A Safety, Tolerability and Efficacy Study in Chronic Obstructive Pulmonary Disease (COPD) Patients With QBM076.

A Two Part, Double Blind, Placebo Controlled, Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effects of Multiple Doses of QBM076 in Patients With COPD

This was a 2 Part study. Part 1 was a safety and tolerability study in GOLD I-III COPD patients. Part 2 was an efficacy study in GOLD I-III COPD patients.

Study Overview

• Status: Terminated
• Conditions: COPD
• Intervention / Treatment: Drug: Placebo; Drug: QBM076

Detailed Description

Part 1 was a double-blind, randomized, placebo-controlled, non-confirmatory study in chronic bronchitis COPD patients. Part 1 consisted of up to 27-days of screening period, one baseline period of 1 day, 13 days of bid dosing with study treatment, morning only treatment on Day 14, follow up visits on Days 15 - 17, followed by a Study Completion evaluation. Twenty-seven patients were randomized in a 3:1 ratio to 3 cohorts..

Part 2 was a double-blind, randomized, placebo-controlled, non-confirmatory study in Gold spirometry grades I-III COPD patients. Part 2 consisted of up to 20 days of screening period, a 9 day run in period, one baseline period of 1 day, 55 days of bid dosing, morning only dosing on Day 56, followed by Study Completion evaluation. It was planned to randomize 90 patients in a 2:1 ratio, but part 2 was terminated after 21 patients were enrolled. Three of the 21 part 2 patients experienced moderate to severe (up to 17-fold) asymptomatic and reversible elevation of liver transaminase levels after 3 weeks of treatment with QBM076 150 mg twice daily. Two of these patients had liver transaminase levels high enough to be reported as serious adverse events suspected to be related to the study drug.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Novartis Investigative Site
  • Frankfurt, Germany, 60596
    • Novartis Investigative Site
  • Grosshansdorf, Germany, 22947
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
• Romania
  • Bucharest, Romania, Sector 5
    • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M23 9QZ
    • Novartis Investigative Site
• United States
  • Virginia
    • Richmond, Virginia, United States, 23225
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Part 1: Patients, smokers or ex-smokers with stable chronic bronchitis GOLD class I-III chronic obstructive pulmonary disease (COPD); forced expiratory volume in 1 second ≥40% of predicted and forced expiratory volume in 1 second:forced vital capacity ratio ≤0.7 post bronchodilator, respectively; diffusing capacity of the lung for carbon monoxide ≥40%; a stable medical regimen for at least 4 weeks prior to screening. Current smokers can be enrolled if they currently smoke ≤1ppd for last 3 months.

  • Part 2: Patients, smokers or ex-smokers with GOLD spirometry class I-III COPD; a stable medical regimen for at least 4 weeks prior to screening; high sensitivity C reactive protein≥1.5 mg/L; forced expiratory volume in 1 second ≥30% of predicted and forced expiratory volume in 1 second:forced vital capacity ratio ≤0.7 post bronchodilator, respectively; with mean lung clearance index 2.5% ≥8; Ex-smokers with at least 10 pack year smoking history; or current smokers with at least 10 pack year smoking history who smoke ≤ 1ppd on average for last 3 months.; evidence of air trapping based on radiologic criteria; women of child bearing potential using effective methods of contraception

Exclusion Criteria:

• Part 1:Gold Class IV COPD, of moderate to significant emphysema, or evidence of malignancy; medication considered potential for drug drug interaction; creatinine clearance <30ml/min; more than 1 exacerbation requiring antibiotics or oral steroids and/or hospitalization within 3 months of screening; women of child bearing potential • Part 2: Gold spirometry grade IV COPD; medication considered a potential for drug drug interaction; serum creatinine ≥1.9 mg/dL; more than 1 exacerbation requiring antibiotics or oral steroids within 2 months and/or hospitalization within 3 months of screening; any malignancy; evidence of severe emphysema as determined by HRCT; use of oral steroids, theophylline, phosphodiesterase-4 inhibitors or oral antibiotic use (eg.macrolides)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: QBM076 Part 1 Cohort 1; Participants received QBM076 25 mg twice daily (bid) for 14 days.	Drug: QBM076; Supplied in 25 mg and 75 mg capsules
Experimental: QBM076 Part 1 Cohort 2; Participants received QBM076 75 mg bid for 14 days.	Drug: QBM076; Supplied in 25 mg and 75 mg capsules
Experimental: QBM076 Part 1 Cohort 3; Participants received QBM076 150 mg bid for 14 days.	Drug: QBM076; Supplied in 25 mg and 75 mg capsules
Placebo Comparator: Placebo Part 1; Participants in each cohort received matching placebo for 14 days.	Drug: Placebo; Matching placebo capsules; Other Names: Matching placebo capsules
Experimental: QBM076 Part 2; Participants received QBM076 150 mg bid for 8 weeks.	Drug: QBM076; Supplied in 25 mg and 75 mg capsules
Placebo Comparator: Placebo Part 2; Participants received matching placebo for 8 weeks.	Drug: Placebo; Matching placebo capsules; Other Names: Matching placebo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Adverse Events (Part 1)	Adverse events were counted and corresponding percentages were tabulated.	14 days
Change From Baseline in Lung Clearance Index (LCI) (Part 2)		Baseline, 8 weeks
Change From Baseline in Absolute Number of Sputum Neutrophils (Part 2)		Baseline, 8 weeks
Change From Baseline in Transition Dyspnea Index (TDI) (Part 2)		Baseline, 8 weeks
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) (Part 2)		Baseline, 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval, Tau (AUCtau) (Part 1)	Venous blood samples were collected for concentration-time profiles.	day 1 (from pre-dose to 12 hours post dose)
AUCtau, Steady State (AUCtau,ss) (Part 1)	Venous blood samples were collected for concentration-time profiles.	day 14 (from pre-dose to 72 hours post dose)
Observed Maximum Plasma Concentration Following Drug Administration (Cmax) (Part 1)	Venous blood samples were collected for concentration-time profiles.	day 1 (from pre-dose to 12 hours post dose)
Cmax,ss (Part 1)	Venous blood samples were collected for concentration-time profiles.	day 14 (from pre-dose to 72 hours post dose)
Time to Reach the Maximum Concentration After Drug Administration (Tmax) (Part 1)	Venous blood samples were collected for concentration-time profiles.	day 1 (from pre-dose to 12 hours post dose)
Tmax,ss (Part 1)	Venous blood samples were collected for concentration-time profiles.	day 14 (from pre-dose to 72 hours post dose)
Change From Baseline in Cluster of Differentiation 11b (CD11b) (Part 1)	Whole blood samples were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein in order to measure CD11b expression on neutrophils. A negative change from baseline indicates improvement.	baseline, day 14
Change From Baseline in Chemokine (C-X-C Motif) Receptor 2 (CXCR2) Receptor Occupancy (Part 1)	Whole blood samples were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein in order to measure CXCR2 receptor occupancy on neutrophils. A positive change from baseline indicates improvement.	baseline, day 14
Change From Baseline in Forced Expiratory Volume in One Second (FEV1) (Part 1)	FEV1 is the amount of air that can be exhaled in one second. FEV1 will be measured by spirometry and performed at approximately the same time of day on each visit to avoid diurnal variation. All spirometry calibrations and evaluations followed the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. A positive change from baseline in FEV1 indicates improvement in lung function.	baseline, day 14 pre-dose
Change From Baseline in Lung Clearance Index 2.5 (LCI2.5) (Part 1)	Lung clearance index (LCI) is a measure of abnormal ventilation distribution derived from the multiple breath inert gas washout (MBW) technique. LCI is equal to the cumulative expired volume/functional residual capacity. LCI was measured at baseline and day 14. LCI was analyzed using a Bayesian model for repeated measurements. The model may investigate effects for pre-dose baseline, treatment, time, age, COPD class, treatment by time interaction, and baseline by time interaction. A positive change from baseline indicates improvement.	baseline, day 14 pre-dose
Change From Baseline in Forced Expirtory Flow 25-75 (FEF25-75), Forced Expiratory Volume 3 (FEV3)/Forced Vital Capacity (FVC), 1-(FEV3/FVC), FEV6, FEV1/FEV6 and Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (Part 2)		baseline, day 56
AUC0-24 (Part 2)		day 1, day 56
Cmax Between 0h and 24h (Part 2)		day 1, day 56
Tmax Between 0h and 24h (Part 2)		day 1, day 56
Change From Baseline in Percentage Sputum Neutrophils (Part 2)		baseline, day 56
Change From Baseline in Diffusing Capacity of the Lung for Carbon Monoxide (DLco) (Part 2)		baseline, day 56
Change From Baseline in Scond/Sacin as Measured by Multiple Breath Nitrogen Washout (MBNW) (Part 2)		baseline, day 56

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: October 24, 2013
• First Submitted That Met QC Criteria: October 24, 2013
• First Posted (Estimate): October 30, 2013

Study Record Updates

• Last Update Posted (Estimate): March 24, 2016
• Last Update Submitted That Met QC Criteria: February 24, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: COPD, inflammation, small airways, LCI, PFTs, lung heterogeneity
• Other Study ID Numbers: CQBM076X2203; 2012-005615-92 (EudraCT Number)