Alendronate to Prevent Loss of Bronchoprotection in Asthma (ALFA)

• ClinicalTrials.gov Identifier: NCT02230332
• Recruitment Status: Completed
• First Posted: September 3, 2014
• Results First Posted: December 14, 2017
• Last Update Posted: January 12, 2018
• Sponsor: Milton S. Hershey Medical Center
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): dave mauger, Milton S. Hershey Medical Center

Study Description

Brief Summary:

Beta-2-agonists are effective in reducing airway narrowing in asthma and protecting against stimuli that produce bronchoconstriction. The combination of long-acting beta agonists (LABA) and inhaled corticosteroids (ICS) has become the most commonly used asthma controller medication class in the United States, but unfortunately, even when LABAs are added to ICS and used regularly, 58-81% of patients with asthma fail to achieve total control. Regular use of beta-agonists, both short and long-acting, reduces the ability of these agents to protect against the airway narrowing that occurs in asthma in response to bronchoconstrictor stimuli. We refer to this reduced effect as loss of bronchoprotection. In this proof of concept trial we aim to determine if alendronate, which diminishes beta-2 adrenergic receptor internalization, can reduce the loss of bronchoprotection that occurs with regular use of LABAs, even when used in combination with ICS.

Condition or disease	Intervention/treatment	Phase
Asthma	Drug: Alendronate; Drug: Placebo	Phase 2; Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Proof of Concept Study of Alendronate for Asthma
• Study Start Date: January 2015
• Actual Primary Completion Date: September 2016
• Actual Study Completion Date: September 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Alendronate; Alendronate in 10mg capsules taken once daily	Drug: Alendronate; Other Name: Fasomax
Placebo Comparator: Placebo; Placebo capsule taken once daily	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Salmeterol Protected Methacholine Challenge PC20 [ Time Frame: 8 weeks after randomization ]
   Following administration of Salmeterol, the concentration of Methacholine required to produce a 20% drop in FEV1 - measured in mg/ml and reported on log base 2 scale.

Secondary Outcome Measures :

1. Peripheral Blood Mononuclear Cell ADRB2 Cell Surface Density [ Time Frame: 8 weeks after randomization ]
2. Beta-2 Adrenergic Receptor Agonist-induced cAMP Production [ Time Frame: 8 weeks after randomization ]
   Peripheral blood mononuclear cells cAMP concentrations measured using isoproterenol (ISO) as a beta-2 adrenergic receptor agonist, and using phosphate buffered saline (PBS) as a positive control. The outcome is expressed as the ratio of cAMP concentration using ISO relative to cAMP concentration using PBS.

Other Outcome Measures:

1. Salivary Alpha Amylase Ratio (Post-Salmeterol / Pre-Salmeterol) [ Time Frame: 8 weeks after randomization ]
   Salivary Alpha Amylase (sAA) levels from saliva samples obtained through passive drooling, before and 1 hour after Salmeterol administration. The outcome is expressed as the ratio of the Post-Salmeterol to the Pre-Salmeterol sAA levels.
2. Asthma Control Test (ACT) [ Time Frame: 8 weeks after randomization ]
   Asthma Control Test : Score calculated as the sum total of a 5-item questionnaire. Each item ranges from 1 (poor control) to 5 (good control) so that the range of the total score is 5 to 25. Scores below 20 indicate that asthma is not well controlled.
3. Fractional Exhaled Nitrix Oxide [ Time Frame: 8 weeks after randomization ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Clinical history consistent with moderate asthma for >1 year
• Asthma is controlled with ICS, with an FP dose ≤ 1000mcg/day and >100mcg/day (or equivalent)
• Able to perform reproducible spirometry according to ATS criteria
• Baseline FEV1 ≥ 50% of predicted and ≥1L.
• If FEV1 <80%, a minimum 12% increase in FEV1 post-bronchodilator or a MCh PC20 ≤ 8 mg/mL
• If FEV1 ≥80%, a MCh PC20 ≤ 8 mg/mL
• Salmeterol protected MCh ≤ 16 mg/mL

Exclusion Criteria:

• Uncontrolled asthma, as suggested by an ACT score <18 while on high-dose ICS (FP daily dose >500mcg or equivalent)
• Non-ICS controller medication or LABA use within 4 weeks of study entry.
• Contraindications to use of bisphosphonates: history of intolerance to bisphosphonates, history of esophageal ulcers, history of hematemesis, uncontrolled gastro-esophageal reflux disease, inability to stay erect for 30 minutes after oral drug, history of osteonecrosis of the jaw, dental extraction or root canal in prior 8 weeks, or anticipated during the study
• Calculated GFR of less than 35 mL/min
• History of smoking (cigarettes, cigars, pipes, marijuana or any other substances) within the past 1 year, or > 10 pack-years total if ≥ 18 years of age
• Systemic corticosteroid treatment for any condition within 4 weeks of enrollment at Visit 1, history of significant asthma exacerbation requiring systemic corticosteroids within 4 weeks of Visit 1 or more than five courses of systemic corticosteroids in the past year, history of a life-threatening asthma exacerbation requiring intubation, mechanical ventilation, or resulting in a hypoxic seizure within the last 2 years
• History of a respiratory tract infection within 4 weeks of Visit 1
• Receiving hyposensitization therapy other than an established maintenance regimen defined as a continuous regimen for ≥ 3 months prior to enrollment

Contacts and Locations

Locations

United States, Arizona

University of Arizona College of Medicine

Tucson, Arizona, United States, 85724

United States, California

University of California - San Francisco

San Francisco, California, United States, 94143

United States, Colorado

National Jewish Health

Denver, Colorado, United States, 80206

United States, Illinois

Northwestern Memorial Hospital

Chicago, Illinois, United States, 60611

University of Illinois at Chicago

Chicago, Illinois, United States, 60612

University of Chicago

Chicago, Illinois, United States, 60637

United States, Massachusetts

Brigham & Women's Hospital

Boston, Massachusetts, United States, 02115

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

United States, North Carolina

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States, 27157

United States, Wisconsin

University of Wisconsin

Madison, Wisconsin, United States, 53972

Sponsors and Collaborators

Milton S. Hershey Medical Center

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Study Director: Juan Carlos Cardet, MD; Brigham and Women's Hospital

More Information

Additional Information:

AsthmaNet home page 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cardet JC, Jiang X, Lu Q, Gerard N, McIntire K, Boushey HA, Castro M, Chinchilli VM, Codispoti CD, Dyer AM, Holguin F, Kraft M, Lazarus S, Lemanske RF, Lugogo N, Mauger D, Moore WC, Moy J, Ortega VE, Peters SP, Smith LJ, Solway J, Sorkness CA, Sumino K, Wechsler ME, Wenzel S, Israel E; AsthmaNet Investigators. Loss of bronchoprotection with ICS plus LABA treatment, beta-receptor dynamics, and the effect of alendronate. J Allergy Clin Immunol. 2019 Aug;144(2):416-425.e7. doi: 10.1016/j.jaci.2019.01.049. Epub 2019 Mar 11.

• Responsible Party: dave mauger, Professor of Public Health Sciences, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT02230332
• Other Study ID Numbers: AsthmaNet 009; U10HL098115 ( U.S. NIH Grant/Contract )
• First Posted: September 3, 2014
• Results First Posted: December 14, 2017
• Last Update Posted: January 12, 2018
• Last Verified: December 2017

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Alendronate; Bone Density Conservation Agents; Physiological Effects of Drugs