Clinical trial NCT02190604: Safety, Tolerability, Pharmacokinetics, and Preliminary Pharmacodynamics of QBW251 in Healthy Subjects and Cystic Fibrosis Patients
Official 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Cystic Fibrosis
Keywords: FEV1- Forced Expiratory volume
LCI - Lung Clearance Index
CFTR - cystic fibrosis transmembrane conductance regulator
cystic fibrosis
allergic bronchopulmonary aspergillosis
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-07-15
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251
timeFrame: Day 1 to Day 36
measure: Part 3: Change in Lung Clearance Index (LCI) From Baseline to Day 15
timeFrame: Baseline and Day 15
measure: Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251
timeFrame: Day 1 to Day 56
Secondary outcomes:
measure: Part 3:Change in Forced Expiratory Volume in 1 Second (FEV1) at Day 15
timeFrame: Baseline and Day 15
measure: Part 3: Change in Cystic Fibrosis Questionnaire-Revised Reported Outcomes
timeFrame: Baseline and Day 14
measure: Part 1: AUC0-t in Healthy Volunteers
timeFrame: 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)
measure: Part 1: Maximum Concentration (Cmax) in Healthy Volunteers
timeFrame: 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)
measure: Part 1: Time to Maximum Concentration (Tmax) in Healthy Volunteers
timeFrame: 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)
measure: Part 1: T1/2 in Healthy Volunteers
timeFrame: 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)
measure: Part 1: AUCinf in Healthy Volunteers
timeFrame: 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)
measure: Part 1: CL/F in Healthy Volunteers
timeFrame: 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)
measure: Part 1: Vz/F in Healthy Volunteers
timeFrame: 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)
measure: Part 2: AUCtau in Healthy Volunteers
timeFrame: 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)
measure: Part 2: Maximum Concentration (Cmax) in Healthy Volunteers
timeFrame: 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)
measure: Part 2: Time to Maximum Concentration (Tmax) in Healthy Volunteers
timeFrame: 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)
measure: Part 2: AUC0-t
timeFrame: 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)
measure: Part 2: Cav in Healthy Volunteers
timeFrame: 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)
measure: Part 2: CL/F in Healthy Volunteers
timeFrame: 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)
measure: Part 2: Vz/F in Healthy Volunteers
timeFrame: 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)
measure: Part 2: Racc in Healthy Volunteers
timeFrame: 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)
measure: Part 2: T1/2 in Healthy Volunteers
timeFrame: 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)
measure: Part 3: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of QBW251 in CF Patients
timeFrame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
measure: Part 3: Plasma Concentration at the Last Quantifiable Time Point (Clast) of QBW251 in CF Patients
timeFrame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day2
measure: Part 3: Maximum Concentration (Cmax) in CF Patients
timeFrame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
measure: Part 3: Tlast in CF Patients
timeFrame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
measure: Part 3: Time to Maximum Concentration (Tmax)
timeFrame: Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
measure: Part 2: Ae0-t in Healthy Volunteers
timeFrame: 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
measure: Part 2: CLr in Healthy Volunteers
timeFrame: 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.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Denver
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Chicago
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Louisville
country: United States
facility: Novartis Investigative Site
state: Kentucky
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Chapel Hill
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Columbus
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Brussel
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: PIERRE BENITE Cedex
country: France
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dublin 4
country: Ireland
facility: Novartis Investigative Site
city: Bucuresti
country: Romania
facility: Novartis Investigative Site
city: Livingston
country: United Kingdom
facility: Novartis Investigative Site
state: West Lothian
city: Belfast
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Mid Glamorgan
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Kazani S, Rowlands DJ, Bottoli I, Milojevic J, Alcantara J, Jones I, Kulmatycki K, Machineni S, Mostovy L, Nicholls I, Nick JA, Rowe SM, Simmonds NJ, Vegesna R, Verheijen J, Danahay H, Gosling M, Ayalavajjala PS, Salman M, Strieter R. Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251). J Cyst Fibros. 2021 Mar;20(2):250-256. doi: 10.1016/j.jcf.2020.11.002. Epub 2020 Dec 6.