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

Cystic Fibrosis Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02190604
• Other study ID #: CQBW251X2101
• Secondary ID: 2011-005085-37
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: July 31, 2012
• Est. completion date: November 30, 2015

Study information

• Verified date: March 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 153
• Est. completion date: November 30, 2015
• Est. primary completion date: November 30, 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• Placebo
Capsule- oral dose
• QBW251
Capsule - oral dose

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Brussel
Belgium	Novartis Investigative Site	Gent
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	PIERRE BENITE Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Ireland	Novartis Investigative Site	Dublin 4
Romania	Novartis Investigative Site	Bucuresti
United Kingdom	Novartis Investigative Site	Belfast
United Kingdom	Novartis Investigative Site	Livingston	West Lothian
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Mid Glamorgan
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Denver	Colorado
United States	Novartis Investigative Site	Louisville	Kentucky
United States	Novartis Investigative Site	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1 and 2:Number of Participants (Healthy Volunteers) With Reported Adverse Events Receiving QBW251	All adverse events (in healthy volunteers) reported.	Day 1 to Day 36
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.	Baseline and Day 15
Primary	Part 3: Number of Participants (Patients) With Reported Adverse Events Receiving QBW251	All adverse events and serious adverse events (in patients) reported.	Day 1 to Day 56
Secondary	Part 3:Change in Forced Expiratory Volume in 1 Second (FEV1) at 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	Baseline and Day 15
Secondary	Part 3: Change in Cystic Fibrosis Questionnaire-Revised Reported Outcomes	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	Baseline and Day 14
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)	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)
Secondary	Part 1: Maximum Concentration (Cmax) in Healthy Volunteers	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	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)
Secondary	Part 1: Time to Maximum Concentration (Tmax) in Healthy Volunteers	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).	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)
Secondary	Part 1: T1/2 in Healthy Volunteers	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).	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)
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)	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)
Secondary	Part 1: CL/F in Healthy Volunteers	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)	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)
Secondary	Part 1: Vz/F in Healthy Volunteers	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.	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)
Secondary	Part 2: AUCtau in Healthy Volunteers	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	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)
Secondary	Part 2: Maximum Concentration (Cmax) in Healthy Volunteers	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.	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)
Secondary	Part 2: Time to Maximum Concentration (Tmax) in Healthy Volunteers	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.	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)
Secondary	Part 2: AUC0-t	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.	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)
Secondary	Part 2: Cav in Healthy Volunteers	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.	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)
Secondary	Part 2: CL/F in Healthy Volunteers	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.	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)
Secondary	Part 2: Vz/F in Healthy Volunteers	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.	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)
Secondary	Part 2: Racc in Healthy Volunteers	Accumulation ratio (Racc). In this analysis Racc will be reported using blood samples taken on Days 1 - 14 from 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)
Secondary	Part 2: T1/2 in Healthy Volunteers	terminal elimination half-life (T1/2). In this analysis T1/2 will be reported using blood samples taken on Day 14 from 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)
Secondary	Part 3: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of QBW251 in CF Patients	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
Secondary	Part 3: Plasma Concentration at the Last Quantifiable Time Point (Clast) of QBW251 in CF Patients	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	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day2
Secondary	Part 3: Maximum Concentration (Cmax) in CF Patients	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	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
Secondary	Part 3: Tlast in CF Patients	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	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
Secondary	Part 3: Time to Maximum Concentration (Tmax)	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	Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
Secondary	Part 2: Ae0-t in Healthy Volunteers	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.	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
Secondary	Part 2: CLr in Healthy Volunteers	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.	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.

External Links

•   A Plain Language Trial Summary is available on novartisclinicaltrials.com