biomarkers that reflect CFTR function and ion transport are the sweat chloride concentration, the nasal potential difference measurement or intestinal current measurement. Other biomarkers reflect early pathogenic processes, e.g. the mucociliary clearance. A combination of endpoints can be used during the evaluation of a new therapy in patients with CF.Given the importance of accurately assessing new therapies, our research has focused on 2 types of outcome measures.^ First, outcome measures that reflect the basic CF defect and that are thus especially useful in phase 2 clinical trials with disease modifying drugs: nasal potential difference (NPD) and sweat chloride. Next, outcome measures that reliably quantify CF lung disease, the major cause of death in CF. These parameters are especially useful in phase 3 clinical trials, when proof of clinical benefit must be provided. We explored the value of lung clearance index (LCI) and FEF25-75.Study objectives, methods and results1.Nasal potential differenceA nasal potential difference (NPD) measurement quantifies the voltage across the nasal epithelium resulting from the mucosal ion transport. It directly assesses the CFTR function by measuring chloride transport, taking into account the function of ENaC, a sodium transporter, which is inhibited by CFTR. A catheter is placed in the nose, with a sensing electrode to measure the potential and a channel to perfuse solutions locally on the nasal mucosa.^ A fixed perfusion sequence is used: Ringer solution and Ringer with amiloride assessing sodium transport through ENaC, followed by a zero-chloride solution and subsequent addition of isoproterenol. The change in potential induced by the latter two solutions is called the total chloride response (TCR) and is a measure of chloride transport through CFTR.The NPD differentiates patients with CF from healthy controls. Patients with CF and mild phenotypes show intermediate NPD values reflecting the degree of residual CFTR function.(5) NPD has been used as an exploratory endpoint in trials, measuring the change in CFTR function during treatment with disease modifying therapies.^ With ivacaftor, a dose response was observed: progressive improvement of chloride transport with increasing drug doses.(6)The NPD is thus a unique way to measure CFTR function in the airways, reflecting the first step of the pathophysiological cascade initiating the respiratory illness responsible for most of the morbidity and mortality of CF. The challenges with NPD as endpoint are the lack of standardization and the poor repeatability of the measurements.Therefore, we investigated the impact of several technical aspects of the NPD measurement, with an emphasis on improving repeatability to reduce the sample size in clinical trials.Vermeulen, F., Proesmans, M., Feyaerts, N., & De Boeck, K. (2011). Nasal potential measurements on the nasal floor and under the inferior turbinate: does it matter? Pediatr Pulmonol, 46(2), 145-152.Nasal potential is not uniform over the nasal mucosa. Therefore, the place of the catheter in the nostril could have an impact on the results obtained.^ We examined the influence of the place of the catheter by comparing the values obtained with the nasal catheter placed medially on the nasal floor in one nostril (the ‘European’ floor protocol), and laterally under the inferior turbinate in the opposite nostril (the ‘American’ turbinate protocol). Thirty-four patients with CF, 26 heterozygotes and 61 control subjects underwent simultaneous measurements with both techniques, with a repeat test in 57 to measure repeatability. Both protocols discriminated well between CF and control subjects, and the mean NPD values were not different. Repeatability was similar with the two methods. Sample size projections using the proportion of interpretable measurements, and mean values in CF and in control subjects slightly favored the use of the ‘floor catheter’ (Table 1).Bronsveld, I.*,Vermeulen, F.*, Sands, D., Leal, T., Leonard, A., Melotti, P., European Cystic Fibrosis Society - Diagnostic Network Working, G. (2013).^ Influence of perfusate temperature on nasal potential difference. Eur Respir J, 42(2), 389-393. (*First authors equal contributions)The effect of the temperature of the perfused solutions was evaluated. Different devices were in use to warm the solutions to 34-37°C during local perfusion, while some operators used solutions at room temperature. To assess the effect of the temperature of the solutions, NPD was measured in healthy subjects (CF subjects have virtually absent chloride transport) at different perfusion temperatures: Warmed (34-37°C, W) or room temperature (RT). Two ER -