E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cystic fibrosis with the S1251N mutation |
|
E.1.1.1 | Medical condition in easily understood language |
Cystic fibrosis with the S1251N mutation |
|
E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011762 |
E.1.2 | Term | Cystic fibrosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of two oral doses of GLPG1837 in subjects with CF and at least one copy of the S1251N mutation. |
|
E.2.2 | Secondary objectives of the trial |
To assess changes in sweat chloride from baseline (Day 1) as the biomarker of CFTR ion channel function
To explore the changes in pulmonary function (FEV1) from baseline.
To assess the pharmacokinetics of GLPG1837.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Male or female subjects ≥ 18 years of age, on the day of signing the
Informed Consent Form (ICF), with a confirmed diagnosis of cystic
fibrosis:
a. Clinical diagnosis of cystic fibrosis with signs/symptoms involving at
least two organ systems, and
b. Medical history of elevated sweat chloride ≥60 mmol/L by quantitative pilocarpine iontophoresis (documented in the subject's medical record) or 2 disease causing CFTR mutations (documented in the subject's medical record).
2.Gating S1251N CFTR mutation on at least one allele in the CFTR gene
(documented in the subject's medical record or CF registry); any known
or unknown mutation allowed on the 2nd allele. Subject inclusion can be performed, provided that genotype information is available in source
data.
3.Subject must meet one of the following:
a. Subjects currently receiving treatment with ivacaftor must be on a
stable regimen for at least 2 weeks prior to screening
Or
b. Subjects not on a treatment regimen with ivacaftor for at least 2 weeks prior to screening
4.Weight ≥ 40.0 kg.
5.Subjects on stable concomitant treatment regimen for at least 4 weeks prior to baseline (excluding ivacaftor).
6.Pre- or post-bronchodilator FEV1 ≥ 40% of predicted normal for age,
gender, height at screening.
7.Female subjects must have a negative blood pregnancy test.
Determination of serum follicle-stimulating hormone (FSH) will be done
for any suspected postmenopausal female with at least 12 months of
continuous spontaneous amenorrhea, with FSH levels > 40 IU/mL being
confirmative for menopause. For hysterectomy and tubal ligation,
documented confirmation will be requested.
8.Subjects will have to use highly effective contraceptive methods prior
to the first dose of the study drug, during the study, and for at least 12
weeks after the last dose of the study drug.
a. If the subject is a sexually active woman of childbearing potential, she and her male partner are required to simultaneously use 2 effective
contraceptive methods as listed in the protocol. Hormonal contraceptives will not be considered as an effective method; however, female subjects are not required to discontinue hormonal contraceptives. Female subjects who use contraception must have done so for at least 14 days prior to the first dose of the study drug.
b. Non-vasectomized sexually active male subjects with female partners
of childbearing potential must be willing to use a condom in addition to
having their female partner use another form of contraception as listed
in the protocol. |
|
E.4 | Principal exclusion criteria |
1.History of sensitivity to any component of the study drug, or a history
of drug or other allergy that, in the investigator's opinion,
contraindicates the subject's participation in the study.
2.On an ivacaftor-containing treatment regimen and unable or unwilling to discontinue ivacaftor for the washout and treatment periods of the study.
3.Concomitant use of antifungal drugs (e.g. itraconazole, ketoconazole,
voriconazole, posaconazole) within 4 weeks of baseline.
4.A history of a clinically meaningful unstable or uncontrolled chronic
disease including underlying cystic fibrosis that makes the subject
unsuitable for inclusion in the study in the opinion of the investigator.
5.Liver cirrhosis and portal hypertension.
6.History of malignancy within the past 5 years (except for carcinoma in
situ of the uterine cervix and basal cell carcinoma of the skin that has
been treated with no evidence of recurrence).
7.Any significant change in the medical regimen (including dose and
frequency) for pulmonary health within 4 weeks of baseline, including:
antibiotics; corticosteroids (as defined in the protocol); inhaled
bronchodilators, hypertonic saline, mannitol or dornase alfa; ibuprofen
and airway clearance techniques. Individuals taking inhaled antibiotics
for suppression of chronic airways infection must be on a stable regimen
for at least 8 weeks prior to baseline and willing to continue the same
antibiotic through Day 29.
8.Unstable pulmonary status or respiratory tract infection (including
pulmonary exacerbation), based on the investigator's opinion, or
changes in therapy for pulmonary disease within 4 weeks of baseline as
defined in the protocol.
9.History of lung volume reduction surgery or lung transplant.
10.Use of continuous (24 hours per day) supplemental oxygen therapy.
11.Clinically significant abnormalities detected on electrocardiogram
(ECG) regarding either rhythm or conduction (e.g., QTcF ≥ 450 ms, or a known long QT syndrome). A first degree heart block will not be
considered as a significant abnormality.
12.Use of medication known to prolong the QT interval (including herbal and naturopathic therapy).
13.History of solid organ or haematological transplantation or currently
on a transplantation waiting list.
14.Abnormal liver function defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT), GGT > 3 x upper limit of the normal range or bilirubin > 2 x upper limit of the normal range.
15.Abnormal renal function defined as creatinine clearance < 50mL/min
using the Cockroft-Gault equation. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability will be assessed through:
•Adverse events (AEs)
•Physical examinations
•Vital signs
•12-lead ECG
•Oxygen saturation
•Safety laboratory assessments |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Various time points throughout the trial as specified in the protocol |
|
E.5.2 | Secondary end point(s) |
Efficacy will be assessed through:
•sweat chloride concentration testing
•measuring pulmonary function
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Various time points throughout the trial as specified in the protocol |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |