Alendronate to Prevent Loss of Bronchoprotection in Asthma

Proof of Concept Study of Alendronate for Asthma

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02230332

Acronym

ALFA

Enrollment

Registered

2014-09-03

Start date

2015-01-31

Completion date

2016-09-30

Last updated

2018-01-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asthma

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.

Interventions

DRUGAlendronate

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

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

Design outcomes

Primary

Measure	Time frame	Description
Salmeterol Protected Methacholine Challenge PC20	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

Measure	Time frame	Description
Peripheral Blood Mononuclear Cell ADRB2 Cell Surface Density	8 weeks after randomization	—
Beta-2 Adrenergic Receptor Agonist-induced cAMP Production	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

Measure	Time frame	Description
Salivary Alpha Amylase Ratio (Post-Salmeterol / Pre-Salmeterol)	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.
Asthma Control Test (ACT)	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.
Fractional Exhaled Nitrix Oxide	8 weeks after randomization	—

Countries

United States

Participant flow

Recruitment details

Eligible participants were recruited from the community between January 2015 and May 2016 at 9 U.S. sites from the NHLBI AsthmaNet research network.

Pre-assignment details

Participants with persistent asthma were first treated with fluticasone propionate 250mcg twice daily for 2 weeks during the run-in. Most of the participants who were not randomized did not meet the Salmeterol Protected Methacholine Challenge inclusion criterion.

Participants by arm

Arm	Count
Alendronate Alendronate in 10mg capsules taken once daily Alendronate	38
Placebo Placebo capsule taken once daily Placebo	40
Total	78

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	1
Overall Study	Lost to Follow-up	1	0
Overall Study	Protocol Violation	1	0

Baseline characteristics

Characteristic	Alendronate	Placebo	Total
Age, Continuous	38.3 years STANDARD_DEVIATION 13.1	39.3 years STANDARD_DEVIATION 12.3	38.8 years STANDARD_DEVIATION 12.6
Asthma Control Test score	21 units on a scale	21 units on a scale	21 units on a scale
FEV1 - percent of predicted	81.3 percent of predicted STANDARD_DEVIATION 14.9	83.1 percent of predicted STANDARD_DEVIATION 14	82.2 percent of predicted STANDARD_DEVIATION 14.4
Race/Ethnicity, Customized Asian/Pacific Islander	1 Participants	3 Participants	4 Participants
Race/Ethnicity, Customized Black	10 Participants	13 Participants	23 Participants
Race/Ethnicity, Customized Hispanic or Latio	3 Participants	3 Participants	6 Participants
Race/Ethnicity, Customized White	24 Participants	21 Participants	45 Participants
Region of Enrollment United States	38 participants	40 participants	78 participants
Salmeterol Protected Methcholine PC20	5.4 mg/ml STANDARD_DEVIATION 0.8	3.7 mg/ml STANDARD_DEVIATION 1	4.5 mg/ml STANDARD_DEVIATION 0.9
Sex: Female, Male Female	20 Participants	27 Participants	47 Participants
Sex: Female, Male Male	18 Participants	13 Participants	31 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 38	0 / 40
other Total, other adverse events	9 / 38	13 / 40
serious Total, serious adverse events	0 / 38	2 / 40

Outcome results

Primary

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.