Safety, tolerability, pharmacokinetics and preliminary pharmacodynamics of QBW251 in healthy subjects and cystic fibrosis patients.

• Register: EUCTR
• Last refreshed on: 27 July 2020
• Main ID: EUCTR2011-005085-37-GB
• Date of registration: 24/05/2012
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: Safety, tolerability, pharmacokinetics and preliminary pharmacodynamics of QBW251 in healthy subjects and cystic fibrosis patients.
• Scientific title: A randomized, double blind placebo-controlled study to assess the safety, tolerability, pharmacokinetics and preliminary pharmacodynamics of single and multiple ascending doses of QBW251 in healthy subjects and multiple doses in cystic fibrosis patients.
• Date of first enrolment: 20/07/2012
• Target sample size: 156
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-005085-37
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: yes; Other trial design description: 4-parts dose-escalation study; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, France, Germany, Ireland, Netherlands, Romania, United Kingdom, United States

Contacts

• Name: Medical Collaboration Centre
• Affiliation: Novartis Pharmaceuticals UK Ltd

• Name: Medical Collaboration Centre
• Affiliation: Novartis Pharmaceuticals UK Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
Parts 3 and 4 (cystic fibrosis patients) - see protocol for full list of inclusion criteria
1. Written informed consent must be obtained before any assessment is performed
2. Male and female patients of 18 to 55 years of age (inclusive) 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 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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 156
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Parts 3 and 4 (cystic fibrosis patients) - see protocol for full details:
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 screening
4. 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 of the protocol
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. Current or historical 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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

cystic fibrosis
MedDRA version: 17.0 Level: PT Classification code 10011762 Term: Cystic fibrosis System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Intervention(s)

Product Code: QBW251
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not assigned
CAS Number: Not assigned
Current Sponsor code: QBW251
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Code: QBW251
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not assigned
CAS Number: Not assigned
Current Sponsor code: QBW251
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Part 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

Main Objective: Part 3: To assess the safety and tolerability of multiple ascending oral doses in cystic fibrosis patients and to evaluate the preliminary efficacy of multiple doses of QBW251 on change from baseline 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.

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.

Secondary Objective: •To evaluate the pharmacokinetics of multiple doses in cystic fibrosis patients (Parts 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.

Secondary Outcome(s)

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).

Secondary end point(s): Part 3 and 4:
•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).

Secondary ID(s)

CQBW251X2101

Source(s) of Monetary Support

Novartis Pharma Services AG

Ethics review

Status: Approved
Approval date: 18/05/2012
Contact:

Results

• Results available: Yes
• Date Posted: 12/07/2018
• Date Completed: 30/11/2015
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005085-37/results