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

NCT ID: NCT02190604

Last Updated: 2020-12-30

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 153 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2015-11-30

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.

Conditions

Cystic Fibrosis

Keywords

FEV1- Forced Expiratory volume; LCI - Lung Clearance Index; CFTR - cystic fibrosis transmembrane conductance regulator; cystic fibrosis; allergic bronchopulmonary aspergillosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Part 1 Cohort 1: QBW251

Single dose of QBW251 10 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 1 Cohort 2: QBW251

Single dose of QBW251 25 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 1 Cohort 3: QBW251

Single dose of QBW251 75 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 1 Cohort 4: QBW251

Single dose of QBW251 150 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 1 Cohort 5: QBW251

Single dose of QBW251 300 mg in healthy volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 1 Cohort 6: QBW251

Single dose of QBW251 500 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 1 Cohort 6: QBW251(fed)

Single dose of QBW251 500 mg (fed). single dose with food for a preliminary assessment of the effect of food on the absorption of QBW251 in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 1 Cohort 7: QBW251

Single dose of QBW251 750 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 1 Cohort 8: QBW251

Single dose of QBW251 1000 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 1 Placebo

Placebo to QBW251 in all cohorts of part 1 in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Capsule- oral dose

Part 2 Cohort 1: QBW251

Multiple doses of QBW25 150 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 2 Cohort 2: QBW251

Multiple doses of QBW251 400 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 2 Cohort 3: QBW251

Multiple doses of QBW251 750 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 2 Cohort 4: QBW251

Multiple doses of QBW251 450 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 2 Cohort 5: QBW251

Multiple doses of QBW251 750 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 2 Placebo

Placebo to QBW251 in all cohorts of part 2 in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Capsule- oral dose

Part 3 Cohort 1: QBW251

150 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 3 Cohort 2: QBW251

450 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 3 Cohort 3: QBW251

450 mg b.i.d. Multiple doses. Patients who are homozygous for the F508del mutation in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

Group Type: EXPERIMENTAL

QBW251

Intervention Type: DRUG

Capsule - oral dose

Part 3 Placebo

Placebo to QBW251 in all cohorts of part 3 in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Capsule- oral dose

Interventions

Placebo

Capsule- oral dose

Intervention Type: DRUG

QBW251

Capsule - oral dose

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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.

• 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.

Exclusion Criteria

• 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.

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Birmingham, Alabama, United States

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

Novartis Investigative Site

Ghent, , Belgium

Novartis Investigative Site

Montpellier, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Pierre-Bénite, , France

Novartis Investigative Site

Cologne, North Rhine-Westphalia, Germany

Novartis Investigative Site

Berlin, , Germany

Novartis Investigative Site

Dublin, , Ireland

Novartis Investigative Site

Bucharest, , Romania

Novartis Investigative Site

Livingston, West Lothian, United Kingdom

Novartis Investigative Site

Belfast, , United Kingdom

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

Manchester, , United Kingdom

Novartis Investigative Site

Mid Glamorgan, , United Kingdom

Countries

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

References

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.

Reference Type: DERIVED

PMID: 33293212 (View on PubMed)

Related Links

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=127

A Plain Language Trial Summary is available on novartisclinicaltrials.com

Other Identifiers

2011-005085-37

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CQBW251X2101

Identifier Type: -

Identifier Source: org_study_id