AMP-BPT and His-BPT for Assessment of Asthma

Asthma Clinical Trial

— AMPHis  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02318043
• Other study ID #: GWJ
• Status: Completed
• Phase: N/A
• First received: December 7, 2014
• Last updated: December 11, 2014
• Start date: January 2007
• Est. completion date: December 2007

Study information

• Verified date: December 2014
• Source: Guangzhou Institute of Respiratory Disease
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Ministry of Science and Technology
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 84
• Est. completion date: December 2007
• Est. primary completion date: December 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Asthma

Intervention

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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Guangzhou Institute of Respiratory Disease

References & Publications (25)

Ali S, Mustafa SJ, Driver AG, Metzger WJ. Release of adenosine in bronchoalveolar lavage fluid following allergen bronchial provocation in allergic rabbits. Am Rev Respir Dis 1991;143:A417

Brusasco V, Crapo R, Viegi G; American Thoracic Society; European Respiratory Society. Coming together: the ATS/ERS consensus on clinical pulmonary function testing. Eur Respir J. 2005 Jul;26(1):1-2. Review. — View Citation

De Meer G, Heederik D, Postma DS. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine differ in their relationship with airway allergy and baseline FEV(1). Am J Respir Crit Care Med. 2002 Feb 1;165(3):327-31. — View Citation

Dor A, Liebhart J, Malolepszy J. [Comparison of exercise and histamine provocation tests in patients with bronchial asthma]. Pneumonol Alergol Pol. 1999;67(1-2):22-7. Polish. — View Citation

Driver AG, Kukoly CA, Ali S, Mustafa SJ. Adenosine in bronchoalveolar lavage fluid in asthma. Am Rev Respir Dis. 1993 Jul;148(1):91-7. — View Citation

Guan W, Zheng J, Gao Y, Jiang C, An J, Yu X, Liu W. Leukotriene D4 bronchial provocation test: methodology and diagnostic value. Curr Med Res Opin. 2012 May;28(5):797-803. doi: 10.1185/03007995.2012.678936. Epub 2012 May 3. — View Citation

Guan W, Zheng J, Gao Y, Jiang C, Xie Y, An J, Yu X, Liu W, Zhong N. Leukotriene D4 and methacholine bronchial provocation tests for identifying leukotriene-responsiveness subtypes. J Allergy Clin Immunol. 2013 Feb;131(2):332-8.e1-4. doi: 10.1016/j.jaci.2012.08.020. Epub 2012 Oct 4. — View Citation

Guan WJ, Zheng JP, Gao Y, Jiang CY, Shi X, Xie YQ, Liu QX, Jiang M, An JY, Yu XX, Liu WT, Zhong LP, Wu ZP, Zhong NS. Impulse oscillometry for leukotriene D4 inhalation challenge in asthma. Respir Care. 2013 Dec;58(12):2120-6. doi: 10.4187/respcare.02417. Epub 2013 May 28. — View Citation

Guan WJ, Zheng JP, Gao Y, Jiang CY, Xie YQ, Shi X, Zhu Z, An JY, Yu XX, Liu WT, Zhong NS. Responsiveness to leukotriene D4 and methacholine for predicting efficacy of montelukast in asthma. J Thorac Dis. 2013 Jun;5(3):298-301. doi: 10.3978/j.issn.2072-1439.2013.02.01. — View Citation

Guan WJ, Zheng JP, Shi X, Xie YQ, Jiang CY, Gao Y, Zhu Z, An JY, Yu XX, Liu WT. Response--dose ratio is a surrogate of cumulative provocative dosage for bronchial provocation tests in asthma. Lung. 2014 Oct;192(5):701-9. doi: 10.1007/s00408-014-9612-7. Epub 2014 Jun 24. — View Citation

Hanania NA. Targeting airway inflammation in asthma: current and future therapies. Chest. 2008 Apr;133(4):989-98. doi: 10.1378/chest.07-0829. Review. — View Citation

Hogg JC, James AL, Pare PD. Evidence for inflammation in asthma. Am Rev Respir Dis. 1991 Mar;143(3 Pt 2):S39-42. — View Citation

Janssens T, Verleden G, De Peuter S, Petersen S, Van den Bergh O. Predicting asthma treatment outcome at diagnosis: the role of symptom perception during a histamine challenge test. J Asthma. 2012 Apr;49(3):230-6. doi: 10.3109/02770903.2012.656864. Epub 2012 Feb 9. — View Citation

Kim CK, Choi SJ, Lee JK, Suh DI, Koh YY. Bronchial hyperresponsiveness to methacholine and adenosine monophosphate and the degree of atopy in children with allergic rhinitis. Ann Allergy Asthma Immunol. 2011 Jan;106(1):36-41. doi: 10.1016/j.anai.2010.10.019. — View Citation

Leuppi JD. Bronchoprovocation tests in asthma: direct versus indirect challenges. Curr Opin Pulm Med. 2014 Jan;20(1):31-6. doi: 10.1097/MCP.0000000000000009. Review. — View Citation

Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005 Jul;26(1):153-61. Review. — View Citation

Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005 Aug;26(2):319-38. — View Citation

O'Byrne P, Bateman ED, Bousquet JD. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. Updated 2006. Available at http://www.ginasthma.org/Guidelines/guidelines-resources.html Latest accessed: Sep 20, 2014

O'Byrne PM, Inman MD. Airway hyperresponsiveness. Chest. 2003 Mar;123(3 Suppl):411S-6S. Review. — View Citation

Polosa R, Ng WH, Crimi N, Vancheri C, Holgate ST, Church MK, Mistretta A. Release of mast-cell-derived mediators after endobronchial adenosine challenge in asthma. Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):624-9. — View Citation

Suh DI, Lee JK, Kim CK, Koh YY. Bronchial hyperresponsiveness to methacholine and adenosine 5'-monophosphate, and the presence and degree of atopy in young children with asthma. Clin Exp Allergy. 2011 Mar;41(3):338-45. doi: 10.1111/j.1365-2222.2010.03664.x. Epub 2011 Jan 24. — View Citation

Suh DI, Lee JK, Kim CK, Koh YY. Methacholine and adenosine 5'-monophosphate (AMP) responsiveness, and the presence and degree of atopy in children with asthma. Pediatr Allergy Immunol. 2011 Feb;22(1 Pt 2):e101-6. doi: 10.1111/j.1399-3038.2010.01110.x. — View Citation

The Respiratory Society of the Chinese Medical Association. Guidelines for lung function testing (Part 3): Histamine and methacholine bronchial provocation test. Zhonghua Jie He He Hu Xi Za Zhi 2014; 37:566-71

van den Berge M, Kerstjens HA, Meijer RJ, de Reus DM, Koëter GH, Kauffman HF, Postma DS. Corticosteroid-induced improvement in the PC20 of adenosine monophosphate is more closely associated with reduction in airway inflammation than improvement in the PC20 of methacholine. Am J Respir Crit Care Med. 2001 Oct 1;164(7):1127-32. — View Citation

Zheng J, Zhong N. Normative values of pulmonary function testing in Chinese adults. Chin Med J (Engl). 2002 Jan;115(1):50-4. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	incidence of adverse events of both BPTs	adverse events of AMP-BPT and His-BPT	up to 12 months (Jan 2007 to Dec 2007)	Yes
Primary	Cumulative dose eliciting 20% fall in FEV1 (PD20FEV1)	Cumulative dose eliciting 20% fall in FEV1 (PD20FEV1), reported as	up to 12 months (Jan 2007 to Dec 2007)	No
Primary	Asthma symptom score as proposed by Hoggs et al	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)	No
Secondary	Baseline spirometry (FVC, FEV1, FEV1/FVC, MMEF, PEF)	FVC, FEV1, FEV1/FVC, MMEF, PEF	up to 12 months (Jan 2007 to Dec 2007)	No
Secondary	Maximal decrease in FVC following bronchial provocation (expressed as percentage)	Maximal decrease in FVC following bronchial provocation, expressed as percentage as compared with baseline levels	up to 12 months (Jan 2007 to Dec 2007)	No
Secondary	Maximal decrease in FEV1 following bronchial provocation (expressed as percentage)	Maximal decrease in FEV1 following bronchial provocation, expressed as percentage as compared with baseline levels	up to 12 months (Jan 2007 to Dec 2007)	No
Secondary	Maximal decrease in MMEF following bronchial provocation (expressed as percentage)	Maximal decrease in MMEF following bronchial provocation, expressed as percentage as compared with baseline levels	up to 12 months (Jan 2007 to Dec 2007)	No
Secondary	Maximal decrease in PEF following bronchial provocation (expressed as percentage)	Maximal decrease in PEF following bronchial provocation, expressed as percentage as compared with baseline levels	up to 12 months (Jan 2007 to Dec 2007)	No
Secondary	Assay positivity of AMP-BPT and His-BPT (expressed as percentage)	Assay positivity of AMP-BPT and His-BPT, expressed as percentage	up to 12 months (Jan 2007 to Dec 2007)	No
Secondary	Diagnostic performance of AMP-BPT and His-BPT (area under the receiver operation characteristic curve, sensitivity, specificity, Youden index)	area under the receiver operation characteristic curve, sensitivity, specificity, Youden index	up to 12 months (Jan 2007 to Dec 2007)	No
Secondary	Changes in post-treatment asthma symptom scores	post-treatment minus pre-treatment asthma symptom score	up to 12 months (Jan 2007 to Dec 2007)	No
Secondary	Changes in post-treatment PD20FEV1	post-treatment minus pre-treatment PD20FEV1	up to 12 months (Jan 2007 to Dec 2007)	No