Dose Finding Study of CHF 4226 for Treating Patients With COPD

A Randomized, Controlled,14-Treatment Day, Multicenter Study to Determine the Optimal Efficacious and Safe Dose of CHF 4226 in a Metered Dose Inhaler in Treating Patients With Chronic Obstructive Pulmonary Disease

The purpose of this study is to identify the optimal once-daily dose of CHF 4226 to be further developed for the treatment of patients with COPD.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: carmoterol (CHF 4226); Drug: carmoterol (CHF 4226); Drug: carmoterol (CHF 4226); Drug: placebo; Drug: salmeterol

• Study Type: Interventional
• Enrollment (Actual): 278
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czech Republic
  • Beroun, Czech Republic, 266 01
    • Ordinace pro nemoci dychaciho ustroji
  • Kutna Hora, Czech Republic, 284 01
    • OTRAN
  • Kutna Hora, Czech Republic, 284 01
    • Plicni a alergologicka ambulance
  • Lovosice, Czech Republic, 310 02
    • Pneumolog, internista
  • Praha 3 - Zizkov, Czech Republic, 130 00
    • Plicni ambulance
  • Praha 5, Czech Republic, 15030
    • Nemocnice Na Homolce Plicni ambulance
  • Rokycany, Czech Republic, 337 01
    • Plicni ambulance Rokycany
• Germany
  • Berlin, Germany, 14057
    • MEDARS GmbH
  • Geesthacht, Germany, 21502
    • Lungenzentrum Geesthacht
  • Grosshansdorf, Germany, 22927
    • Pneumologisches Forschungsinstitut GmbH
  • Hamburg, Germany, 20535
    • Pneumologisches Forschungsinstitut Niederlassung Hamburg
  • Leipzig, Germany, 04207
    • Robert-Koch-Klinik
  • Magdeburg, Germany, 39112
    • SMO, MD GmbH
  • Ruedersdorf, Germany, 15565
    • IFG GmbH
• Poland
  • Gdansk, Poland, 80-433
    • Medcare Specjalistyczna Opieka Medyczna NZOZ
  • Gdansk, Poland, 80-847
    • NZOZ Non-nocere
  • Lodz, Poland, 90-153
    • Klinika Pulmonologii i Alergologii
  • Proszowice, Poland, 32-100
    • SPZOZ w Proszowicach Oddzial Chorob Pluc
• Romania
  • Brasov, Romania, 500326
    • Spitalul Clinic Judetean de Urgenta Brasov
  • Bucharest, Romania, 010457
    • Spitalul de Urgenta "Prof. Dr. Dimitrie Gerota"
  • Bucharest, Romania, 010825
    • Spitalul Clinic de Urgenta Militar Central "Davila"
  • Bucharest, Romania, 011172
    • Spitalul Clinic "Sf. Maria"
  • Bucharest, Romania, 050159
    • Institutul National de Pneumoftisiologie "M. Nasta"
  • Constanta, Romania, 900002
    • Spitalul de Pneumoftiziologie Constanta
• South Africa
  • Bellville, South Africa, 7530
    • Tiervlei Trial Center, Karl Bremer Hospital
  • Cape Town
    • Mowbray, Cape Town, South Africa, 7700
      • UCT Lung institute
• United States
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
      • Clopton Clinic
  • California
    • Fresno, California, United States, 93720
      • ABM Research Center
    • San Diego, California, United States, 92103
      • UCSD - Clinical Trials Center
    • San Diego, California, United States, 92120
      • Institute of Healthcare Assessment Inc.
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Medical and Research Center
  • Florida
    • Clearwater, Florida, United States, 33765
      • Clinical Research of West Florida
    • DeLand, Florida, United States, 32720
      • University Clinical Research - Deland, LLC
    • Tampa, Florida, United States, 33603
      • Clinical Research of West Florida, Inc.
    • West Palm Beach, Florida, United States, 33409
      • Palm Beach Research Center
  • Illinois
    • Naperville, Illinois, United States, 60540
      • Edward Hospital and Helath Services, Center for Clinical Trials
  • Indiana
    • Anderson, Indiana, United States, 46011
      • Community Clinical Research Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • ClinSite, LLC
    • Canton, Michigan, United States, 48187
      • Clinsite
  • New Jersey
    • Cherry Hill, New Jersey, United States, 08003
      • Delaware Valley Clinical Research
  • North Carolina
    • Statesville, North Carolina, United States, 28625
      • Carolina Pharmaceutical Research
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • New Horizons Clinical Research
    • Sylvania, Ohio, United States, 43560
      • Toledo Center for Clinical Research
  • Oregon
    • Medford, Oregon, United States, 97504
      • Clinical Research Institute of Southern Oregon PC
    • Medford, Oregon, United States, 97504
      • Pulmonary Consultants - Research Department
  • South Carolina
    • North Charleston, South Carolina, United States, 29406
      • Lowcountry Lung and Critical Care, PA
  • Texas
    • Amarillo, Texas, United States, 79124
      • Amarillo Center for Clinical Research, Ltd.
    • Katy, Texas, United States, 77450
      • Breath of Life Research Institute
    • Tyler, Texas, United States, 75708
      • The University of Texas Health Center at Tyler
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin-Allergy/Asthma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient has signed an IRB-/Ethics Committee-approved Informed Consent form
• Patient is a male or non-pregnant female between the ages of 40 - 75 years, inclusive
• Patient has a current or past smoking history of at least 15 pack-years
• Patient has a clinical diagnosis of COPD in accordance with the recommendations of the National Heart Lung and Blood Institute/World Health Organization (NHLBI/WHO) Global Initiative for Chronic Obstructive Lung Disease (GOLD)
• Patient meets the following requirements after an FEV1 albuterol reversibility test (i.e., 30 minutes following 200 mcg (metered dose) albuterol/salbutamol pMDI):
• FEV1 is at least 0.9L
• FEV1 of 40% - 70%, inclusive, of patient's predicted normal value

• Change in FEV1 > 4% of patient's predicted normal value

  • If change in FEV1 < 4% of patient's predicted normal value, then this requirement must be met after retesting during the run-in period, at least 24 hours prior to Day -1
• FEV1/FVC < 70%

Exclusion Criteria:

• Patient has a history of asthma, allergic rhinitis, or atopy
• Patient has a blood eosinophil count > 500/microliter
• Patient had a COPD exacerbation or a lower respiratory tract infection within 8 weeks prior to screening, or during the run-in period, that resulted in the use of an antibiotic, or oral or parenteral corticosteroids
• Patient is on an inhaled corticosteroid that has been initiated, or the effective dose has been changed, within 4 weeks prior to screening or during the run-in period
• Patient has an uncontrolled cardiovascular (e.g., uncontrolled hypertension), respiratory, hematologic, immunologic, renal, neurologic, hepatic, endocrine (e.g., uncontrolled diabetes mellitus) or other disease, or any condition that might, in the judgment of the Investigator, place the patient at undue risk or potentially compromise the results or interpretation of the study
• Patient has a history of coronary artery disease, cerebrovascular disease, cardiac arrhythmias
• Patient has a concomitant disease of poor prognosis (e.g., cancer)
• Patient has a serum potassium value ≤ 3.5 mEq/L or >5.5mEq/L and/or a fasting serum glucose value ≥ 140 mg/dL
• Patient has an abnormal QTc Fridericia interval value in the Screening visit ECG test (i.e., > 450 msec in males or > 470 msec in females)
• Patient has developed Cor Pulmonale
• Patient is receiving long term oxygen therapy, i.e., ≥ 16 hours/24-hour period, every day
• Patient has a known intolerance/hypersensitivity to Beta2-adrenergic agonists, propellant gases/excipients
• Patient is receiving treatment with a tricyclic antidepressant or a monoamine oxidase inhibitor (MAOI)
• Patient has received a live-attenuated virus vaccination within two weeks prior to screening or during the run-in
• Patient is pregnant or lactating female, or female at risk of pregnancy (i.e., not using an adequate contraceptive method)
• Patient is mentally or legally incapacitated
• Patient has participated in another investigational study within 30 days prior to screening
• Patient abuses alcohol or other substances
• Patient is potentially non-compliant or unable to perform required outcome measurements of the protocol

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; carmoterol (CHF 4226) 1.0 μg once a day, in the morning	Drug: carmoterol (CHF 4226); carmoterol pMDI 2.0 μg once a day, in the morning (1 puff of carmoterol 1.0 mcg + 1 puff of carmoterol 1.0 mcg); Other Names: CHF 4226; Drug: carmoterol (CHF 4226); carmoterol pMDI 1.0 μg once a day, in the morning (1 puff of carmoterol 1.0 mcg + 1 puff of placebo pMDI)); Other Names: CHF 4226; Drug: carmoterol (CHF 4226); carmoterol pMDI 4.0 μg once a day, in the morning (1 puff of carmoterol 2.0 mcg + 1 puff of carmoterol 2.0 mcg); Other Names: CHF 4226
Experimental: B; carmoterol (CHF 4226) 2.0 μg once a day, in the morning	Drug: carmoterol (CHF 4226); carmoterol pMDI 2.0 μg once a day, in the morning (1 puff of carmoterol 1.0 mcg + 1 puff of carmoterol 1.0 mcg); Other Names: CHF 4226; Drug: carmoterol (CHF 4226); carmoterol pMDI 1.0 μg once a day, in the morning (1 puff of carmoterol 1.0 mcg + 1 puff of placebo pMDI)); Other Names: CHF 4226; Drug: carmoterol (CHF 4226); carmoterol pMDI 4.0 μg once a day, in the morning (1 puff of carmoterol 2.0 mcg + 1 puff of carmoterol 2.0 mcg); Other Names: CHF 4226
Experimental: C; carmoterol (CHF 4226) 4.0 μg once a day, in the morning	Drug: carmoterol (CHF 4226); carmoterol pMDI 2.0 μg once a day, in the morning (1 puff of carmoterol 1.0 mcg + 1 puff of carmoterol 1.0 mcg); Other Names: CHF 4226; Drug: carmoterol (CHF 4226); carmoterol pMDI 1.0 μg once a day, in the morning (1 puff of carmoterol 1.0 mcg + 1 puff of placebo pMDI)); Other Names: CHF 4226; Drug: carmoterol (CHF 4226); carmoterol pMDI 4.0 μg once a day, in the morning (1 puff of carmoterol 2.0 mcg + 1 puff of carmoterol 2.0 mcg); Other Names: CHF 4226
Placebo Comparator: D; Placebo once a day, in the morning	Drug: placebo; Placebo pMDI once a day, in the morning (1 puff of placebo pMDI + 1 puff of placebo pMDI)
Active Comparator: E; Salmeterol 50 μg BID, in the morning and in the evening	Drug: salmeterol; Salmeterol 50 μg DPI, in the morning and in the evening (1 blister BID); Other Names: Serevent® Diskus®/Accuhaler®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in FEV1	Day 1 to Day 14 (+3 days)

Secondary Outcome Measures

Outcome Measure	Time Frame
FEV1	10 and 30 min, 1, 2, and 3 hrs post dose on Day 1, Day 2 and Day 14 (+3)
ECG/QTc	pre dose and post dose at 30' on Days 1, 2 and 14 (+3)
Fasting serum potassium	pre dose and post dose at 30' on Days 1, 2 and 14 (+3)
Fasting glucose	pre dose and post dose at 30' on Days 1, 2 and 14 (+3)
Change in FEV1	10 and 30 min, 1, 2, and 3 hrs post dose on Day 1, Day 2 and Day 14 (+3)

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.
• Collaborators: Chiesi USA, Inc.
• Investigators: Principal Investigator: Barry Make, MD, National Jewish Medical & Research Center; Study Director: Steven E Linberg, Ph.D., Chiesi Farmaceutici S.p.A.

Publications and helpful links

General Publications

• Matera MG, Cazzola M. ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? Drugs. 2007;67(4):503-15. doi: 10.2165/00003495-200767040-00002.
• Cazzola M, Matera MG, Lotvall J. Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2005 Jul;14(7):775-83. doi: 10.1517/13543784.14.7.775.
• Matsukawa M, Takeda K, Shima H, Tagawa K, Banno K, Sato T. Enzyme-linked immunosorbent assay for TA-2005-glucuronide in human plasma. J Pharm Biomed Anal. 1998 Jun;17(2):245-54. doi: 10.1016/s0731-7085(97)00186-6.
• Kikkawa H, Isogaya M, Nagao T, Kurose H. The role of the seventh transmembrane region in high affinity binding of a beta 2-selective agonist TA-2005. Mol Pharmacol. 1998 Jan;53(1):128-34. doi: 10.1124/mol.53.1.128.
• Rossoni G, Manfredi B, Razzetti R, Civelli M, Bongrani S, Berti F. Positive interaction of the beta2-agonist CHF 4226.01 with budesonide in the control of bronchoconstriction induced by acetaldehyde in the guinea-pigs. Br J Pharmacol. 2005 Feb;144(3):422-9. doi: 10.1038/sj.bjp.0706096.
• Rossoni G, Manfredi B, Razzetti R, Civelli M, Berti F. Positive interaction of the novel beta2-agonist carmoterol and tiotropium bromide in the control of airway changes induced by different challenges in guinea-pigs. Pulm Pharmacol Ther. 2007;20(3):250-7. doi: 10.1016/j.pupt.2006.01.004. Epub 2006 Mar 14.
• Voss HP, Shukrula S, Wu TS, Donnell D, Bast A. A functional beta-2 adrenoceptor-mediated chronotropic response in isolated guinea pig heart tissue: selectivity of the potent beta-2 adrenoceptor agonist TA 2005. J Pharmacol Exp Ther. 1994 Oct;271(1):386-9.
• Kikkawa H, Kanno K, Ikezawa K. TA-2005, a novel, long-acting, and selective beta 2-adrenoceptor agonist: characterization of its in vivo bronchodilating action in guinea pigs and cats in comparison with other beta 2-agonists. Biol Pharm Bull. 1994 Aug;17(8):1047-52. doi: 10.1248/bpb.17.1047.
• Voss HP, Donnell D, Bast A. Atypical molecular pharmacology of a new long-acting beta 2-adrenoceptor agonist, TA 2005. Eur J Pharmacol. 1992 Dec 1;227(4):403-9. doi: 10.1016/0922-4106(92)90158-r.
• Kikkawa H, Naito K, Ikezawa K. Tracheal relaxing effects and beta 2-selectivity of TA-2005, a newly developed bronchodilating agent, in isolated guinea pig tissues. Jpn J Pharmacol. 1991 Oct;57(2):175-85. doi: 10.1254/jjp.57.175.
• Spadari-Bartfisch RC, Santos IN, Vanderlei LC, Marcondes FK. Pharmacological evidence for beta2-adrenoceptor in right atria from stressed female rats. Can J Physiol Pharmacol. 1999 Jun;77(6):432-40.

Helpful Links

• Study Record on EU Clinical Trials Register including results

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Actual): June 1, 2007
• Study Completion (Actual): June 1, 2007

Study Registration Dates

• First Submitted: January 18, 2008
• First Submitted That Met QC Criteria: January 18, 2008
• First Posted (Estimate): January 31, 2008

Study Record Updates

• Last Update Posted (Actual): April 11, 2017
• Last Update Submitted That Met QC Criteria: April 7, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Salmeterol Xinafoate
• Other Study ID Numbers: US/PR/033009/001/05; EudraCT Number: 2006-000531-10

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No