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Organoid Study R334W

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04254705
Recruitment Status : Not yet recruiting
First Posted : February 5, 2020
Last Update Posted : February 5, 2020
Vertex Pharmaceuticals Incorporated
KU Leuven
University of Lisbon
Information provided by (Responsible Party):
Universitaire Ziekenhuizen Leuven

Brief Summary:
In contrary to what is seen in FRT cells, rectal organoids of patients with a R334W mutation do respond to CFTR modulators ivacaftor and lumacaftor. The present study will investigate the response to modulators in organoids of 30 patients with CF and a R334W mutation, to allow further stratificaton for a future clinical trial assessing the clinical effect of ivacaftor/tezacaftor in patients with CF and a R334W mutation.

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Procedure: Rectal Biopsy Not Applicable

Detailed Description:

Rationale: CF is caused by mutations in the 'Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)' channel that codes for the CFTR protein, an anion channel. More than 2000 different CFTR mutations have been described. CFTR modulator drugs treat the underlying protein defect by improving folding and trafficking of nascent protein (corrector) or by improving channel opening at the cell membrane (potentiator). In the European Union, treatment with CFTR modulators has only been approved for patients who are homozygous for F508del or carry a mutation of class III or one of a limited number of residual function mutations.

The R334W-CFTR mutation is a rare mutation (270 subjects in the European CF Registry ECFSPR), described in CFTR2 as disease causing. Clinically there is evidence for residual CFTR function in these subjects since only 36% of the patients with R334W are pancreatic insufficient and the mean age of all patients in the CFTR2 database is a bit older (22 years) than patients with CF and 2 known disease causing mutations (20 years). On the other hand, patients with R334W have on average a high sweat chloride (mean 95 mmol/L) and severe lung disease; their mean FEV1 reported to the CFTR database [1] is very similar to that of other patients with the F508del CF causing mutation. In the Leuven clinic we have one subject with R334W/F508del who is 60 year old and has very severe lung disease (FEV1 in the low 40s).

When studied in FRT (Fisher rat thyroid) cells and compared to wild type, the R334W mutation is reported to give rise to normal levels of protein at the cell membrane, but very much decreased function (short circuit current measurement) of 1.3% of wild type. On the other hand there is very limited rescue of CFTR function after addition of the potentiator ivacaftor: from 1% to 5 % of normal.

In contrast with expression in heterologous systems, intestinal organoids allow study of CFTR function in patient specific material. When tested in intestinal organoids from the patient with F508del/R334W in the Leuven clinic, this mutation resulted in some residual function documented by forskolin induced swelling at higher forskolin concentrations, even before addition of CFTR potentiator or corrector. However, addition of ivacaftor and to a lesser degree lumacaftor results in moderate to good rescue of function; the degree of rescue (FIS result) is intermediate between that seen in F508del homozygous subjects and class III mutation subjects. Comparable results are obtained in prof M Amaral's lab in 3 subjects compound heterozygous for F508del/R334W (results in nasal cells, and intestinal organoids). A CFTR functional rescue in organoids from a subject with the R334W/R746X is also reported by the Dutch Utrecht group in organoids; the forskolin induced swelling induced by luma/iva was again between the response seen with iva in organoids from subjects with gating mutations and by luma/iva in organoids derived from F508del homozygous subjects. These findings suggest that R334W might be a suitable candidate for TEZ/IVA treatment.

The study described in this protocol will be the first step of a larger project that also includes a clinical trial. With the present study, the response of organoids of patients with mutation R334W to available

CFTR-modulators will be tested to identify the in vitro response. An interventional clinical trial, submitted as a separate protocol, will subsequently assess the response to modulators in vivo in the same patients. The clinical trial is thus not part of this protocol.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: For stratification of subjects in the subsequent clinical trial
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Response to CFTR-modulators in Intestinal Organoids of Patients With CF Having at Least One R334W Mutation
Estimated Study Start Date : March 1, 2020
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : March 1, 2021

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Subjects with CF and R334W mutation
Subjects with CF and R334W mutation
Procedure: Rectal Biopsy
Suction biopsy or forceps biopsy

Primary Outcome Measures :
  1. Response to CFTR-modulator in Intestinal Organoids: Increase in Forskolin induced swelling by addition of tezacaftor+ivacaftor after stimulation with Forskolin (0.8 µmol/L) [ Time Frame: At study completion (when rectal biopsy is performed or when organoids are retrieved from the biobank and FIS has been performed), an average of 2 months ]
    Response to tezacaftor+ivacaftor in the Forskolin Induced Swelling (FIS) assay in rectal organoids

Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • In order to be eligible to participate in this study, a subject must meet all of the following criteria:

    1. Male or female with confirmed diagnosis of CF. The subject must have the following:

      a. One or more characteristic phenotypic features, such as chronic cough and sputum production, persistent chest radiograph abnormalities, or airway obstruction manifested by wheezing and air trapping; or a history of CF in a sibling; or a positive newborn screening test result;

    2. Two CFTR mutations identified of which one is R334W OR only the R334W mutation identified and a sweat chloride value above 60 mmol/L
    3. Age 12 years and older
    4. Subject will sign and date an informed consent form (ICF) and or assent (for subjects 12 to 16 years old).

Exclusion Criteria:

  • A potential subject who meets any of the following criteria will be excluded from participation:

    1. Subject has one of the following CFTR-mutations:

      G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, R117H, P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A>G, S945L, S977F, R1070W, D1152H, 2789+5G>A, 3272 26A>G, 3849+10kbC>T

    2. A history of hemorrhoids and recent rectal bleeding
    3. FEV1 above 90% predicted or below 30% predicted during stable disease
    4. History of lung transplantation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04254705

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Contact: François Vermeulen, MD PhD +32 16 34 06 49 ext +3216343599 Franç
Contact: Els Aertgeerts +32 16 34 38 31 ext +3216343599

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University Hospital of Leuven
Leuven, Belgium
Centre Hospitalier Lyon Sud
Lyon, France
Centre Hospitalier Régional Universitaire Montpellier
Montpellier, France
Hôpital Cochin
Paris, France
Hôpital Necker
Paris, France
Instituto G. Gaslini
Genova, Italy
Fondazione Ospedale Maggiore Policlinico
Milan, Italy
Ospedale Pediatrico Bambino Gesù
Roma, Italy
Sapienza university - Centra Fibrosi Cistica Regione Lazio
Roma, Italy
Azieda Ospedaliera Universitaria Integrata
Verona, Italy
Hospital Santa Maria
Lisboa, Portugal
Hospital Universitari Vall d'Hebron
Barcelona, Spain
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
Vertex Pharmaceuticals Incorporated
KU Leuven
University of Lisbon
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Principal Investigator: François Vermeulen, MD PhD Universitaire Ziekenhuizen Leuven
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Responsible Party: Universitaire Ziekenhuizen Leuven Identifier: NCT04254705    
Other Study ID Numbers: ORGANOID-R334W
First Posted: February 5, 2020    Key Record Dates
Last Update Posted: February 5, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Cystic Fibrosis
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases