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Drug & research development » Clinical trials » 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

Clinical Trials gov number: NCT02190604

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Purpose: 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.

Phase: 2

Type: Interventional

Study sponsor: Novartis Pharmaceuticals

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 55 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)
•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

Intervention
Genetic, QBW251

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

Number of Participants
101-1000 (18-55 years)

Primary Endpoint

• Number of participants (Healthy Volunteers) with reported adverse events receiving QBW251 [Days 1-36]
• Change in Forced Expiratory Volume in 1 second (FEV1) [Baseline and Day 29]
• Change in Lung Clearance Index (LCI) [Baseline-Day 15]
• Number of participants with reported adverse events receiving QBW251 [Days 1-56]

Secondary Endpoint

• Change in Forced Expiratory Volume in 1 second (FEV1) [Day 15]
• Change in Lung Clearance Index (LCI) [Baseline-Day 29]
• Change in Cystic Fibrosis Questionnaire-Revised reported outcomes [Baseline-Day 28]
Time frame: Days 1-5
• PK of QBW251 in plasma: area under the plasma concentration versus time curve from time zero to time of last measurable concentration (AUC0-t)
• PK of QBW251 in plasma: observed maximum plasma concentration following administration of QBW251 (Cmax) in healthy volunteers
• PK of QBW251 in plasma: time to reach the maximum concentration after administration of QBW251 (Tmax) in healthy volunteers
• PK of QBW251 in plasma: terminal elimination half-life (T1/2) in healthy volunteers
• PK of QBW251 in plasma: area under the plasma concentration time curve from time zero to infinity (AUCinf) in healthy volunteers
• PK of QBW251 in plasma: apparent systemic clearance from plasma following extravascular administration (CL/F) in healthy volunteers
• PK of QBW251 in plasma: apparent volume of distribution during the terminal elimination phase following extravascular administration (Vz/F) in healthy volunteers
• PK of QBW251 in urine: amount of drug excreted in urine from time zero until last measurable concentration (Ae0-t) in healthy volunteers [Day 1]
Time frame: Days 1 and 14
• PK of QBW251 in urine: renal clearance following drug administration (CLr) in healthy volunteers [Day 1]
• PK 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 (AUCtau) in healthy volunteers
• PK of QBW251 in plasma after multiple doses: observed maximum plasma concentration following QBW251 at steady state (Cmax) in healthy volunteers
• PK of QBW251 in plasma after multiple doses: time to reach the maximum concentration after administration of QBW251 (Tmax) in healthy volunteers
• PK of QBW251 in plasma: area under the plasma concentration versus time curve from time zero to time of last measurable concentration (AUC0-t) [Day 14]
• PK of QBW251 in plasma: the average drug concentration in plasma during multiple dosing in healthy volunteers (Cav)
• PK of QBW251 in plasma after multiple doses: apparent systemic clearance from plasma following extravascular administration (CL/F) in healthy volunteers [Day 14]
• PK of QBW251 in plasma after multiple doses: apparent volume of distribution during the terminal elimation phase following extravascular administration (Vz/F) in healthy volunteers [Day 14]
• PK of QBW251 in plasma after multiple doses: accumulation ratio (Racc) in healthy volunteers
• PK of QBW251 in plasma after multiple doses: terminal elimination half-life (T1/2) in healthy volunteers [Day 14]

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Experimental: QBW251
Oral dose for healthy volunteers and patients

Placebo Comparator: Placebo
Oral dose for healthy volunteers and patients

View Trial Results