Our primary objective is to investigate whether a further gain in efficacy of oral Ivacaftor treatment can be reached by co-supplementation of genistein, as suggested by their highly synergistic action in intestinal organoidsOur secondary objectives…
ID
Source
Brief title
Condition
- Respiratory disorders congenital
- Congenital respiratory tract disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameter is pulmonary function (Forced Expiratory volume in 1
second; FEV1) measured before and after the use of genistein and before and
after the use of placebo.
Secondary outcome
Secondary endpoints to evaluate in vivo effect are:
* Sweat chloride concentration (SCC)
* Airway resistance (Rint and bodybox)
* Body Mass Index (BMI)
* Quality of life (measured with the Cystic Fibrosis Questionnnaire; (CFQ))
* Elastase measurements in the feces
* The CFTR stimulating ability of the concentration of genistein in the
patient*s blood samples. We will also determine the plasma levels of genistein;
Assessment of ß-adrenergic sweat secretion by evaporimetry is included as an
exploratory endpoint.
Background summary
The cystic fibrosis trans membrane conductance regulator (CFTR), a chloride and
bicarbonate channel encoded by the CFTR gene, is essential for fluid and
electrolyte homeostasis at the epithelial surfaces of many organs, including
the lung, intestine, and sweat gland. Over 1900 CFTR mutations have been
identified causing impaired protein production (class I), folding (class II),
channel gating (class III), conductance (class IV), or reduced synthesis (class
V). Recently the first CFTR potentiator-drug Ivacaftor was approved for the
treatment of CF patients with a (class III) gating mutation.
Using various primary cell models from CF patients (organoids), we found that
adding the natural food supplement genistein to the approved CFTR potentiator
Ivacaftor, might increase the function of the CFTR protein, thereby enhancing
function of these mutants significantly.
Study objective
Our primary objective is to investigate whether a further gain in efficacy of
oral Ivacaftor treatment can be reached by co-supplementation of genistein, as
suggested by their highly synergistic action in intestinal organoids
Our secondary objectives are:
1: to evaluate the correlations between individual Ivacaftor genistein induced
CFTR function in vitro (organoid-based measurements) and the in vivo treatment
effect.
2: to evaluate the correlation between serum levels of Ivacaftor and genistein
and the in vivo treatment effect.
Study design
A multicentre randomized double-blind placebo controlled trial.
Intervention
Patients will be randomized to receive genistein or placebo during a period of
8 weeks (treatment period 1). After an 4-week washout, patients will be crossed
over to receive the opposite treatment (Treatment period 2).
Study burden and risks
Patients participating in this study will be treated at home and will visit the
hospital for four study visits. During each visit several tests will be
performed.
The patients will receive genistein and placebo during eight weeks. Genistein
is a registered natural widely used food components. In a previously conducted
study (the TICTAC I study) a total of 13 subjects received genistein in a
maximum dose of 5,0 mg/Kg/day. There were no serious adverse events reported
during this study. The dose of genistein that patients will receive in this
study will not exceed the previously tested dose of 10mg/Kg/day. We do not
expect serious problems or side effects during this study because of the
limited side effects that have been described in earlier studies in which the
same dose was used (also see Investigator brochure).
When our hypothesis is confirmed and a further gain in efficacy of oral
Ivacaftor treatment can be reached by co-supplementation of genistein this is a
major benefit not only for the individual patient but for the entire
CF-population. With the use of organoids we will then be able to generate
optimal treatment strategies for individuals based on (combinations of) current
and future drugs with only limited patient discomfort.
Lundlaan 6
Utrecht 3584 EA
NL
Lundlaan 6
Utrecht 3584 EA
NL
Listed location countries
Age
Inclusion criteria
*CFTR genotype associated with residual CFTR function;
*Already had a rectal biopsy to produce an organoid;
*Use of Ivacaftor;
*Male and female patients, aged 6 years or older on the date of informed consent;
*Signed informed consent form (IC).
Exclusion criteria
*Use of genistein or curcumin at start or within four weeks prior to start of the study;
*Severe acute exacerbation or pulmonary infection during last four weeks (needing intravenous treatment and/or systemic corticosteroids);
*(History of) hypothyroidism;
*Women who are trying to become pregnant or are pregnant or breastfeeding;
*Women with estrogen receptor-positive tumors;
*Postmenopausal women on tamoxifen therapy for estrogen-responsive breast cancer;
*Participation in another drug-investigating clinical study at the start or within four weeks prior to the start;
*Inability to follow instructions of the investigator.
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 |
|---|---|
| EudraCT | EUCTR2016-001619-19-NL |
| CCMO | NL57585.041.16 |
| OMON | NL-OMON24579 |