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Alendronate to Prevent Loss of Bronchoprotection in Asthma (ALFA)

Primary Purpose

Asthma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Alendronate
Placebo
Sponsored by
Milton S. Hershey Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Asthma

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Arizona College of Medicine
  • University of California - San Francisco
  • National Jewish Health
  • Northwestern Memorial Hospital
  • University of Illinois at Chicago
  • University of Chicago
  • Brigham & Women's Hospital
  • Washington University
  • Wake Forest University Health Sciences
  • University of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Alendronate

Placebo

Arm Description

Alendronate in 10mg capsules taken once daily

Placebo capsule taken once daily

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Peripheral Blood Mononuclear Cell ADRB2 Cell Surface Density
Beta-2 Adrenergic Receptor Agonist-induced cAMP Production
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.

Full Information

First Posted
August 29, 2014
Last Updated
December 13, 2017
Sponsor
Milton S. Hershey Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT02230332
Brief Title
Alendronate to Prevent Loss of Bronchoprotection in Asthma
Acronym
ALFA
Official Title
Proof of Concept Study of Alendronate for Asthma
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
January 2015 (undefined)
Primary Completion Date
September 2016 (Actual)
Study Completion Date
September 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Milton S. Hershey Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
78 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Alendronate
Arm Type
Experimental
Arm Description
Alendronate in 10mg capsules taken once daily
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo capsule taken once daily
Intervention Type
Drug
Intervention Name(s)
Alendronate
Other Intervention Name(s)
Fasomax
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Salmeterol Protected Methacholine Challenge PC20
Description
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.
Time Frame
8 weeks after randomization
Secondary Outcome Measure Information:
Title
Peripheral Blood Mononuclear Cell ADRB2 Cell Surface Density
Time Frame
8 weeks after randomization
Title
Beta-2 Adrenergic Receptor Agonist-induced cAMP Production
Description
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.
Time Frame
8 weeks after randomization
Other Pre-specified Outcome Measures:
Title
Salivary Alpha Amylase Ratio (Post-Salmeterol / Pre-Salmeterol)
Description
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.
Time Frame
8 weeks after randomization
Title
Asthma Control Test (ACT)
Description
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.
Time Frame
8 weeks after randomization
Title
Fractional Exhaled Nitrix Oxide
Time Frame
8 weeks after randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juan Carlos Cardet, MD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Study Director
Facility Information:
Facility Name
University of Arizona College of Medicine
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
University of California - San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
National Jewish Health
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Brigham & Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
University of Wisconsin
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53972
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
30872116
Citation
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.
Results Reference
derived
Links:
URL
http://asthmanetresearch.org/
Description
AsthmaNet home page

Learn more about this trial

Alendronate to Prevent Loss of Bronchoprotection in Asthma

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