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

NCT07402434 | Not Yet Recruiting DMC

• 1 other identifier: 362887
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cystic Fibrosis (CF); CFTR-related Disorders

Keywords

CFTR-related disorders; Advanced Diagnostics; Personalised medicine; Cystic Fibrosis (CF); Nasal potential difference (NPD); Intestinal current measurements (ICM); Organoids; Sweat chloride concentration (SCC)

Outcome Measures

Primary Outcomes (1)

• Quantitative assessment of CFTR function

  The primary outcome is a single or composite measurement of CFTR function derived from organoid function, Sweat Chloride Concentration (SCC), Nasal Potential Difference (NPD), and Intestinal Current Measurements (ICM). These quantitative values are then used to correlate with clinical phenotype and final diagnosis, but the outcome measure itself is CFTR functional measurement across the four test modalities.

  30 months

Secondary Outcomes (2)

• To individually phenotype patients with difficult-to-diagnose CF

  30 months

• CFTR modulator response in intestinal organoids

  30 months

Study Arms (3)

Group A - Difficult Cystic Fibrosis Diagnosis Cohort

'Difficult-to-diagnose' patients will be recruited from the 'Difficult CF Diagnosis' service via our established referral pathway. These patients will have non-diagnostic first line CFTR testing (individuals who do not fulfil CF diagnostic criteria \[2 CF-causing CFTR gene variants and/or sweat chloride concentration ≥60 mmol/L\]) . These patients will be 16 years or older and will be willing to undergo a rectal biopsy.

Procedure: Rectal Biopsy

Group B - Cystic Fibrosis Patient Cohort

Patients aged 16 years or older with a confirmed Cystic Fibrosis diagnosis. They would need to be willing to undergo a rectal biopsy.

Procedure: Rectal Biopsy

Group C - Non-Cystic Fibrosis Patient Cohort

Patients aged 16 years or older without a Cystic Fibrosis or CFTR-related disorder diagnosis who would be willing to undergo a rectal biopsy for this study (if undergoing a lower GI endoscopy for other purposes).

Procedure: Rectal biopsy taken opportunistically during endoscopy procedure for other reasons.; Genetic: Blood test for CFTR Genotyping

Interventions

Rectal Biopsy PROCEDURE

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 intestinal current measurements and create organoids or 'mini-organs' to allow CFTR protein function to be further characterised.

Group A - Difficult Cystic Fibrosis Diagnosis Cohort; Group B - Cystic Fibrosis Patient Cohort

Blood test for CFTR Genotyping GENETIC

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.

Group C - Non-Cystic Fibrosis Patient Cohort

Rectal biopsy taken opportunistically during endoscopy procedure for other reasons. PROCEDURE

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.

Group C - Non-Cystic Fibrosis Patient Cohort

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The investigators aim to recruit 40-50 patients from the DCFD service over a 30 month period. A formal power calculation is not possible due to the exploratory nature of the analyses. Recruitment will be opportunistic, based on estimates from the DCFD service. Up to 15 healthy (non-CFTR disease) and 15 CF controls will also be recruited to validate the tests and anchor extremes in the assays.

You may qualify if:

• Group A: Difficult Cystic Fibrosis Diagnosis Cohort
• 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
• 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
• 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)

You may not qualify if:

• Group A: Difficult Cystic Fibrosis Diagnosis Cohort
• 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
• 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
• Contra-indication to rectal biopsy (e.g. significant bleeding diathesis)

Sponsors & Collaborators

• Royal Brompton & Harefield NHS Foundation Trust: lead
• King's College London: collaborator
• UMC Utrecht: collaborator
• Imperial College London: collaborator

Study Sites (1)

Royal Brompton Hospital

London, SW36NP, United Kingdom

Location

Related Publications (24)

• 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 BACKGROUND

• 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 BACKGROUND

• www.cftr2.com

  BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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. No abstract available.

  PMID: 24882694 BACKGROUND

• 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 BACKGROUND

• Hug MJ, Derichs N, Bronsveld I, Clancy JP. Measurement of ion transport function in rectal biopsies. Methods Mol Biol. 2011;741:87-107. doi: 10.1007/978-1-61779-117-8_7.

  PMID: 21594780 BACKGROUND

• Solomon GM, Bronsveld I, Hayes K, Wilschanski M, Melotti P, Rowe SM, Sermet-Gaudelus I. Standardized Measurement of Nasal Membrane Transepithelial Potential Difference (NPD). J Vis Exp. 2018 Sep 13;(139):57006. doi: 10.3791/57006.

  PMID: 30272672 BACKGROUND

• Dekkers JF, Alieva M, Wellens LM, Ariese HCR, Jamieson PR, Vonk AM, Amatngalim GD, Hu H, Oost KC, Snippert HJG, Beekman JM, Wehrens EJ, Visvader JE, Clevers H, Rios AC. High-resolution 3D imaging of fixed and cleared organoids. Nat Protoc. 2019 Jun;14(6):1756-1771. doi: 10.1038/s41596-019-0160-8. Epub 2019 May 3.

  PMID: 31053799 BACKGROUND

• Vonk AM, van Mourik P, Ramalho AS, Silva IAL, Statia M, Kruisselbrink E, Suen SWF, Dekkers JF, Vleggaar FP, Houwen RHJ, Mullenders J, Boj SF, Vries R, Amaral MD, de Boeck K, van der Ent CK, Beekman JM. Protocol for Application, Standardization and Validation of the Forskolin-Induced Swelling Assay in Cystic Fibrosis Human Colon Organoids. STAR Protoc. 2020 Jun 3;1(1):100019. doi: 10.1016/j.xpro.2020.100019. eCollection 2020 Jun 19.

  PMID: 33111074 BACKGROUND

• Rowe SM, Clancy JP, Wilschanski M. Nasal potential difference measurements to assess CFTR ion channel activity. Methods Mol Biol. 2011;741:69-86. doi: 10.1007/978-1-61779-117-8_6.

  PMID: 21594779 BACKGROUND

• Boj SF, Vonk AM, Statia M, Su J, Vries RR, Beekman JM, Clevers H. Forskolin-induced Swelling in Intestinal Organoids: An In Vitro Assay for Assessing Drug Response in Cystic Fibrosis Patients. J Vis Exp. 2017 Feb 11;(120):55159. doi: 10.3791/55159.

  PMID: 28287550 BACKGROUND

• Morris-Rosendahl DJ, Edwards M, McDonnell MJ, John S, Alton EWFW, Davies JC, Simmonds NJ. Whole-Gene Sequencing of CFTR Reveals a High Prevalence of the Intronic Variant c.3874-4522A>G in Cystic Fibrosis. Am J Respir Crit Care Med. 2020 Jun 1;201(11):1438-1441. doi: 10.1164/rccm.201908-1541LE. No abstract available.

  PMID: 32017858 BACKGROUND

• Cirilli N, Southern KW, Barben J, Vermeulen F, Munck A, Wilschanski M, Nguyen-Khoa T, Aralica M, Simmonds NJ, De Wachter E; ECFS Diagnostic Network Working Group. Standards of care guidance for sweat testing; phase two of the ECFS quality improvement programme. J Cyst Fibros. 2022 May;21(3):434-441. doi: 10.1016/j.jcf.2022.01.004. Epub 2022 Jan 19.

  PMID: 35063396 BACKGROUND

• Dekkers JF, Berkers G, Kruisselbrink E, Vonk A, de Jonge HR, Janssens HM, Bronsveld I, van de Graaf EA, Nieuwenhuis EE, Houwen RH, Vleggaar FP, Escher JC, de Rijke YB, Majoor CJ, Heijerman HG, de Winter-de Groot KM, Clevers H, van der Ent CK, Beekman JM. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med. 2016 Jun 22;8(344):344ra84. doi: 10.1126/scitranslmed.aad8278.

  PMID: 27334259 BACKGROUND

• de Winter-de Groot KM, Janssens HM, van Uum RT, Dekkers JF, Berkers G, Vonk A, Kruisselbrink E, Oppelaar H, Vries R, Clevers H, Houwen RHJ, Escher JC, Elias SG, de Jonge HR, de Rijke YB, Tiddens HAWM, van der Ent CK, Beekman JM. Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as a biomarker of CFTR function. Eur Respir J. 2018 Sep 17;52(3):1702529. doi: 10.1183/13993003.02529-2017. Print 2018 Sep.

  PMID: 30166324 BACKGROUND

• Muilwijk D, de Poel E, van Mourik P, Suen SWF, Vonk AM, Brunsveld JE, Kruisselbrink E, Oppelaar H, Hagemeijer MC, Berkers G, de Winter-de Groot KM, Heida-Michel S, Jans SR, van Panhuis H, van der Eerden MM, van der Meer R, Roukema J, Dompeling E, Weersink EJM, Koppelman GH, Vries R, Zomer-van Ommen DD, Eijkemans MJC, van der Ent CK, Beekman JM. Forskolin-induced organoid swelling is associated with long-term cystic fibrosis disease progression. Eur Respir J. 2022 Aug 18;60(2):2100508. doi: 10.1183/13993003.00508-2021. Print 2022 Aug.

  PMID: 35086832 BACKGROUND

• Derichs N, Sanz J, Von Kanel T, Stolpe C, Zapf A, Tummler B, Gallati S, Ballmann M. Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: validation and reference data. Thorax. 2010 Jul;65(7):594-9. doi: 10.1136/thx.2009.125088.

  PMID: 20627915 BACKGROUND

• Castellani C, De Boeck K, De Wachter E, Sermet-Gaudelus I, Simmonds NJ, Southern KW; ECFS Diagnostic Network Working Group. ECFS standards of care on CFTR-related disorders: Updated diagnostic criteria. J Cyst Fibros. 2022 Nov;21(6):908-921. doi: 10.1016/j.jcf.2022.09.011. Epub 2022 Oct 8.

  PMID: 36220763 BACKGROUND

• Simmonds NJ. Is it cystic fibrosis? The challenges of diagnosing cystic fibrosis. Paediatr Respir Rev. 2019 Aug;31:6-8. doi: 10.1016/j.prrv.2019.02.004. Epub 2019 Feb 28.

  PMID: 30967347 BACKGROUND

• Balfour-Lynn IM, Puckey M, Simmonds NJ, Davies JC. Revisiting a diagnosis of cystic fibrosis - Uncertainties and considerations. Paediatr Respir Rev. 2022 Jun;42:29-34. doi: 10.1016/j.prrv.2021.11.002. Epub 2021 Dec 8.

  PMID: 34998674 BACKGROUND

• Barry PJ, Simmonds NJ. Diagnosing Cystic Fibrosis in Adults. Semin Respir Crit Care Med. 2023 Apr;44(2):242-251. doi: 10.1055/s-0042-1759881. Epub 2023 Jan 9.

  PMID: 36623819 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Rectal biospies will be taken for both organoid formation and intestinal current measurements. Organoids will then be used for two different CFTR functional assays: Forskolin-induced swelling assays and Morphological assessment (e.g. Steady-state and high resolution 3D imaging analysis by artificial intelligence).

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Hematologic Tests

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Study Officials

• Nicholas J Simmonds

  Royal Brompton Hospital and Imperial College London

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Emma C Russell-Jones, MBBS

CONTACT

02073528121; emma.russell-jones@nhs.net

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2026
• First Posted: February 11, 2026
• Study Start: February 2, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: February 17, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)