E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• Part 3: To assess the safety and tolerability of multiple ascending multiple oral doses in cystic fibrosis patients and to evaluate the preliminary efficacy of multiple doses of QBW251 on change from baseline in LCI in cystic fibrosis patients at Day 15
• Part 4: evaluate the efficacy of multiple doses of QBW251 on change from baseline in percent of predicted FEV1 in cystic fibrosis patients at Day 29 |
|
E.2.2 | Secondary objectives of the trial |
•To evaluate the pharmacokinetics of of multiple doses in cystic fibrosis patients, Part 3 and 4.
•Part 3: To evaluate the preliminary efficacy of multiple ascending doses of QBW251 on percent predicted FEV1 in cystic fibrosis patients at Day 15.
•Part 4: To assess the safety and tolerability of multiple doses of QBW251 in cystic fibrosis patients.
•Part 4: to evaluate the efficacy of multiple doses of QBW251 on LCI in cystic fibrosis patients at Day 29.
•Part 4: To evaluate the efficacy of multiple doses of QBW251 in cystic fibrosis patients as reflected in changes in the Cystic Fibrosis Questionnaire-Revised (CFQ R PRO) at Day 14, Part 3; at Day 28, Part 4. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For Parts 3 and 4
1.Written informed consent must be obtained before any assessment is performed.
2.Male and female patients of 18 to 55 years of age (included) with a confirmed diagnosis of cystic fibrosis as per the Cystic Fibrosis Foundation (CFF) consensus guidelines .
3.A documented CFTR genotype defined as a class III, IV, V, or VI mutation on one allele and on the other allele any other CFTR mutation with the exception of F508del/F508del due to its designation as either a class II or III mutation.
4. Patients must be willing to undergo genetic testing to confirm the CFTR genotype.
5.At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes and again after three minutes in the standing position. Sitting vital signs should be within the following ranges:
•oral body temperature between 35.0-37.5°C
•systolic blood pressure, 90-140 mm Hg
•diastolic blood pressure, 50-90 mm Hg
•pulse rate, 40 - 90 bpm
Patients should be excluded if their standing vital signs (relative to sitting) show findings which, in the opinion of the Investigator, are associated with clinical manifestation of postural hypotension (i.e. absence of any other cause).
6.Patients must have a body mass index (BMI) within the range of 15 -35 kg/m2.
7.FEV1 at Screening must be 50 to 90% predicted (inclusive) for Part 3 and 40 to 100% predicted (inclusive) for Part 4 by NHANES/Hankinson standards.
8.Oxygen saturation (O2) at screening must be ≥ 90 % on room air.
9.Able to perform reliable, reproducible pulmonary function test maneuvers per American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines (Miller et al 2005) at screening.
10.Able to perform reliable, reproducible Lung Clearance Index test maneuvers as evaluated by over reading by EcoMedics at screening.
11.Able to communicate well with the investigator, to understand and comply with the requirements of the study. Subjects should be able to understand and sign the written informed consent. |
|
E.4 | Principal exclusion criteria |
For Part 3 and 4
1.Use of other investigational drugs at the time of enrollment; or within 5 half-lives or within 30 days of enrollment, or until the expected PD effect has returned to baseline.
2.History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
3.A history of clinically significant ECG abnormalities, or ECG abnormalities at screening4. History or presence of prolonged QT syndrome.
5.History of malignancy of any organ system (other than localized basal cell carcinoma of the skin) within the past 5 years.
6.Pregnant or nursing (lactating) women.
7.Women of child-bearing potential, unless they are using contraception during the study and until study completion.
8.Sexually active males must use a condom during intercourse while taking drug and for 2 weeks after stopping study medication and should not father a child in this period.
9.Use of any herbal supplements within 4 weeks prior to initial dosing.
10.Smokers
11.Use of prescription drugs prohibited in Section 5.4.9.2.
12.Donation or loss of 400 mL or more of blood within 8 weeks prior to
initial dosing, or longer if required by local regulation.
13.Plasma donation (>400 mL) within 28 days prior to first dosing.
14.Hemoglobin levels below 10.0 g/dl at screening.
15.Clinical instability.
16.Recent and/or recurrent history of autonomic dysfunction.
17.Any surgical or medical condition which might significantly alter the
absorption, distribution, metabolism, or excretion of drugs, or which
may jeopardize the subject in case of participation in the study.
18.History of immunodeficiency diseases, including a positive HIV test result.
19.A positive Hepatitis B surface antigen or Hepatitis C test result.
20.History of drug or alcohol abuse
21.Unwilling to avoid direct sun exposure.
22.Any upper respiratory tract infection.
23.Any changes in concomitant medications for 14 days prior to screening throughout the end of study visit.
24.History of Burkholderia cepacia respiratory tract infection and/or Mycobacterium abbesses and/or other atypical mycobacterial species infection.
25.History of lung transplant.
26.History of clinically significant hemoptysis.
27.Patients with known adrenal dysfunction (+/- adrenal replacement therapy).
28.Patient is currently receiving (or has received within 4 weeks of baseline visit) VX-770/Ivacaftor.
29.Vulnerable subjects |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Parts 3-4: safety and tolerability
Part 3: changes in lung function (LCI) from baseline to Day 15.
Part 4: absolute change from baseline in lung function (percent of predicted FEV1) from baseline to Day 29. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Parts 3-4: safety and tolerability
Part 3: changes in lung function (LCI) from baseline to Day 15.
Part 4: absolute change from baseline in lung function (percent of predicted FEV1) from baseline to Day 29. |
|
E.5.2 | Secondary end point(s) |
•Pharmacokinetics multiple doses in cystic fibrosis patients (Parts 3 and 4).
•Part 3: percent predicted FEV1 in cystic fibrosis patients at Day 15.
•Part 4: safety and tolerability of multiple doses of QBW251 in cystic fibrosis patients.
•Part 4: LCI in cystic fibrosis patients at Day 29.
•Parts 3 and 4: changes in the Cystic Fibrosis Questionnaire-Revised (CFQ-R PRO) at Day 14 (Part 3) and at Day 28 (Part 4). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Pharmacokinetics multiple doses in cystic fibrosis patients (Parts 3 and 4).
•Part 3: percent predicted FEV1 in cystic fibrosis patients at Day 15.
•Part 4: safety and tolerability of multiple doses of QBW251 in cystic fibrosis patients.
•Part 4: LCI in cystic fibrosis patients at Day 29.
•Parts 3 and 4: changes in the Cystic Fibrosis Questionnaire-Revised (CFQ-R PRO) at Day 14 (Part 3) and at Day 28 (Part 4). |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
The study will complete when the last subject completes their Study Completion visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |