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

NCT02190604 | Terminated Phase 1 Results DMC

• 2 other identifiers: CQBW251X21012011-005085-37
• Study Type: interventional
• Target: 153
• Locations: 7 countries
• Sites: 23

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

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• 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 Outcomes (25)

• Part 3:Change in Forced Expiratory Volume in 1 Second (FEV1) at Day 15

  Baseline and Day 15

• Part 3: Change in Cystic Fibrosis Questionnaire-Revised Reported Outcomes

  Baseline and Day 14

• Part 1: AUC0-t in 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 2-5)

• Part 1: Maximum Concentration (Cmax) in 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)

• Part 1: Time to Maximum Concentration (Tmax) in 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)

Study Arms (20)

Part 1 Cohort 1: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 1 Cohort 2: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 1 Cohort 3: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 1 Cohort 4: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 1 Cohort 5: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 1 Cohort 6: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 1 Cohort 6: QBW251(fed)

EXPERIMENTAL

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).

Drug: QBW251

Part 1 Cohort 7: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 1 Cohort 8: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 1 Placebo

PLACEBO COMPARATOR

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).

Drug: Placebo

Part 2 Cohort 1: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 2 Cohort 2: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 2 Cohort 3: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 2 Cohort 4: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 2 Cohort 5: QBW251

EXPERIMENTAL

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).

Drug: QBW251

Part 2 Placebo

PLACEBO COMPARATOR

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).

Drug: Placebo

Part 3 Cohort 1: QBW251

EXPERIMENTAL

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.

Drug: QBW251

Part 3 Cohort 2: QBW251

EXPERIMENTAL

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.

Drug: QBW251

Part 3 Cohort 3: QBW251

EXPERIMENTAL

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.

Drug: QBW251

Part 3 Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

Placebo DRUG

Capsule- oral dose

Part 1 Placebo; Part 2 Placebo; Part 3 Placebo

QBW251 DRUG

Capsule - oral dose

Part 1 Cohort 1: QBW251; Part 1 Cohort 2: QBW251; Part 1 Cohort 3: QBW251; Part 1 Cohort 4: QBW251; Part 1 Cohort 5: QBW251; Part 1 Cohort 6: QBW251; Part 1 Cohort 6: QBW251(fed); Part 1 Cohort 7: QBW251; Part 1 Cohort 8: QBW251; Part 2 Cohort 1: QBW251; Part 2 Cohort 2: QBW251; Part 2 Cohort 3: QBW251; Part 2 Cohort 4: QBW251; Part 2 Cohort 5: QBW251; Part 3 Cohort 1: QBW251; Part 3 Cohort 2: QBW251; Part 3 Cohort 3: QBW251

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.
• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (23)

Novartis Investigative Site

Birmingham, Alabama, 35294-0006, United States

Location

Novartis Investigative Site

Denver, Colorado, 80206, United States

Location

Novartis Investigative Site

Chicago, Illinois, 60611, United States

Location

Novartis Investigative Site

Louisville, Kentucky, 40202, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02114, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02115, United States

Location

Novartis Investigative Site

St Louis, Missouri, 63110, United States

Location

Novartis Investigative Site

Chapel Hill, North Carolina, 27514, United States

Location

Novartis Investigative Site

Columbus, Ohio, 43205, United States

Location

Novartis Investigative Site

Brussels, 1090, Belgium

Location

Novartis Investigative Site

Ghent, 9000, Belgium

Location

Novartis Investigative Site

Montpellier, 34059, France

Location

Novartis Investigative Site

Paris, 75014, France

Location

Novartis Investigative Site

Pierre-Bénite, 69495, France

Location

Novartis Investigative Site

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Novartis Investigative Site

Berlin, 10098, Germany

Location

Novartis Investigative Site

Dublin, 4, Ireland

Location

Novartis Investigative Site

Bucharest, 050159, Romania

Location

Novartis Investigative Site

Livingston, West Lothian, EH54 6PP, United Kingdom

Location

Novartis Investigative Site

Belfast, BT9 7AB, United Kingdom

Location

Novartis Investigative Site

London, SW 6NP, United Kingdom

Location

Novartis Investigative Site

Manchester, M23 9QZ, United Kingdom

Location

Novartis Investigative Site

Mid Glamorgan, CF484DR, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 33293212 DERIVED

Related Links

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

MeSH Terms

Conditions

Cystic Fibrosis; Aspergillosis, Allergic Bronchopulmonary

Interventions

icenticaftor

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Pulmonary Aspergillosis; Aspergillosis; Mycoses; Bacterial Infections and Mycoses; Infections; Lung Diseases, Fungal; Respiratory Tract Infections; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2014
• First Posted: July 15, 2014
• Study Start: July 31, 2012
• Primary Completion: November 30, 2015
• Study Completion: November 30, 2015
• Last Updated: December 30, 2020
• Results First Posted: July 19, 2017

Record last verified: 2019-03

Locations

US (9); BE (2); FR (3); DE (2); IE (1); RO (1); GB (5)