Safety, Pharmacokinetics and Pharmacodynamics Study of Inhaled QBW276 in Patients With Cystic Fibrosis

A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of Inhaled QBW276 in Patients With Cystic Fibrosis

This is a study of multiple doses of inhaled QBW276 in patients with cystic fibrosis on top of standard of care. The study was divided into 3 Cohorts. Cohorts 1 and 2 are designed to be a randomized, double-blind, placebo-controlled, parallel arm, multiple dose study to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of inhaled QBW276 over 1 week (cohort 1) or 2 weeks (cohort 2) in patients with cystic fibrosis regardless of their genotype.

The study was terminated after Cohort 2 due to the resource issues.

Study Overview

• Status: Completed
• Conditions: Pulmonary Cystic Fibrosis
• Intervention / Treatment: Other: Placebo; Drug: QBW276

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Koeln, Germany, 50924
    • Novartis Investigative Site
• United States
  • New York
    • New York, New York, United States, 10032
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75390-9034
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Cohorts 1 and 2 = any genotype on any standard of care treatment
• Cohort 3 = F508del homozygotes on standard of care at that time
• FEV₁between 40 and 100%
• LCI2.5 ≥ 8 if FEV₁is more than 80%

Exclusion Criteria:

• Adrenal or electrolyte abnormalities
• Lung transplant
• Autonomic dysfunction (e.g. recurrent episodes of fainting, palpitations, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CQBW276; Cohorts 1 and 2 will enroll 8 patients each (6:2 QBW276 and placebo, respectively). Cohort 1: dose is 3 mg bid (6 mg daily) QBW276 or placebo for 7 days. Cohort 2: dose and frequency will be confirmed after cohort 1 is complete. The duration is 14 days. Cohort 3: dose and frequency will be confirmed after cohort 2 is complete. The duration is approximately 4 months. Patients will be randomized to one of two treatment sequences: QBW276 in Period 1 and Placebo in Period 2 or Placebo in Period 1 and QBW276 in Period 2. Twenty four patients are required to complete cohort 3.	Drug: QBW276; 0.3 mg and 1.5 mg strengths
Placebo Comparator: Placebo; Cohorts 1 and 2 will enroll 8 patients each (6:2 QBW276 and placebo, respectively). Cohort 1: dose is 3 mg bid (6 mg daily) QBW276 or placebo for 7 days. Cohort 2: dose and frequency will be confirmed after cohort 1 is complete. The duration is 14 days. Cohort 3: dose and frequency will be confirmed after cohort 2 is complete. The duration is approximately 4 months. Patients will be randomized to one of two treatment sequences: QBW276 in Period 1 and Placebo in Period 2 or Placebo in Period 1 and QBW276 in Period 2. Twenty four patients are required to complete cohort 3.	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohorts 1 and 2: Safety Assessments, Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]).	Adverse events were summarized by the number of patients having any adverse event overall and presented in the safety section. Study was prematurely terminated	Cohort 1: day 1-7; Cohort 2: day 1-14
Cohorts 1 and 2: Pharmacokinetics (Cmax) of QBW276, QBP545, and QBV697 in Plasma	Blood collection will be used to observe the maximum plasma concentration (Cmax) following administration of QBW276. Pharmacokinetic blood samples were collected at the time points. In Cohorts 1 and 2 this consisted of multiple samples through 6 hours after inhalation on Days 1 and 7 in Cohort 1 and Days 1 and 14 in Cohort 2 with predose samples on selected days. The Cmax, was determined using the actual recorded sampling times and noncompartmental methods. Since steady state was likely reached by Day 7, Cmax on Days 7 or 14 correspond to Cmax,ss	Cohort 1: day 1, 7; Cohort 2: day 1, 14
Cohorts 1 and 2: Pharmacokinetics (Tmax) of QBW276, QBP545, and QBV697 in Plasma	Blood collection will be used to observe the maximum plasma concentration (Tmax) following administration of QBW276. Pharmacokinetic blood samples were collected at the time points. In Cohorts 1 and 2 this consisted of multiple samples through 6 hours after inhalation on Days 1 and 7 in Cohort 1 and Days 1 and 14 in Cohort 2 with predose samples on selected days. The Tmax, was determined using the actual recorded sampling times and noncompartmental methods. Since steady state was likely reached by Day 7, Tmax on Days 7 or 14 correspond to Tmax,ss	Day 1, 7 and 14
Cohorts 1 and 2: Pharmacokinetics (AUCtau) of QBW276, QBP545, and QBV697 in Plasma	Blood collection will be used to observe the maximum plasma concentration (AUCtau) following administration of QBW276. Pharmacokinetic blood samples were collected at the time points. In Cohorts 1 and 2 this consisted of multiple samples through 6 hours after inhalation on Days 1 and 7 in Cohort 1 and Days 1 and 14 in Cohort 2 with predose samples on selected days. The AUCtau, was determined using the actual recorded sampling times and noncompartmental methods. Since steady state was likely reached by Day 7, AUCtau on Days 7 or 14 correspond to AUClast,ss	Day 1, 7 and 14
Cohorts 1 and 2: Pharmacokinetics Accumulation Ratio (Racc) of QBW276, QBP545, and QBV697 in Plasma	The accumulation ratio (Racc) will be reported using blood samples taken on days 1 -7 in cohort 1 and days 1-14 in cohort 2. Accumulation ratio (Racc) for QBW276 and metabolites was not calculated by PK software for patients where BLOQ values were observed for all blood samples in their PK profile.	Cohort 1: 7 days; Cohort 2: 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohorts 1 and 2: Change From Baseline in Percent Predicted Forced Expiratory Volume in the First Second by Spirometry (% Predicted FEV1)	To evaluate the response to multiple doses of inhaled QBW276 in percent predicted forced expiratory volume in the first second by spirometry according to international standards over 1 or 2 weeks of treatment compared with placebo in patients with cystic fibrosis.	Baseline to End of study (EOS)
Cohorts 1, 2: Change From Baseline in Lung Clearance Index (LCI) From Baseline to Day 7 for Cohort 1, Day 14 for Cohort 2.	Change in Lung Clearance Index (LCI) will be conducted by multiple breath nitrogen washout according to international standards	Baseline to EOS

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2017
• Primary Completion (Actual): April 24, 2018
• Study Completion (Actual): April 24, 2018

Study Registration Dates

• First Submitted: September 18, 2015
• First Submitted That Met QC Criteria: September 30, 2015
• First Posted (Estimate): October 1, 2015

Study Record Updates

• Last Update Posted (Actual): December 30, 2020
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Cystic Fibrosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: CQBW276X2201; 2014-004915-35 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No