AMP-BPT and His-BPT for Assessment of Asthma (AMPHis)

December 11, 2014 updated by: Jinping Zheng, Guangzhou Institute of Respiratory Disease

Is Adenosine Monophosphate Superior to Histamine for Bronchial Provocation Test in Evaluation of Asthma?

Adenosine monophosphate (AMP) may reflect airway inflammation and hyperresponsiveness, but relationship between AMP and histamine (His, a conventional stimulus) bronchial provocation test (BPT) in asthma is not fully elucidated.

The investigators aimed to compare both BPTs and determine their usefulness in reflecting changes of asthmatic symptoms.

BPTs were performed in cross-over fashion, at 2-4day intervals. Cumulative doses eliciting 20% FEV1fall (PD20FEV1), diagnostic performance and adverse events were compared. Patients with PD20FEV1 lower than geometric mean were defined as responders, otherwise poor responders. Patients with uncontrolled and partly controlled asthma, who maintained their original inhaled corticosteroids therapy, underwent reassessment of airway responsiveness and asthmatic symptoms 3 and 6 months after.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Airway hyperresponsiveness, the pivotal feature of asthma, can be assessed by bronchial provocation tests (BPTs), which may elicit bronchoconstriction via inhalation of stimuli. Histamine has been a direct stimulus for inducing bronchoconstriction via vasodilation, eosinophil chemotaxis and tissue edema. Clinically, histamine BPT (His-BPT) has gained extensive application for decades owing to the assay sensitivity and feasibility, but could not ideally predict anti-inflammatory treatment outcomes in practice. Additionally, mild adverse events (flushing and hoarseness) and insufficient capacity of identifying exercise-induced asthma have hampered further clinical applications.

Adenosine monophosphate (AMP) is an inflammatory mediator that serves as an indirect bronchial stimulus for detecting airway hyperresponsiveness in asthma. Compared with histamine, AMP may be pathophysiologically more relevant to airway inflammation and hyperresponsiveness and has been linked to presence and magnitude of atopy. However, differences of response to AMP-BPT and His-BPT in different asthma control levels and their associations with asthmatic symptom scores have not been fully elucidated.

We hypothesized that asthmatic patients, regardless of control levels, responded differentially to AMP-BPT and His-BPT, and that greater reduction in airway responsiveness to AMP (esp. responders of AMP-BPT) was associated with significant symptom alleviation. Henceforth, we sought to: 1) compare diagnostic performance and safety of AMP-BPT and His-BPT in different asthma control levels; 2) determine the association between airway responsiveness and asthmatic symptom scores.

Currently, His-BPT is recommended by the Chinese guideline and shares considerable similarity with methacholine (another conventional stimulus) BPT, we therefore did not perform the latter in this study.

Study Type

Interventional

Enrollment (Actual)

84

Phase

  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. aged 18~65 years;
  2. nil respiratory infection within 3 weeks;
  3. normal chest radiography;
  4. baseline FEV1>60% predicted;
  5. withdrawn from, if any, oral leukotriene modifiers, corticosteroid or anti-histamine for 5 days, oral xanthenes or long-acting bronchodilators for 2 days, inhaled corticosteroids (ICSs) for 24 hours, and salbutamol for 6 hours

Exclusion Criteria:

  1. FEV1 fall ≥20% following saline inhalation;
  2. other chronic lower respiratory diseases (i.e. COPD);
  3. severe systemic diseases (i.e. uncontrolled hypertension, malignancy);
  4. limited understanding.

For healthy subjects, they had to be aged 18~65 years and had nil respiratory infection within 3 weeks, systemic diseases and had normal lung function.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: DIAGNOSTIC
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: AMP-BPT
Methods of AMP-BPT, by applying dosimeters, resembled that reported previously [see references 21-25]. Briefly, dilutions were delivered via nebulizers (output: 160 μl/min) using automated APS pro system (JAEGER, Hochburg, Germany). Inhalation challenge with normal saline served as control step. Challenge steps were proceeded if FEV1 fall <15% and restored to <10% within 1 minute. Subsequent inhalation challenges were performed at 1-minute intervals, and ceased when FEV1 fell by ≥20%. Salbutamol was administered via spacer (Volumatic, Allen & Hanbury's, UK). Spirometry was reexamined at minutes 3, 5, 10 and thereafter, to ensure safety, before discharge.
Drug: inhaled corticosteroids (usually budesonide/fomorterol 160/4.5mcg; fluticasone/salmeterol 250/50mcg)
Patients with uncontrolled and partly controlled asthma, following accomplishment of study 1, were invited to participate in observational study (study 2), which sought to determine usefulness of both BPTs in reflecting improvement of asthmatic symptoms following 3 and 6 months of moderate-dose ICSs treatment (400~800μg budesonide or equivalent). Patient continued to administer their original ICS during follow-up. During two follow-up visits (3 months apart), AMP-BPT, His-BPT and Hogg's symptom scores were reassessed.
ACTIVE_COMPARATOR: His-BPT
Methods of His-BPT, by applying dosimeters, resembled that reported previously [see references 21-25]. Briefly, dilutions were delivered via nebulizers (output: 160 μl/min) using automated APS pro system (JAEGER, Hochburg, Germany). Inhalation challenge with normal saline served as control step. Challenge steps were proceeded if FEV1 fall <15% and restored to <10% within 1 minute. Subsequent inhalation challenges were performed at 1-minute intervals, and ceased when FEV1 fell by ≥20%. Salbutamol was administered via spacer (Volumatic, Allen & Hanbury's, UK). Spirometry was reexamined at minutes 3, 5, 10 and thereafter, to ensure safety, before discharge.
Drug: inhaled corticosteroids (usually budesonide/fomorterol 160/4.5mcg; fluticasone/salmeterol 250/50mcg)
Patients with uncontrolled and partly controlled asthma, following accomplishment of study 1, were invited to participate in observational study (study 2), which sought to determine usefulness of both BPTs in reflecting improvement of asthmatic symptoms following 3 and 6 months of moderate-dose ICSs treatment (400~800μg budesonide or equivalent). Patient continued to administer their original ICS during follow-up. During two follow-up visits (3 months apart), AMP-BPT, His-BPT and Hogg's symptom scores were reassessed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cumulative dose eliciting 20% fall in FEV1 (PD20FEV1)
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
Cumulative dose eliciting 20% fall in FEV1 (PD20FEV1), reported as
up to 12 months (Jan 2007 to Dec 2007)
Asthma symptom score as proposed by Hoggs et al
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
Asthma symptom score recorded within 1 week, with the highest possible score of 42 for the whole week
up to 12 months (Jan 2007 to Dec 2007)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Baseline spirometry (FVC, FEV1, FEV1/FVC, MMEF, PEF)
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
FVC, FEV1, FEV1/FVC, MMEF, PEF
up to 12 months (Jan 2007 to Dec 2007)
Maximal decrease in FVC following bronchial provocation (expressed as percentage)
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
Maximal decrease in FVC following bronchial provocation, expressed as percentage as compared with baseline levels
up to 12 months (Jan 2007 to Dec 2007)
Maximal decrease in FEV1 following bronchial provocation (expressed as percentage)
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
Maximal decrease in FEV1 following bronchial provocation, expressed as percentage as compared with baseline levels
up to 12 months (Jan 2007 to Dec 2007)
Maximal decrease in MMEF following bronchial provocation (expressed as percentage)
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
Maximal decrease in MMEF following bronchial provocation, expressed as percentage as compared with baseline levels
up to 12 months (Jan 2007 to Dec 2007)
Maximal decrease in PEF following bronchial provocation (expressed as percentage)
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
Maximal decrease in PEF following bronchial provocation, expressed as percentage as compared with baseline levels
up to 12 months (Jan 2007 to Dec 2007)
Assay positivity of AMP-BPT and His-BPT (expressed as percentage)
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
Assay positivity of AMP-BPT and His-BPT, expressed as percentage
up to 12 months (Jan 2007 to Dec 2007)
Diagnostic performance of AMP-BPT and His-BPT (area under the receiver operation characteristic curve, sensitivity, specificity, Youden index)
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
area under the receiver operation characteristic curve, sensitivity, specificity, Youden index
up to 12 months (Jan 2007 to Dec 2007)
Changes in post-treatment asthma symptom scores
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
post-treatment minus pre-treatment asthma symptom score
up to 12 months (Jan 2007 to Dec 2007)
Changes in post-treatment PD20FEV1
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
post-treatment minus pre-treatment PD20FEV1
up to 12 months (Jan 2007 to Dec 2007)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
incidence of adverse events of both BPTs
Time Frame: up to 12 months (Jan 2007 to Dec 2007)
adverse events of AMP-BPT and His-BPT
up to 12 months (Jan 2007 to Dec 2007)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Guangzhou Institute of Respiratory Disease

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2007

Primary Completion (ACTUAL)

December 1, 2007

Study Completion (ACTUAL)

December 1, 2007

Study Registration Dates

First Submitted

December 7, 2014

First Submitted That Met QC Criteria

December 11, 2014

First Posted (ESTIMATE)

December 17, 2014

Study Record Updates

Last Update Posted (ESTIMATE)

December 17, 2014

Last Update Submitted That Met QC Criteria

December 11, 2014

Last Verified

December 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GWJ

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