Clinical trial NCT01972776: A Safety, Tolerability and Efficacy Study in Chronic Obstructive Pulmonary Disease (COPD) Patients With QBM076.
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: COPD
Keywords: COPD, inflammation, small airways, LCI, PFTs, lung heterogeneity
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-10-30
Enrollment: 48
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of Participants With Adverse Events (Part 1)
timeFrame: 14 days
measure: Change From Baseline in Lung Clearance Index (LCI) (Part 2)
timeFrame: Baseline, 8 weeks
measure: Change From Baseline in Absolute Number of Sputum Neutrophils (Part 2)
timeFrame: Baseline, 8 weeks
measure: Change From Baseline in Transition Dyspnea Index (TDI) (Part 2)
timeFrame: Baseline, 8 weeks
measure: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) (Part 2)
timeFrame: Baseline, 8 weeks
Secondary outcomes:
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval, Tau (AUCtau) (Part 1)
timeFrame: day 1 (from pre-dose to 12 hours post dose)
measure: AUCtau, Steady State (AUCtau,ss) (Part 1)
timeFrame: day 14 (from pre-dose to 72 hours post dose)
measure: Observed Maximum Plasma Concentration Following Drug Administration (Cmax) (Part 1)
timeFrame: day 1 (from pre-dose to 12 hours post dose)
measure: Cmax,ss (Part 1)
timeFrame: day 14 (from pre-dose to 72 hours post dose)
measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) (Part 1)
timeFrame: day 1 (from pre-dose to 12 hours post dose)
measure: Tmax,ss (Part 1)
timeFrame: day 14 (from pre-dose to 72 hours post dose)
measure: Change From Baseline in Cluster of Differentiation 11b (CD11b) (Part 1)
timeFrame: baseline, day 14
measure: Change From Baseline in Chemokine (C-X-C Motif) Receptor 2 (CXCR2) Receptor Occupancy (Part 1)
timeFrame: baseline, day 14
measure: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) (Part 1)
timeFrame: baseline, day 14 pre-dose
measure: Change From Baseline in Lung Clearance Index 2.5 (LCI2.5) (Part 1)
timeFrame: baseline, day 14 pre-dose
measure: 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)
timeFrame: baseline, day 56
measure: AUC0-24 (Part 2)
timeFrame: day 1, day 56
measure: Cmax Between 0h and 24h (Part 2)
timeFrame: day 1, day 56
measure: Tmax Between 0h and 24h (Part 2)
timeFrame: day 1, day 56
measure: Change From Baseline in Percentage Sputum Neutrophils (Part 2)
timeFrame: baseline, day 56
measure: Change From Baseline in Diffusing Capacity of the Lung for Carbon Monoxide (DLco) (Part 2)
timeFrame: baseline, day 56
measure: Change From Baseline in Scond/Sacin as Measured by Multiple Breath Nitrogen Washout (MBNW) (Part 2)
timeFrame: baseline, day 56
Other outcomes:
Locations:
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Grosshansdorf
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: