Identify the predicted best clinical responders and predicted low-responders (based on amount of organoid swelling) to new CFTR-modulators out of 500 unique patient-specific intestinal organoids screened for in-vitro drug efficacy. The 81 identified…
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
- Congenital respiratory tract disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Intestinal organoid response of 500 subjects to three drug products of
different pharmaceutical companies, ranked by best response per drug product.
Secondary outcome
NVT
Background summary
CF is caused by mutations in the *Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR)* channel. To re-establish the function of this complex
chloride channel, typically two to three drug mode of actions are needed. Seven
biotech and two large pharma companies have one or more CF drugs in their
pipeline. All these companies focus their development on patients carrying the
F508del mutation, which is present in ~80% of CF patients, or gating mutations
which are present in 5% of CF patients (gating mutations result in a reduced
opening of the CFTR-channel at the cell surface which limits the flow of
chloride ions through the CFTR channel). Although CF is a monogenetic disease,
the 15% remaining patients carry >1800 different rare and mostly
uncharacterized CFTR mutations. It is unknown which of these would respond to
which of the drugs present in the development pipeline. We hypothesize that we
can identify a subset of patients with rare CFTR mutations that will clinically
respond to (one of) the drugs in the development pipeline, by using their
individual intestinal organoids to screen for drug response.
To further evaluate this hypothesis, we have designed a project called HIT-CF.
The core of the project exists of a two-step approach to identify patients
outside the existing drug label that also benefit from CFTR-modulator
treatment.
The first step will be to test novel CFTR-modulators (and combinations) on
organoids of 500 European CF-patients with rare CFTR-mutations, to identify
patients that we predict will clinically benefit from these treatments. The
second step is to evaluate the clinical efficacy of these drugs in a 3-armed
platform trial, in which we will study the effect of 3 different study drugs
(or combinations) in the patients identified by their organoid response.
The study described in this protocol will be the first step of this HIT-CF
project, namely testing novel CFTR-modulators on organoids of 500 CF-patients,
and identifying in vitro responders to include in the subsequent clinical
trials. The clinical trials will be separate protocols, and are not part of
this protocol. However, the outline of the total project will be described in
this protocol.
Study objective
Identify the predicted best clinical responders and predicted low-responders
(based on amount of organoid swelling) to new CFTR-modulators out of 500 unique
patient-specific intestinal organoids screened for in-vitro drug efficacy. The
81 identified subjects with the best in-vitro response and 27 subjects with a
low in-vitro response will be eligible for participation in subsequent clinical
trials studying these CFTR-modulators.
Study design
The study design will be a multi-center, interventional study. At one
time-point during the study, intestinal biopsies are collected for each subject
to create patient-specific intestinal organoids. This will be executed for 500
subjects in different clinical centers across Europe that are capable and
willing to collect rectal biopsies. Investigational study drugs will be tested
on each organoid in one of the three Academic laboratories (Utrecht, Leuven and
Lisbon). For the top 50 responders per Academic laboratory, these experiments
will be repeated at the HUB laboratory, and the outcome of the in-vitro testing
will be reported. Thus, study duration per subject will be only one day (the
day of collecting the biopsies), but we estimate total study duration to be
around 2 years.
Study burden and risks
The only intervention that will take place is a rectal biopsy. Collecting
biopsies using forceps during endoscopy has a very low risk of complications.
In a recently published article, the safety of this procedure was evaluated. No
major complications were reported when studying 353 biopsies taken. Only one
patient complained of abdominal pain following the procedure, but fully
recovered after 4 hours observation.
Collecting biopsies using a rectal suction device has a very low risk of
complications. Friedman et al. have recently published a systematic review, in
which the risk of any complication is 0.63%. Persistent rectal bleeding was the
most common complication with an incidence of 0.5%. The article states that in
very young children (<1 years of age), the risk is relatively higher. We will
perform this procedure in adult* subjects.
The potential benefit for the patient could be participation in a clinical
trial, and possibly subsequent successful treatment with a drug. The patients
involved in this study are currently not targeted by any drug development
effort, and therefore this could be a unique opportunity for these patients to
get access to CFTR-modulator treatment.
*16 or 18 years depending on country-specific ethical regulations
Lundlaan 6
Utrecht 3584EA
NL
Lundlaan 6
Utrecht 3584EA
NL
Listed location countries
Age
Inclusion criteria
1. Male or female with confirmed diagnosis of CF. The subject must have of the following:
o 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 new-born screening test result;
2. An increased sweat chloride concentration (above 60 mmol/L) by pilocarpine iontophoresis (documented in patient records)
3. Adult age* on the date of informed consent for biopsy taking. Younger patients will not be included due to extensive and long-term safety data needed before a trial in younger paediatric patients is considered safe.
*16 or 18 years depending on country-specific ethical regulations
4. Subject will sign and date an informed consent form (ICF).
Exclusion criteria
1. Subject has at least one of the following CFTR-mutations:
508del, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, R117H, A455E, 3849+10kbC>T
2. Subject has a combination of any two (2) of the following mutations:
G542X, 1717-1G>A, 621+1G>T, 3120+1G>A, 1898+1G->A, CFTRdele2,3 and 2183AA->G
3. History of any comorbidity reviewed at the Screening Visit that, in the opinion of the investigator, might pose an additional risk in potentially administering study drug to the subject if he or she enters the subsequent clinical study. For example, a history of cirrhosis with portal hypertension.
4. History of lung transplantation.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL65123.041.18 |
| OMON | NL-OMON24027 |