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

Phase 2TerminatedNCT02190604

Novartis Pharmaceuticals153 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

153

Conditions

Cystic Fibrosis

Interventions

PlaceboDRUG

Capsule- oral dose

QBW251DRUG

Capsule - oral dose

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (23)

Novartis Investigative Site

Birmingham, Alabama, United States

Outcomes

Primary Outcomes

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

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

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

Secondary Outcomes

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

Time frame: Baseline and Day 15

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

Time frame: Baseline and Day 14

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)

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Novartis Investigative Site

Denver, Colorado, United States

Novartis Investigative Site

Chicago, Illinois, United States

Novartis Investigative Site

Louisville, Kentucky, United States

Novartis Investigative Site

Boston, Massachusetts, United States

Novartis Investigative Site

Boston, Massachusetts, United States

Novartis Investigative Site

St Louis, Missouri, United States

Novartis Investigative Site

Chapel Hill, North Carolina, United States

Novartis Investigative Site

Columbus, Ohio, United States

Novartis Investigative Site

Brussels, Belgium

...and 13 more locations

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

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