Cystic Fibrosis (CF)ADVANCE-CFTRNCT07402434
A Prospective Study of Advanced Diagnostics in People With an Unclear Diagnosis of Cystic Fibrosis
An observational study of Cystic Fibrosis (CF) and CFTR-related Disorders, run by Royal Brompton & Harefield NHS Foundation Trust at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 16 years and olderHealthy volunteers can take part
- Conditions the study is for
- Cystic Fibrosis (CF), CFTR-related Disorders
- What is being tested?
- Rectal Biopsy, Rectal biopsy taken opportunistically during endoscopy procedure for other reasons. and Blood test for CFTR Genotyping
- Type of treatment
- Surgery or procedure
- How many people
- 80 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 2 Feb 2026to 1 Sep 2028
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
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.
Who may be able to join
- 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.
Show all 16Show fewer
- 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)
- Able to comply with the study
Who cannot join
- 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
Show all 17Show fewer
- 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)
- Female who is pregnant or breastfeeding
- Unable to provide informed consent
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United Kingdom1 site
Royal Brompton Hospital
London, SW36NP
Emma Russell-Jones, MBBS, emma.russell-jones@nhs.net
About this study
Official title: 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.
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.
Read the detailed description
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.
- Conditions
- Cystic Fibrosis (CF), CFTR-related Disorders
- Being tested
- Rectal Biopsy, Rectal biopsy taken opportunistically during endoscopy procedure for other reasons., Blood test for CFTR Genotyping
- Keywords
- CFTR-related disorders, Advanced Diagnostics, Personalised medicine, Cystic Fibrosis (CF), Nasal potential difference (NPD), Intestinal current measurements (ICM), Organoids, Sweat chloride concentration (SCC)
- Medical subject headings
- Cystic Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rectal BiopsyProcedure or surgery
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.
Rectal biopsy taken opportunistically during endoscopy procedure for other reasons.Procedure or surgery
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.
Blood test for CFTR GenotypingGenetic
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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). Receives: Procedure: Rectal biopsy taken opportunistically during endoscopy procedure for other reasons.; Genetic: Blood test for CFTR Genotyping |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 30 months
Secondary outcomes (2)
To individually phenotype patients with difficult-to-diagnose CF
To measure individual CFTR function in people with difficult-to-diagnose disease using multiple CFTR functional assays (organoids (Forskolin-induced-swelling assays and AI morphological analysis), Sweat chloride concentration, Nasal potential difference measurements and Intestinal current measurements), and to correlate this with their clinical phenotype, genotype and final diagnosis.
Measured: 30 months
CFTR modulator response in intestinal organoids
To measure CFTR modulator responses of intestinal organoids derived from individuals with difficult to-diagnose disease, taken by rectal biopsy. Response will be measured using Forskolin-induced-swelling assays and AI morphological analysis.
Measured: 30 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Feb 2026
- Study start2 Feb 2026 (estimated)
- Primary completion1 Jun 2028 (estimated)
- Study completion1 Sep 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for Cystic Fibrosis (CF)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Royal Brompton & Harefield NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- King's College London, UMC Utrecht, Imperial College London
- Responsible party
- Sponsor
- Investigators
- Nicholas J Simmonds, Principal investigator, Royal Brompton Hospital and Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07402434
- Sponsor's protocol ID
- 362887
- Acronym
- ADVANCE-CFTR
- Status last verified
- Feb 2026
- First submitted
- 4 Feb 2026
- Last updated
- 17 Feb 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 11491166De 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.
PubMed 15463951www.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.
PubMed 27364092Servidoni 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.
PubMed 23688510Cuyx 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.
PubMed 33859053Beekman 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.
PubMed 24882694Farrell 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.
PubMed 28129811Hug 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.
PubMed 21594780Solomon 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.
PubMed 30272672Dekkers 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.
PubMed 31053799Vonk 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.
PubMed 33111074Rowe 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.
PubMed 21594779Boj 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.
PubMed 28287550Morris-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.
PubMed 32017858
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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.
- ClinicalTrials.gov ID
- NCT07402434
- Acronym / sponsor ID
- ADVANCE-CFTR / 362887
- 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)
- Study type
- Observational
- Recruitment status
- Not yet recruiting
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Royal Brompton & Harefield NHS Foundation TrustUniversity, hospital or other
- Collaborators
- King's College London, UMC Utrecht, Imperial College London
- Study start
- 2 Feb 2026 (estimated)
- Primary completion
- 1 Jun 2028 (estimated)
- Study completion
- 1 Sep 2028 (estimated)
- First posted
- 11 Feb 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Group A - Difficult Cystic Fibrosis Diagnosis Cohort | – | Procedure: Rectal Biopsy'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. |
| Group B - Cystic Fibrosis Patient Cohort | – | Procedure: Rectal BiopsyPatients aged 16 years or older with a confirmed Cystic Fibrosis diagnosis. They would need to be willing to undergo a rectal biopsy. |
| Group C - Non-Cystic Fibrosis Patient Cohort | – | Procedure: Rectal biopsy taken opportunistically during endoscopy procedure for other reasons., Genetic: Blood test for CFTR GenotypingPatients 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). |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- 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.
Key inclusion criteria (16 listed)
- 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
Key exclusion criteria (17 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Rectal BiopsyRectal 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. | Procedure or surgery | Group A - Difficult Cystic Fibrosis Diagnosis Cohort, Group B - Cystic Fibrosis Patient Cohort |
| 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. | Procedure or surgery | Group C - Non-Cystic Fibrosis Patient Cohort |
| Blood test for CFTR GenotypingBlood 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. | Genetic | Group C - Non-Cystic Fibrosis Patient Cohort |
Primary outcome
Quantitative assessment of CFTR function
Time frame: 30 months
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.
2 secondary outcomes
To individually phenotype patients with difficult-to-diagnose CF
Time frame: 30 months
CFTR modulator response in intestinal organoids
Time frame: 30 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2026.
- Background: PubMed 11491166Wilschanski 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.
- Background: PubMed 15463951De 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.
- Backgroundwww.cftr2.com
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- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Nicholas J Simmonds principal investigator
Royal Brompton Hospital and Imperial College London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Cystic Fibrosis (CF) and CFTR-related Disorders, run by Royal Brompton & Harefield NHS Foundation Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 17 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Emma C Russell-Jones, MBBS (02073528121 ext. 88940, emma.russell-jones@nhs.net), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Quantitative assessment of CFTR function (time frame: 30 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07402434, which also lists 24 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2026.