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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

Tracking Information
First Submitted Date  ICMJE January 27, 2020
First Posted Date  ICMJE February 5, 2020
Last Update Posted Date February 5, 2020
Estimated Study Start Date  ICMJE March 1, 2020
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 3, 2020)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Organoid Study R334W
Official Title  ICMJE Response to CFTR-modulators in Intestinal Organoids of Patients With CF Having at Least One R334W Mutation
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE 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
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE Procedure: Rectal Biopsy
Suction biopsy or forceps biopsy
Study Arms  ICMJE Subjects with CF and R334W mutation
Subjects with CF and R334W mutation
Intervention: Procedure: Rectal Biopsy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: February 3, 2020)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 1, 2021
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 99 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: François Vermeulen, MD PhD +32 16 34 06 49 ext +3216343599 Franç
Contact: Els Aertgeerts +32 16 34 38 31 ext +3216343599
Listed Location Countries  ICMJE Belgium,   France,   Italy,   Portugal,   Spain
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT04254705
Other Study ID Numbers  ICMJE ORGANOID-R334W
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Universitaire Ziekenhuizen Leuven
Study Sponsor  ICMJE Universitaire Ziekenhuizen Leuven
Collaborators  ICMJE
  • Vertex Pharmaceuticals Incorporated
  • KU Leuven
  • University of Lisbon
Investigators  ICMJE
Principal Investigator: François Vermeulen, MD PhD Universitaire Ziekenhuizen Leuven
PRS Account Universitaire Ziekenhuizen Leuven
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP