A Prospective Study of Advanced Diagnostics in People With an Unclear Diagnosis of Cystic Fibrosis

Официальное название

Advanced Diagnostic Validation and Novel Clinical Evaluation Across the CFTR Spectrum (ADVANCE-CFTR): a Prospective Study of CFTR Functional Assays, Including Rectal Organoids, to Improve the Accuracy of Diagnosing Cystic Fibrosis.

Обзор

Sometimes it is very difficult to tell if someone has cystic fibrosis (CF), especially when they have rare CF genes. Without this certainty, they are unlikely to get the correct treatment so their health may be affected. More accurate ways to test for CF are therefore needed in this situation. The aim of this study is to develop a more accurate test using what are called "organoids" or "mini organs." Organoids are grown in the laboratory from a small piece of gut tissue. As they have the person's exact genes, they can show if the CF gene ("CFTR") is working correctly or not and thus if the person has CF. The investigators will compare the organoid response with the current more established tests, such as the sweat test and CF genetics, and other recognised specialist tests called nasal potential difference (NPD) and intestinal current measurement (ICM). The gut tissue is usually taken by a quick, relatively painless, outpatient procedure (rectal biopsy). The additional benefit of organoids is that they can also help us to work out the best treatment for that individual by testing how well the gut tissue responds to different drugs in the laboratory. The investigators wish to carry out this research to prove that gut organoids are a better way to test for CF in this situation. The goal will be to diagnose people faster and for them to get better treatment quicker, both key for leading a longer and healthier life.

Подробное описание

BACKGROUND The diagnosis of cystic fibrosis (CF) can be difficult in an important minority of individuals (\~10-15% CF diagnoses), particularly when one or two rare variants of the CF gene (cystic fibrosis transmembrane conductance regulator; CFTR) are identified and the sweat test (sweat chloride concentration; SCC) is non-diagnostic. Biomarkers of CFTR function enable the quantification of individual CFTR protein function, the key underlying defect associated with CF. Such biomarkers play an important role in diagnosing CF and have the additional key capability of measuring the treatment benefits of CFTR targeting therapies, such as CFTR modulators. The currently validated biomarkers of CFTR function; such as SCC, nasal potential difference (NPD) and intestinal current measurements (ICM) can accurately characterise individuals at the extreme ranges of CFTR function (healthy and pancreatic insufficient (PI) CF), but are less reliable in intermediate ranges, particularly when clinical features are atypical. This 'difficult diagnosis' can lead to both a false positive and negative diagnostic outcome, with missed opportunities for the introduction of effective treatments, such as CFTR modulators. Some individuals remain undiagnosed for many years, even decades, so significant disease, associated with declining health, can occur. Individuals and their families are often frustrated and disillusioned by years of uncertainty. In addition, there is a group of individuals with a more limited phenotype (e.g. pancreatitis or congenital bilateral absence of the vas deferens, CBAVD), in whom the strict CF diagnostic criteria are not satisfied - their condition is termed CFTR-related disorder (RD). Recent European CF Society (ECFS) guidelines have highlighted an urgent need for a more accurate and streamlined pathway to their diagnosis.

The Difficult CF Diagnosis (DCFD) service at the Royal Brompton Hospital (RBH) uses NPD, along with whole gene analysis of CFTR and other associated genes for diagnosing unclear cases. Intestinal current measurements (ICM) - the assessment of CFTR function in Ussing chambers using ex vivo tissue biopsies of the intestinal epithelium - is currently being set-up. It is well known that an important sub-group of patients remain undiagnosed. More recently, CFTR-dependent tests in patient-derived intestinal organoids (established at the Beekman lab, University Medical Center (UMC) Utrecht University, Utrecht, The Netherlands) were also found to have excellent diagnostic capabilities with the added benefits of providing key phenotyping and prognostic information, using two different techniques - forskolin-induced-swelling (FIS) and morphological analysis (e.g. steady state lumen area, SLA). These both rely on CFTR-dependent ion and fluid secretion into the organoid lumen. Organoids can also quantify individual responses to CFTR modulators in the laboratory for estimation of potential clinical benefit and can be biobanked for future studies. How one should optimally use these different biomarkers in the context of difficult-to-diagnose individuals and treatment thereof with CFTR modulators is unclear.

ADVANCE-CFTR study is a prospective cohort study of 40-50 individuals with difficult-to-diagnose disease. The participants will be recruited from the Difficult CF Diagnosis (DCFD) service of the Royal Brompton Hospital. Up to 15 CF patients and 15 healthy (non-CFTR disease) controls will also be recruited to validate the tests and anchor extremes in the assays.

Вмешательства

• Процедура Rectal Biopsy
  Rectal biopsy sampling will be performed using either forceps or a suction device according to the method of Vonk et al (2020). Rectal biopsies will be obtained by trained and competent personnel in an appropriate setting, patients recruited will be fully informed and will have provided written consent. Once biopsy samples have been taken the resulting tissue will be processed, stored and transported using established laboratory protocols. The rectal tissue collected will be used to perform inte
• Процедура Rectal biopsy taken opportunistically during endoscopy procedure for other reasons.
  Rectal Biopsy tissue samples will be taken opportunistically for this patient cohort who are undergoing an endoscopy for other reasons. Rectal biopsies will be obtained by trained and competent personnel in an appropriate setting, patients recruited will be fully informed and will have provided written consent. The rectal tissue collected will be used to perform intestinal current measurements and create organoids or 'mini-organs' to allow CFTR protein function to be further characterised.
• Генная терапия Blood test for CFTR Genotyping
  Blood test for CFTR genotyping will be taken for Group C patients to ensure these patients are 'healthy controls' and that they do not have any CFTR gene variants associated with CF.

Первичные конечные точки

• Quantitative assessment of CFTR function [Срок оценки: 30 months]

Вторичные конечные точки (2)

• To individually phenotype patients with difficult-to-diagnose CF [Срок оценки: 30 months]
• CFTR modulator response in intestinal organoids [Срок оценки: 30 months]

Критерии участия

Критерии включения

Group A: Difficult Cystic Fibrosis Diagnosis Cohort

Критерии включения

• Patients with difficult-to-diagnose CF\*
• Adults (≥16y)
• Willing to undergo rectal biopsy
• Able to comply with the study

• Definition: Non-diagnostic first line CFTR testing (individuals who do not fulfil CF diagnostic criteria \[2 CF-causing CFTR variants and/or sweat chloride concentration ≥60 mmol/L\]). Of note, there are some individuals with <2 CF-causing CFTR variants after extended CFTR genetic analysis but with a SCC >60mmol/L. Expansion of the patient pool to include these is permissible.

Group B: Cystic Fibrosis Patient Cohort

Критерии включения

• Patients with confirmed Cystic Fibrosis
• Adults (≥16y)
• Willing to undergo rectal biopsy for this study
• Able to comply with the study

Group C: Non-Cystic Fibrosis Patient Cohort

Критерии включения

• Patients without Cystic Fibrosis or CFTR-related disorder
• Adults (≥16y)
• Willing to undergo rectal biopsy for this study (if undergoing a lower GI endoscopy for other purposes)
• Able to comply with the study

Критерии исключения

Group A: Difficult Cystic Fibrosis Diagnosis Cohort

Критерии исключения

• Contra-indication to rectal biopsy (e.g. significant bleeding diathesis)
• History of lung transplantation
• Receiving CFTR modulator treatment
• Current participation (or participation within one month of enrolment) in a clinical trial of an investigational medicinal product which affects CFTR function (e.g. CFTR modulators, genetic therapies)
• Female who is pregnant or breastfeeding
• Unable to provide informed consent

Group B: Cystic Fibrosis Patient Cohort

Критерии исключения

• Contra-indication to rectal biopsy (e.g. significant bleeding diathesis)
• Current participation (or participation within one month of enrolment) in a clinical trial of an investigational medicinal product which affects CFTR function (e.g. CFTR modulators, genetic therapies)
• Female who is pregnant or breastfeeding
• Unable to provide informed consent
• Exclude all subjects where diagnosis of CF is in doubt

Group C: Non-Cystic Fibrosis Patient Cohort

Критерии исключения

• Contra-indication to rectal biopsy (e.g. significant bleeding diathesis)
• Female who is pregnant or breastfeeding
• Unable to provide informed consent

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Великобритания · 1 центр

• Royal Brompton Hospital — London

Публикации

• Wilschanski M, Famini H, Strauss-Liviatan N, Rivlin J, Blau H, Bibi H, Bentur L, Yahav Y, Springer H, Kramer MR, Klar A, Ilani A, Kerem B, Kerem E. Nasal potential difference measurements in patients with atypical cystic fibrosis. Eur Respir J. 2001 Jun;17(6):1208-15. doi: 10.1183/09031936.01.00092501. PMID 11491166
• De Jonge HR, Ballmann M, Veeze H, Bronsveld I, Stanke F, Tummler B, Sinaasappel M. Ex vivo CF diagnosis by intestinal current measurements (ICM) in small aperture, circulating Ussing chambers. J Cyst Fibros. 2004 Aug;3 Suppl 2:159-63. doi: 10.1016/j.jcf.2004.05.034. PMID 15463951
• www.cftr2.com
• Waller MD, Simmonds NJ. Phenotypic variability of R117H-CFTR expression within monozygotic twins. Paediatr Respir Rev. 2016 Aug;20 Suppl:21-3. doi: 10.1016/j.prrv.2016.06.009. Epub 2016 Jun 15. PMID 27364092
• Servidoni MF, Sousa M, Vinagre AM, Cardoso SR, Ribeiro MA, Meirelles LR, de Carvalho RB, Kunzelmann K, Ribeiro AF, Ribeiro JD, Amaral MD. Rectal forceps biopsy procedure in cystic fibrosis: technical aspects and patients perspective for clinical trials feasibility. BMC Gastroenterol. 2013 May 20;13:91. doi: 10.1186/1471-230X-13-91. PMID 23688510
• Cuyx S, Ramalho AS, Corthout N, Fieuws S, Furstova E, Arnauts K, Ferrante M, Verfaillie C, Munck S, Boon M, Proesmans M, Dupont L, De Boeck K, Vermeulen F; Belgian Organoid Project. Rectal organoid morphology analysis (ROMA) as a promising diagnostic tool in cystic fibrosis. Thorax. 2021 Nov;76(11):1146-1149. doi: 10.1136/thoraxjnl-2020-216368. Epub 2021 Apr 15. PMID 33859053
• Beekman JM, Sermet-Gaudelus I, de Boeck K, Gonska T, Derichs N, Mall MA, Mehta A, Martin U, Drumm M, Amaral MD. CFTR functional measurements in human models for diagnosis, prognosis and personalized therapy: Report on the pre-conference meeting to the 11th ECFS Basic Science Conference, Malta, 26-29 March 2014. J Cyst Fibros. 2014 Jul;13(4):363-72. doi: 10.1016/j.jcf.2014.05.007. Epub 2014 Jun 2. PMID 24882694
• Farrell PM, White TB, Ren CL, Hempstead SE, Accurso F, Derichs N, Howenstine M, McColley SA, Rock M, Rosenfeld M, Sermet-Gaudelus I, Southern KW, Marshall BC, Sosnay PR. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017 Feb;181S:S4-S15.e1. doi: 10.1016/j.jpeds.2016.09.064. PMID 28129811

Идентификаторы

NCT: NCT07402434 · 362887

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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