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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02190604
• Date of registration: 11/07/2014
• Prospective Registration: No
• Primary sponsor: Novartis Pharmaceuticals
• 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: July 31, 2012
• Target sample size: 153
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT02190604
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).
• Phase: Phase 1/Phase 2

Countries of recruitment

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

Contacts

• Name: Novartis Pharmaceuticals
• Affiliation: Novartis Pharmaceuticals

Key inclusion & exclusion 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 exclusion criteria (Parts 3 and 4)

- Use of herbal supplements within four (4) weeks prior to dosing or within 5 half-lives
of the supplement, whichever is longer

- 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

- Women of child-bearing potential, UNLESS they are using highly effective contraception

- Any changes in concomitant medications for 14 days prior to screening

- History or clinical evidence of pancreatic injury or pancreatitis; clinical evidence
of liver disease or liver injury as indicated by clinically significant abnormal liver
function tests as judged by the investigator such as SGOT, SGPT, GGT, alkaline
phosphatase, or serum bilirubin

- History or presence of impaired renal function as indicated by abnormal creatinine or
BUN values or abnormal urinary constituents (e.g., albuminuria)

- History of Burkholderia cepacia respiratory tract infection (must have at least two
negative cultures and no positive cultures in the past 18 months prior to screening to
be eligible for enrollment)

- Sexually active males unless they use a condom during intercourse while taking drug
and for condom is required to be used also by vasectomized men in order to prevent
delivery of drug via seminal fluid.

- Patient is currently receiving (or has received within 4 weeks of baseline visit)
VX-770/Ivacaftor.

- History of lung transplant



Age minimum: 18 Years
Age maximum: 65 Years
Gender: All

Health Condition(s) or Problem(s) studied

Cystic Fibrosis

Intervention(s)

Drug: Placebo

Drug: QBW251

Primary Outcome(s)

Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251 [Time Frame: Day 1 to Day 56]

Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251 [Time Frame: Day 1 to Day 36]

Part 3: Change in Lung Clearance Index (LCI) From Baseline to Day 15 [Time Frame: Baseline and Day 15]

Secondary Outcome(s)

Part 1: T1/2 in Healthy Volunteers [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 1 - 5)]

Part 1: CL/F in Healthy Volunteers [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 1 - 5)]

Part 2: CLr in Healthy Volunteers [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 Day 1; Day 14 was calculated as urine was only collected up to 12 hours on Day 1 thus CLr cannot be calculated.]

Part 2: Racc in Healthy Volunteers [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 Day 1 - 14; ( If B ID dosing, 12 hours samples will be pre-dosed)]

Part 3: Maximum Concentration (Cmax) in CF Patients [Time Frame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14]

Part 3: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of QBW251 in CF Patients [Time Frame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14]

Part 1: Time to Maximum Concentration (Tmax) in Healthy Volunteers [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 1 - 5)]

Part 1: Vz/F in Healthy Volunteers [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 1 - 5)]

Part 1: AUC0-t in Healthy Volunteers [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)]

Part 1: Maximum Concentration (Cmax) in Healthy Volunteers [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 1 - 5)]

Part 2: AUC0-t [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 Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)]

Part 2: Maximum Concentration (Cmax) in Healthy Volunteers [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 Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)]

Part 2: Cav in Healthy Volunteers [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 Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)]

Part 2: Vz/F in Healthy Volunteers [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 Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)]

Part 2: T1/2 in Healthy Volunteers [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 Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)]

Part 1: AUCinf in Healthy Volunteers [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 1 - 5)]

Part 2: Ae0-t in Healthy Volunteers [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 Day 1]

Part 2: AUCtau in Healthy Volunteers [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 Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)]

Part 2: Time to Maximum Concentration (Tmax) in Healthy Volunteers [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 Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)]

Part 2: CL/F in Healthy Volunteers [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 Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)]

Part 3: Tlast in CF Patients [Time Frame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14]

Part 3:Change in Forced Expiratory Volume in 1 Second (FEV1) at Day 15 [Time Frame: Baseline and Day 15]

Part 3: Plasma Concentration at the Last Quantifiable Time Point (Clast) of QBW251 in CF Patients [Time Frame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day2]

Part 3: Time to Maximum Concentration (Tmax) [Time Frame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14]

Part 3: Change in Cystic Fibrosis Questionnaire-Revised Reported Outcomes [Time Frame: Baseline and Day 14]

Secondary ID(s)

2011-005085-37

CQBW251X2101

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 19/07/2017
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02190604