Safety, Tolerability, Pharmacokinetics, and Preliminary Pharmacodynamics of QBW251 in Healthy Subjects and Cystic Fibrosis Patients

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

Status

Terminated

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02190604

Enrollment

153

Registered

2014-07-15

Start date

2012-07-31

Completion date

2015-11-30

Last updated

2020-12-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cystic Fibrosis

Keywords

FEV1- Forced Expiratory volume, LCI - Lung Clearance Index, CFTR - cystic fibrosis transmembrane conductance regulator, cystic fibrosis, allergic bronchopulmonary aspergillosis

Brief summary

This study is designed to assess the safety, tolerability, pharmacokinetics and preliminary pharmacodynamics (proof of concept) of QBW251 in healthy subjects and cystic fibrosis patients following single and multiple doses. This first-in-human and proof of concept study will consist of 4 parts, with Parts 1 and 2 in healthy volunteers and Parts 3 and 4 in cystic fibrosis patients.

Interventions

DRUGPlacebo

Capsule- oral dose

DRUGQBW251

Capsule - oral dose

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Yes

Inclusion criteria

Key inclusion criteria (Parts 1 and 2) * Healthy female (of non-childbearing potential) and male subjects of 18 to 55 years of age (inclusive) * Body mass index (BMI) must be within the range of 15 to 30 kg/m2 * Oxygen saturation (O2) at screening must be ≥ 96% on room air. Key

Exclusion criteria

(Parts 1 and 2) * Use of any prescription drugs or herbal supplements within four (4) weeks prior to dosing or within 5 half-lives of the drug, whichever is longer * Over-the-counter (OTC) medication (including vitamins, dietary supplements) within two (2) weeks prior to dosing * Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer * Unwilling to avoid direct sun exposure by covering exposed skin, using topical sun block and wearing sunglasses from the first dose of study drug to the end of participation in the study * Pregnant or nursing (lactating) women. Key inclusion criteria (Parts 3 and 4): * Male and female patients of 18 to 65 years of age (inclusive) with a confirmed diagnosis of cystic fibrosis as per the Cystic Fibrosis Foundation (CFF) consensus guidelines * Heterozygous with one allele represented as any CFTR mutation and the other allele must represent a class III, IV, V, VI CFTR mutation (Note: since the CFTR mutation, F508del, can be considered either a class II or III mutation, heterozygous CF patients that have one allele that contains F508del, must have the other allele contain a class III (i.e., not F508del), IV, V, or VI mutation). Patients with F508del/F508del mutation should only be included in Part 3 Cohort 3. * Body mass index (BMI) must be within the range of 15-35 kg/m2 * FEV1 at Screening must be 40 to 100% predicted (inclusive) by NHANES/Hankinson standards * Oxygen saturation (O2) at screening must be \> 90% on room air. Key

Design outcomes

Primary

Measure	Time frame	Description
Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Day 1 to Day 36	All adverse events (in healthy volunteers) reported.
Part 3: Change in Lung Clearance Index (LCI) From Baseline to Day 15	Baseline and Day 15	Change in Lung Clearance Index (LCI) will be conducted according to international standards in cystic fibrosis patients. Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test, A reduction in mean change from baseline for LCI2.5 indicates improvement.
Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	Day 1 to Day 56	All adverse events and serious adverse events (in patients) reported.

Secondary

Measure	Time frame	Description
Part 1: Maximum Concentration (Cmax) in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)	Pharmacokinetics of QBW251 in plasma: observed maximum plasma concentration following administration of QBW251. In this analysis Cmax will be reported using blood samples taken on Days 1- 5 are from healthy volunteers
Part 1: Time to Maximum Concentration (Tmax) in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)	Pharmacokinetics of QBW251 in plasma: time to reach the maximum concentration after administration of QBW251. In this analysis Tmax will be reported using blood samples taken on Days 1 - 5 from healthy volunteers. In this part of the study a single dose was administered and samples were collected up to 5 days. As a result the Tmax is one value as the concentration-time curve goes to Day 5 (for some lower does QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered).
Part 1: T1/2 in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)	Pharmacokinetics of QBW251 in plasma: terminal elimination half-life. In this analysis T1/2 will be reported using blood samples taken on Days 1 - 5 from healthy volunteers. In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the T1/2 goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered).
Part 1: AUCinf in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)	Pharmacokinetics of QBW251 in plasma: area under the plasma concentration time curve from time zero to infinity. In this analysis AUCinf will be reported using blood samples taken on Days 1 - 5 from healthy volunteers. In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the AUCinf goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered)
Part 2: T1/2 in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)	terminal elimination half-life (T1/2). In this analysis T1/2 will be reported using blood samples taken on Day 14 from healthy volunteers.
Part 1: CL/F in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)	Pharmacokinetics of QBW251 in plasma: apparent systemic clearance from plasma following extravascular administration. In this analysis CL/F will be reported using blood samples taken on Days 1 - 5 from healthy volunteers. In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the CL/F goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered)
Part 1: Vz/F in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)	Pharmacokinetics of QBW251 in plasma: apparent volume of distribution during the terminal elimination phase following extravascular administration. In this analysis Vz/F will be reported using blood samples taken on Days 1 - 5 from healthy volunteers.
Part 2: AUCtau in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)	Pharmacokinetics of QBW251 in plasma after multiple doses: the area under the plasma concentration-time curve from time zero to end of the dosing interval tau. In this analysis AUCtau will be reported. Samples taken on Days 1 and 14 from healthy volunteers
Part 2: Maximum Concentration (Cmax) in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)	Pharmacokinetics of QBW251 in plasma after multiple doses: observed maximum plasma concentration following QBW251 at steady state. In this analysis Cmax will be reported using blood samples taken on Days 1 and 14 from healthy volunteers.
Part 2: Time to Maximum Concentration (Tmax) in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)	Pharmacokinetics of QBW251 in plasma after multiple doses: time to reach the maximum concentration after administration of QBW251. In this analysis Tmax will be reported using blood samples taken on Days 1 and 14 from healthy volunteers.
Part 2: AUC0-t	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)	Pharmacokinetics of QBW251 in plasma: area under the plasma concentration versus time curve from time zero to time of last measurable concentration. In this analysis AUC0-t will be reported using blood samples taken on Day 14 are from healthy volunteers.
Part 3:Change in Forced Expiratory Volume in 1 Second (FEV1) at Day 15	Baseline and Day 15	Forced Expiratory Volume in 1 second (FEV1) will be measured via spirometer according to international standards. Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation
Part 2: CL/F in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)	apparent systemic clearance from plasma following extravascular administration. In this analysis CL/F will be reported using blood samples taken on Day 14 from healthy volunteers.
Part 2: Vz/F in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)	Apparent volume of distribution during the terminal elimination phase following extravascular administration. In this analysis Vz/F will be reported using blood samples taken on Day 14 from healthy volunteers.
Part 2: Racc in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 - 14; ( If B ID dosing, 12 hours samples will be pre-dosed)	Accumulation ratio (Racc). In this analysis Racc will be reported using blood samples taken on Days 1 - 14 from healthy volunteers.
Part 3: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of QBW251 in CF Patients	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)
Part 3: Plasma Concentration at the Last Quantifiable Time Point (Clast) of QBW251 in CF Patients	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day2	Blood samples were collected at timepoints prespecified in the study protocol. Tlast of QBW251 was the last time point when blood sample collected was quantifiable
Part 3: Maximum Concentration (Cmax) in CF Patients	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14	Observed maximum plasma concentration following administration of QBW251. In this analysis Cmax will be reported using blood samples taken on Day 1and day 14 from patients
Part 3: Tlast in CF Patients	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14	Blood samples were collected at timepoints prespecified in the study protocol. Tlast of QBW251 was the last time point when blood sample collected was quantifiable day 1 and day 14
Part 3: Time to Maximum Concentration (Tmax)	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14	Pharmacokinetics of QBW251 in plasma after multiple doses: time to reach the maximum concentration after administration of QBW251. In this analysis Tmax will be reported using blood samples taken on Days 1 and 14 in patients
Part 2: Ae0-t in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1	Pharmacokinetics of QBW251 in urine: amount of drug excreted in urine from time zero until last measurable concentration. In this analysis Ae0-t will be reported using urine samples taken on Day 1 from healthy volunteers.
Part 2: CLr in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1; Day 14 was calculated as urine was only collected up to 12 hours on Day 1 thus CLr cannot be calculated.	Pharmacokinetics of QBW251 in urine: renal clearance following drug administration. In this analysis CLr will be reported using urine samples taken on Day 1 from healthy volunteers.
Part 2: Cav in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)	The average drug concentration in plasma during multiple dosing. In this analysis Cav will be reported using blood samples taken on Days 1 and 14 are from healthy volunteers.
Part 3: Change in Cystic Fibrosis Questionnaire-Revised Reported Outcomes	Baseline and Day 14	Change in Cystic Fibrosis Questionnaire data will be obtained from patient reported outcomes (CFQ-R PRO). Respiratory Domain, cores range from 0 to 100, with higher scores indicating better health, a change of 4 is considered clinically relevant
Part 1: AUC0-t in Healthy Volunteers	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 2-5)	Pharmacokinetics of QBW251 in plasma: area under the plasma concentration versus time curve from time zero to time of last measurable concentration (AUC0-t). In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the AUC0-t goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered)

Countries

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

Participant flow

Recruitment details

For Cohort 6 continuing into the food effect part of the study the subjects remained on the same treatment assignment that was required during the fed state. Therefore no randomization f the subject occurred during the food effect arm. Only 5 of the 6 subjects went into the fed cohort.

Pre-assignment details

In parts 1 and 2, participants (Healthy Volunteers) were randomized 3:1 to receive QBW251X or placebo. In part 3, participants (cystic fibrosis (CF) patients) were randomized 3:1 to receive QBW251X or placebo.

Participants by arm

Arm	Count
Part 1 Cohort 1: QBW251 Single dose of QBW251 10 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).	6
Part 1 Cohort 2: QBW251 Single dose of QBW251 25 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).	6
Part 1 Cohort 3: QBW251 Single dose of QBW251 75 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).	6
Part 1 Cohort 4: QBW251 Single dose of QBW251 150 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).	6
Part 1 Cohort 6: QBW251 Single dose of QBW251 500 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).	6
Part 1 Cohort 6: QBW251 (Fastin / Fed), Same Subjects Single dose of QBW251 500 mg (fed). single dose with food for a preliminary assessment of the effect of food on the absorption of QBW251 in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).	6
Part 1 Cohort 7: QBW251 Single dose of QBW251 750 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).	6
Part 1 Cohort 8: QBW251 Single dose of QBW251 1000 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).	6
Part 1 Placebo Placebo to QBW251 in all cohorts of part 1 in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).	16
Part 2 Cohort 1: QBW251 Multiple doses of QBW25 150 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).	6
Part 2 Cohort 2: QBW251 Multiple doses of QBW251 400 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).	6
Part 2 Cohort 3: QBW251 Multiple doses of QBW251 750 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).	6
Part 2 Cohort 4: QBW251 Multiple doses of QBW251 450 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).	6
Part 2 Cohort 5: QBW251 Multiple doses of QBW251 750 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).	6
Part 2 Placebo Placebo to QBW251 in all cohorts of part 2 in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).	10
Part 3 Cohort 1: QBW251 150 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.	6
Part 3 Cohort 2: QBW251 450 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.	12
Part 3 Cohort 3: QBW251 450 mg b.i.d. Multiple doses. Patients who are homozygous for the F508del mutation in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.	19
Part 3 Placebo Placebo to QBW251 in all cohorts of part 3 in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.	12
Total	153

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008	FG009	FG010	FG011	FG012	FG013	FG014	FG015	FG016	FG017	FG018
Part 1 and 2 (Healthy Volunteers)	Adverse Event	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0	0	0	0
Part 1 and 2 (Healthy Volunteers)	Lost to Follow-up	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0

Baseline characteristics

Characteristic	Part 1 Cohort 1: QBW251	Part 1 Cohort 2: QBW251	Part 1 Cohort 3: QBW251	Part 1 Cohort 4: QBW251	Part 1 Cohort 6: QBW251	Part 1 Cohort 6: QBW251 (Fastin / Fed), Same Subjects	Part 1 Cohort 7: QBW251	Part 1 Cohort 8: QBW251	Part 1 Placebo	Part 2 Cohort 1: QBW251	Part 2 Cohort 2: QBW251	Part 2 Cohort 3: QBW251	Part 2 Cohort 4: QBW251	Part 2 Cohort 5: QBW251	Part 2 Placebo	Part 3 Cohort 1: QBW251	Part 3 Cohort 2: QBW251	Part 3 Cohort 3: QBW251	Part 3 Placebo	Total
Age, Continuous Part 1, HV (n= 64)	36.3 Years STANDARD_DEVIATION 8.69	35 Years STANDARD_DEVIATION 14.25	43.5 Years STANDARD_DEVIATION 3.39	33.3 Years STANDARD_DEVIATION 9.61	44.2 Years STANDARD_DEVIATION 8.23	43.6 Years STANDARD_DEVIATION 9.07	28.2 Years STANDARD_DEVIATION 9.28	33.2 Years STANDARD_DEVIATION 9.47	30.3 Years STANDARD_DEVIATION 9.18	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	34.4 Years STANDARD_DEVIATION 9.92
Age, Continuous Part 2, HV (n=40)	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	30.3 Years STANDARD_DEVIATION 5.13	30.5 Years STANDARD_DEVIATION 5.89	29.2 Years STANDARD_DEVIATION 11.62	31.7 Years STANDARD_DEVIATION 13.22	27.8 Years STANDARD_DEVIATION 5	29 Years STANDARD_DEVIATION 6.22	NA Years	NA Years	NA Years	NA Years	29.7 Years STANDARD_DEVIATION 7.82
Age, Continuous Part 3, CF patients (n=49)	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	NA Years	39.3 Years STANDARD_DEVIATION 5.47	32.7 Years STANDARD_DEVIATION 13.77	27 Years STANDARD_DEVIATION 5.44	27.9 Years STANDARD_DEVIATION 6.37	30.1 Years STANDARD_DEVIATION 9.18
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	5 Participants	9 Participants	4 Participants	19 Participants
Sex: Female, Male Male	6 Participants	6 Participants	6 Participants	6 Participants	6 Participants	6 Participants	6 Participants	6 Participants	16 Participants	6 Participants	6 Participants	6 Participants	6 Participants	6 Participants	10 Participants	5 Participants	7 Participants	10 Participants	8 Participants	134 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk	EG012 affected / at risk	EG013 affected / at risk	EG014 affected / at risk	EG015 affected / at risk	EG016 affected / at risk	EG017 affected / at risk	EG018 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	8 / 16	3 / 6	2 / 6	1 / 6	2 / 6	2 / 6	1 / 5	1 / 6	4 / 6	7 / 10	3 / 6	6 / 6	3 / 6	6 / 6	4 / 6	8 / 12	5 / 6	8 / 12	18 / 19
serious Total, serious adverse events	0 / 16	0 / 6	0 / 6	0 / 6	0 / 6	0 / 6	0 / 5	0 / 6	0 / 6	0 / 10	0 / 6	0 / 6	0 / 6	0 / 6	0 / 6	0 / 12	1 / 6	1 / 12	1 / 19

Outcome results

Primary

Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251

All adverse events (in healthy volunteers) reported.

Time frame: Day 1 to Day 36

Population: All treated subjects were included in the data analysis. Subjects were analyzed according to the study treatment(s) received.

Arm	Measure	Group	Value (NUMBER)
Part 1 Cohort 4: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	1 Participants
Part 1 Cohort 4: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 1 Cohort 4: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Cohort 5: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Cohort 5: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	2 Participants
Part 1 Cohort 5: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 1 Cohort 6: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 1 Cohort 6: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	2 Participants
Part 1 Cohort 6: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Cohort 6: QBW251(Fed)	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Cohort 6: QBW251(Fed)	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	1 Participants
Part 1 Cohort 6: QBW251(Fed)	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 1 Cohort 7: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 1 Cohort 7: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	1 Participants
Part 1 Cohort 7: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Cohort 8: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 1 Cohort 8: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	4 Participants
Part 1 Cohort 8: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Placebo	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	8 Participants
Part 1 Placebo	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Placebo	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 2 Cohort 1: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 2 Cohort 1: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 2 Cohort 1: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	3 Participants
Part 2 Cohort 2: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 2 Cohort 2: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	6 Participants
Part 2 Cohort 2: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 2 Cohort 3: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 2 Cohort 3: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	3 Participants
Part 2 Cohort 3: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 2 Cohort 4: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	6 Participants
Part 2 Cohort 4: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 2 Cohort 4: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 2 Cohort 5: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	4 Participants
Part 2 Cohort 5: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 2 Cohort 5: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 2 Placebo	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 2 Placebo	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	7 Participants
Part 2 Placebo	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 1 Cohort 1: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	3 Participants
Part 1 Cohort 1: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Cohort 1: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 1 Cohort 2: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	2 Participants
Part 1 Cohort 2: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants
Part 1 Cohort 2: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Cohort 3: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Serious adverse events	0 Participants
Part 1 Cohort 3: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Adverse events	0 Participants
Part 1 Cohort 3: QBW251	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	Death	0 Participants

Primary

Part 3: Change in Lung Clearance Index (LCI) From Baseline to Day 15

Change in Lung Clearance Index (LCI) will be conducted according to international standards in cystic fibrosis patients. Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test, A reduction in mean change from baseline for LCI2.5 indicates improvement.

Time frame: Baseline and Day 15

Population: Pharmacodynamics (PD) analysis set: All randomized patients were included in the PD analysis

Arm	Measure	Value (MEAN)	Dispersion
Part 1 Cohort 4: QBW251	Part 3: Change in Lung Clearance Index (LCI) From Baseline to Day 15	0.27 Ratio	Standard Deviation 0.769
Part 1 Cohort 5: QBW251	Part 3: Change in Lung Clearance Index (LCI) From Baseline to Day 15	-0.85 Ratio	Standard Deviation 1.798
Part 1 Cohort 6: QBW251	Part 3: Change in Lung Clearance Index (LCI) From Baseline to Day 15	-0.13 Ratio	Standard Deviation 2.276
Part 1 Cohort 6: QBW251(Fed)	Part 3: Change in Lung Clearance Index (LCI) From Baseline to Day 15	0.28 Ratio	Standard Deviation 1.959

Primary

Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251

All adverse events and serious adverse events (in patients) reported.

Time frame: Day 1 to Day 56

Population: Safety analysis set: All randomized patients were included in the safety analysis

Arm	Measure	Group	Value (NUMBER)
Part 1 Cohort 4: QBW251	Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	Adverse Events (AE)	6 Participants
Part 1 Cohort 4: QBW251	Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	Serious Adverse Events (SAE)	1 Participants
Part 1 Cohort 5: QBW251	Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	Serious Adverse Events (SAE)	1 Participants
Part 1 Cohort 5: QBW251	Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	Adverse Events (AE)	8 Participants
Part 1 Cohort 6: QBW251	Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	Adverse Events (AE)	18 Participants
Part 1 Cohort 6: QBW251	Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	Serious Adverse Events (SAE)	1 Participants
Part 1 Cohort 6: QBW251(Fed)	Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	Adverse Events (AE)	8 Participants
Part 1 Cohort 6: QBW251(Fed)	Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	Serious Adverse Events (SAE)	0 Participants

Secondary

Part 1: AUC0-t in Healthy Volunteers

Pharmacokinetics of QBW251 in plasma: area under the plasma concentration versus time curve from time zero to time of last measurable concentration (AUC0-t). In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the AUC0-t goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered)

Time frame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 2-5)

Population: All subjects with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received study drug, and experienced no protocol deviations with relevant impact on PK data were included in the PK data analysis.

Arm	Measure	Value (MEAN)	Dispersion
Part 1 Cohort 4: QBW251	Part 1: AUC0-t in Healthy Volunteers	52.5 hr*ng/mL	Standard Deviation 28.1
Part 1 Cohort 5: QBW251	Part 1: AUC0-t in Healthy Volunteers	73.7 hr*ng/mL	Standard Deviation 51.8
Part 1 Cohort 6: QBW251	Part 1: AUC0-t in Healthy Volunteers	692 hr*ng/mL	Standard Deviation 389
Part 1 Cohort 6: QBW251(Fed)	Part 1: AUC0-t in Healthy Volunteers	1650 hr*ng/mL	Standard Deviation 907
Part 1 Cohort 7: QBW251	Part 1: AUC0-t in Healthy Volunteers	5470 hr*ng/mL	Standard Deviation 1070
Part 1 Cohort 8: QBW251	Part 1: AUC0-t in Healthy Volunteers	9450 hr*ng/mL	Standard Deviation 1740
Part 1 Placebo	Part 1: AUC0-t in Healthy Volunteers	7470 hr*ng/mL	Standard Deviation 2190
Part 2 Cohort 1: QBW251	Part 1: AUC0-t in Healthy Volunteers	20200 hr*ng/mL	Standard Deviation 11500
Part 2 Cohort 2: QBW251	Part 1: AUC0-t in Healthy Volunteers	35900 hr*ng/mL	Standard Deviation 9100
Part 2 Cohort 3: QBW251	Part 1: AUC0-t in Healthy Volunteers	NA hr*ng/mL	—

Secondary

Part 1: AUCinf in Healthy Volunteers

Pharmacokinetics of QBW251 in plasma: area under the plasma concentration time curve from time zero to infinity. In this analysis AUCinf will be reported using blood samples taken on Days 1 - 5 from healthy volunteers. In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the AUCinf goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered)