Confirmatory Dose Finding Study of 2 Dosages of CHF 4226 pMDI (Carmoterol) in Patients With COPD

Chronic Obstructive Pulmonary Disease Clinical Trial

Official title:

Evaluation of the Effect of 2 Weeks Treatment With CHF 4226 pMDI 2µg and 4µg, Given Once Daily in the Morning, on 24-Hour FEV1 in Patients With COPD

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00640484
• Other study ID #: CCD-0706-PR-0026
• Status: Completed
• Phase: Phase 2
• First received: March 18, 2008
• Last updated: August 24, 2010
• Start date: April 2008
• Est. completion date: October 2008

Study information

• Verified date: August 2010
• Source: Chiesi Farmaceutici S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to confirm the dose of CHF 4226 (carmoterol) that should be given once a day to patients with COPD in order for the effect to last for 24 hours.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: October 2008
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 75 Years

Eligibility

Inclusion Criteria:

• Signed IRB approved Informed Consent form

• Male or non-pregnant female, 40 -75 years old, inclusive

• Current or past cigarette smoking history of at least 15 pack-years

• Clinical diagnosis of COPD in accordance with recommendations of the National Heart Lung and Blood Institute/World Health Organization (NHLBI/WHO) Global Initiative for Chronic Obstructive Lung Disease (GOLD)

• Patient meets following requirements after FEV1 albuterol reversibility test (i.e., 30 minutes after 200µg (metered dose) albuterol MDI):

• FEV1/FVC < 70%

• FEV1 is at least 0.9L

• FEV1 30% - 80%, inclusive, of patient's predicted normal value; ?FEV1 > 5% of pre-albuterol value

• If ?FEV1 < 5% of pre-albuterol value, requirement must be met after retesting during run-in period, at least 24 hours prior to Period 1/Visit 1.

Exclusion Criteria:

• History of asthma

• Blood eosinophil count > 500/microliters

• History of allergic rhinitis or atopy

• COPD exacerbation or lower respiratory tract infection within 8 weeks prior to screening, or during run-in period, that resulted in use of an antibiotic, or oral or parenteral corticosteroids

• Inhaled corticosteroid that has been initiated, or effective dose has been changed, within 4 weeks prior to screening or during run-in period

• 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 Investigator's judgment, place patient at undue risk or potentially compromise study results or interpretation

• History of coronary artery disease, cerebrovascular disease, cardiac arrhythmias

• Lung cancer or history of lung cancer

• Active cancer or history of cancer with < 5 years disease free survival time (with or without evidence of local recurrence or metastases). Localized basal cell carcinoma (without metastases) of skin is acceptable.

• Serum potassium value = 3.5 mEq/L or > 5.5mEq/L and/or fasting serum glucose value = 140 mg/dL

• Abnormal QTcF interval value in Screening visit ECG test (i.e., > 450 msec in males or > 470 msec in females)

• Cor Pulmonale

• Long term oxygen therapy, i.e., > 16 hours/24-hour period, every day, unless patient resides at elevation > 4000ft

• Use of any of the following medications prior to Screening, without meeting specified minimum washout period:

• Long acting anti-cholinergic agent (i.e., tiotropium): 7 days

• Short acting anti-cholinergics: 8 hours

• Fixed combinations of ß2-agonists and inhaled corticosteroids: 48 hours

• Fixed combinations of an anti-cholinergic and short acting ß2-agonist: 8 hours

• Long-acting ß2-agonists: 48 hours

• Short acting ß2-agonists (other than those prescribed in the study): 6 hours

• Theophylline and other xanthines: 1 week

• Parenteral or oral corticosteroids: 1 month

• Patient has taken any non-permitted medication

• Patient has received live-attenuated virus vaccination within two weeks prior to screening or during run-in (inactivated Influenza vaccination is acceptable if given > 48 hours prior to Screening)

• Known intolerance/hypersensitivity to ß2-adrenergic agonists, propellant gases/excipients

• Patient is pregnant or lactating female, or female at risk of pregnancy (i.e., not using adequate contraceptive method: surgical sterilization [e.g., bilateral tubal ligation], hormonal contraception [implantable, patch, oral], IUD, and double-barrier methods [any double combination of: male or female condom with spermicidal gel, diaphragm, sponge, cervical cap]).

• Patient is mentally or legally incapacitated

• Patient has participated in another investigational study within 30 days prior to screening

• Abuse of alcohol or other substances

• Patient does not maintain regular day/night, waking/sleeping cycles (e.g., night shift worker)

• Patient is potentially non-compliant or unable to perform required protocol outcome measurements

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• carmoterol (CHF 4226)
carmoterol (CHF 4226) 2 µg once a day, in the morning (1 puff of carmoterol 2 µg + 1 puff of placebo pMDI)
• carmoterol (CHF 4226)
carmoterol (CHF 4226) 4 µg once a day, in the morning (1 puff of carmoterol 2 µg + 1 puff of carmoterol 2µg)
• placebo
placebo once a day, in the morning (1 puff of placebo pMDI + 1 puff of placebo pMDI)
• salmeterol
Salmeterol 50 µg twice daily, in the morning and in the evening (1 blister of Serevent Diskus BID)

Locations

Country	Name	City	State
United States	Pulmonary Medicine and Critical Care	Austell	Georgia
United States	New Horizons Clinical Research	Cincinnati	Ohio
United States	University Clinical Research - DeLand, LLC	DeLand	Florida
United States	Horizon Clinical Research Associates, PLLC	Gilbert	Arizona
United States	UCLA David Geffen School of Medicine	Los Angeles	California
United States	Commonwealth BioMedical Research	Madisonville	Kentucky
United States	Clinical Research Institute of Southern Oregon, PC	Medford	Oregon
United States	Sneeze, Wheeze & Itch Associates, LLC	Normal	Illinois
United States	Lynn Health Science Institute	Oklahoma City	Oklahoma
United States	Pulmonary Associates, PA	Phoenix	Arizona
United States	Asthma Allergy Associates	Portland	Oregon
United States	North Carolina Clinical Research	Raleigh	North Carolina
United States	University of Utah	Salt Lake City	Utah
United States	Spartanburg Medical Research	Spartanburg	South Carolina
United States	Reichman Associates	Sugar Land	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Chiesi Farmaceutici S.p.A.	Chiesi Pharmaceuticals Inc.

Country where clinical trial is conducted

United States, 

References & Publications (11)

Cazzola M, Matera MG, Lötvall 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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Matera MG, Cazzola M. ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? Drugs. 2007;67(4):503-15. Review. — View Citation

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. — View Citation

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. Epub 2006 Mar 14. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	FEV1 AUC0-24 standardized by time		on Day 15 (after 14 days of dosing)	No
Secondary	FEV1(L)		30 min, 1, 2 ,3, 4, 6, 10, 12, 14, 16, 22, 23, and 24 hrs post dose at Visit 2 at all treatment periods	No
Secondary	blood pressure		at the beginning and end of each of the four 14-day treatment periods	Yes
Secondary	heart rate		at the beginning and end of each of the four 14-day treatment periods	Yes
Secondary	FEV1 percent change		30 min, 1, 2 ,3, 4, 6, 10, 12, 14, 16, 22, 23, and 24 hrs post dose at Visit 2 at all treatment periods	No