Alendronate to Prevent Loss of Bronchoprotection in Asthma

NCT02230332 | Completed Phase 2 Results DMC

• 2 other identifiers: AsthmaNet 009U10HL098115
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 10

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.

Conditions

Asthma

Outcome Measures

Primary Outcomes (1)

• Salmeterol Protected Methacholine Challenge PC20

  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.

  8 weeks after randomization

Secondary Outcomes (2)

• Peripheral Blood Mononuclear Cell ADRB2 Cell Surface Density

  8 weeks after randomization

• Beta-2 Adrenergic Receptor Agonist-induced cAMP Production

  8 weeks after randomization

Other Outcomes (3)

• Salivary Alpha Amylase Ratio (Post-Salmeterol / Pre-Salmeterol)

  8 weeks after randomization

• Asthma Control Test (ACT)

  8 weeks after randomization

• Fractional Exhaled Nitrix Oxide

  8 weeks after randomization

Study Arms (2)

Alendronate

EXPERIMENTAL

Alendronate in 10mg capsules taken once daily

Drug: Alendronate

Placebo

PLACEBO COMPARATOR

Placebo capsule taken once daily

Drug: Placebo

Interventions

Alendronate DRUG

Also known as: Fasomax

Alendronate

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Milton S. Hershey Medical Center: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (10)

University of Arizona College of Medicine

Tucson, Arizona, 85724, United States

Location

University of California - San Francisco

San Francisco, California, 94143, United States

Location

National Jewish Health

Denver, Colorado, 80206, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

University of Illinois at Chicago

Chicago, Illinois, 60612, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Brigham & Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

University of Wisconsin

Madison, Wisconsin, 53972, United States

Location

Related Publications (1)

• 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.

  PMID: 30872116 DERIVED

Related Links

• AsthmaNet home page

MeSH Terms

Conditions

Asthma

Interventions

Alendronate

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals

Results Point of Contact

• Title: David Mauger, PhD
• Organization: Penn State University Dept of Public Health Sciences

dmauger@psu.edu

717.531.3584

Study Officials

• Juan Carlos Cardet, MD

  Brigham and Women's Hospital

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Public Health Sciences

Study Record Dates

• First Submitted: August 29, 2014
• First Posted: September 3, 2014
• Study Start: January 1, 2015
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: January 12, 2018
• Results First Posted: December 14, 2017

Record last verified: 2017-12

Locations

US (10)