Webinar Playback: Clinical Research Considerations for Cystic Fibrosis Studies

Live Webinar Q & As 

How many of CTN places have experience with LCI?

ECFS-CTN is composed of 57 highly-experienced CF study-centers in 17 different countries in Europe (https://www.ecfs.eu/ctn). 44 CF centers have been certified to perform LCI for clinical trials.

Interpretation of MBW test results is highly dependent on the quality of the data obtained by the operator. To ensure the correct interpretation of MBW measurements, standardized training, certification, quality control and over-reading protocols have been developed to systematically evaluate clinical trial data where LCI is an outcome measure (https://www.ecfs.eu/ctn/lci/lci-core-facility-definition).

The certification process includes a special course on LCI as well as LCI measurements in healthy individuals and CF patients (Children, adolescents as well as adults). The traces are being analyzed by the reference centre for LCI according to certain quality parameters before the sites receive the certificate. For clinical trials there is the possibility to have all measurements assessed by quality and evaluated according to their results by the European Reference Center which is located at the Bromton Hospital/London for European trials run via ECFS-CTN before they enter the study database. So by this way it is guaranteed, that only LCI-certified sites take part in these trials, moreover, all the measurements undergo a quality control before they are taken into account as outcome parameters for the specific trial. By this way the chance to detect even very small differences during the study interval is very high, which is important for LCI as a clinical outcome parameter.

LCI does also respond to antibiotics if an infection is cured?

So far, data has shown that LCI is also a good lung function parameter which can detect differences after antibiotic treatments in CF; e.g. “Lung clearance index to monitor treatment response in pulmonary exacerbations in preschool children with CF” (https://thorax.bmj.com/content/thoraxjnl/73/5/451.full.pdf) or “Reasons for heterogeneous change in LCI in children with cystic fibrosis after antibiotic treatment” (https://thorax.bmj.com/content/thoraxjnl/69/2/183.full.pdf).

How many centers of the European Network have experience of the LCI technology?

ECFS-CTN is composed of 57 highly-experienced CF study-centers in 17 different countries in Europe (https://www.ecfs.eu/ctn). 44 CF centers have been certified to perform LCI for clinical trials.

Interpretation of MBW test results is highly dependent on the quality of the data obtained by the operator. To ensure the correct interpretation of MBW measurements, standardized training, certification, quality control and over-reading protocols have been developed to systematically evaluate clinical trial data where LCI is an outcome measure (https://www.ecfs.eu/ctn/lci/lci-core-facility-definition).

The certification process includes a special course on LCI as well as LCI measurements in healthy individuals and CF patients (Children, adolescents as well as adults). The traces are being analyzed by the reference centre for LCI according to certain quality parameters before the sites receive the certificate. For clinical trials there is the possibility to have all measurements assessed by quality and evaluated according to their results by the European Reference Center which is located at the Bromton Hospital/London for European trials run via ECFS-CTN before they enter the study database. So by this way it is guaranteed, that only LCI-certified sites take part in these trials, moreover, all the measurements undergo a quality control before they are taken into account as outcome parameters for the specific trial. By this way the chance to detect even very small differences during the study interval is very high, which is important for LCI as a clinical outcome parameter.

Is there a tentative schedule for EMA approval of LCI as a primary end point?

So far, this has not been communicated by EMA; however, we have been working hard within the CF community to reach this aim, namely having LCI approved as a primary endpoint by all authorities. EMA is aware of the changing landscape in CF -as I have pointed out during my presentation- and the importance to focus on alternatives to FEV1 for showing differences in treatments within clinical trials. This point can be discused with EMA/FDA when seeking advice for the study protocol (for EMA: protocol assistance by the product development and scientific support department and CHMP – Article 57(1)(n) of Regulation (EC) 726/2004 of the European Parliament and of the Council).

Is there some experience on LCI use as an end point for anti-infective drugs?

LCI has been included into clinical trials protocols as outcome parameter esp. in antiinfective compounds for which I took part in designing; however, the studies have not been started or been finished yet and there are no data available – as far as I know- so far.

What are the clinical research considerations for FDA/EMA approval we should take into account for 1) proof of concept Phase 2 trials; and 2) pivotal registration trials for a broad spectrum, inhaled antibiotic drug in 3 to 5 years down the road from now?

It depends on the primary indication of this broad spectrum, inhaled antibiotic whether it will be used primarily for reducing chronic infection in CF Lung Disease or rather for eradication; also depending on the bacteria mainly adressed, e.g. Pseudomonas aeruginosa? Therefore, more detailed information is needed to answer this question in extenso. For example:

• For Pseudomonas. Proof of concept and registration trial: FDA/EMA accepted bacteria-free cultures (time to re-occurrence of Pseudomonas aer.) as primary outcome parameter for eradication trials of Pseudomonas aer. with for example FEV1 being second outcome parameter during a pre-defined study time-interval e.g. two-years after study intervention. Nowadays, LCI should be included in these trials to detect small differences in lung function.
• For chronic infection: a less bacterial load should correlate with improvement in FEV1 (lower FEV1 groups as inclusion criteria needed), esp. in LCI (if broad spectrum of patients with different level of CF Lung Disease should be included), less pulmonary exacerbations, better score in lung-imaging, etc. A lower bacterial load is good to be shown as this is the direct result of an effective antibiotic treatment, however, authorities want to see an improvement in clinical parameters. EMA also requires some proof of improvement in lung imaging (at least for a subgroup of patients in special sites) in a proof-of-concept study. Also bronchoscopy may be required for a poof-of-concept study as most of the people with CF will be on CFTR-modulator treatment and be non-sputum-producers any more which is the presumption to examine for bacteria.

I hope this helps, as the information about your compound was limited.

Do you see any effects on inflammation with HEMT treatment and number of exacerbations, respectively?

The numbers of PEs are reduced with HEMT; this has been shown in various clinical trials, observational studies as well as in real-life (registry data and personal clinical experience).

The effects on inflammation are still not completely clear and further data are needed (PROMISE and RECOVER trial will provide more insight). So far, it has been concluded that HEMT reduces airway inflammation, however normal levels of inflammatory parameters have not been reached; e.g.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476912/pdf/rccm.201609-1954OC.pdf. This is also in alliance with my personal experience.

And with respect to the protocol review committee, are patients included in this committee as well?

In every protocol review there are two people with CF (either patients themselves or parents of CF children) included in the review team. They provide their patient perspective as well as their advice on study feasibility/performance/visits, etc.

Please contrast the use of MBW vs. spirometry as an endpoint in clinical trials?

So far, the accepted primary outcome parameter for clinical trials by authorities is FEV1 while LCI was accepted as secondary outcome parameter. An improvement in FEV1 had to be shown in proof of concept studies as well as larger phase III trials. However, if an improvement in FEV1 had been shown in former trials, this data could be extrapolated. The FDA approved triple therapy on the basis of in-vitro data for other mutations as safety and efficacy (in FEV1 and other secondary outcome parameters) had been shown in earlier clinical trials. EMA accepted LCI as primary outcome parameter in a pediatric clinical trial as an improvement in FEV1 had been shown in earlier trials in adolescents and adults. So there is some flow in this area and it is worth discussing these endpoints with EMA and FDA when seeking protocl advice by these authorities (for EMA: protocol assistance by the product development and scientific support department and CHMP – Article 57(1)(n) of Regulation (EC) 726/2004 of the European Parliament and of the Council).

Spirometry is very easy to use for study sites as these have a long experience; this method is cheap and well-established; also people with CF are familiar with the spirometric technique. Quality-criteria have been well established (ATS/ERS Guidelines) and these measurements have been globally harmonised for CF.

LCI is still a new method; only some selected study sites are familiar with performing LCI; this is also applicable for people with CF as this lung function testing is not established in all centers for routine clinical care.