AsthmaPhase 3NCT00200967

Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE)

A Phase 3 study testing salmeterol and beclomethasone HFA in people with Asthma, run by Milton S. Hershey Medical Center at 7 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The purpose of this trial is to determine whether regularly scheduled use of an inhaled long-acting beta agonist (salmeterol) in the setting of concomitant use of inhaled corticosteroids (beclomethasone hydroflouroalkane (HFA) inhaler) will have a detrimental effect on asthma control in people who bear the B16-Arg/Arg… Read more about this study

Who is it for?: Ages 18 to 90 years
Conditions the study is for: Asthma
What is being tested?: salmeterol and beclomethasone HFA
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 87 participants
Where: 7 sitesUnited States
Study dates: Dec 2004to Feb 2008
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 90 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Male or female, ages 18 and older
Clinical history consistent with asthma
For subjects regularly using inhaled corticosteroids, FEV1 50% of predicted, methacholine PC20 FEV1 16 mg/ml or 12% and 200 ml, improvement in FEV1 after 2 puffs of inhaled albuterol
For subjects not regularly using inhaled corticosteroids, FEV1 40% of predicted, methacholine PC20 FEV1 8 mg/ml or 12% and 200 ml, improvement in FEV1 after 2 puffs of inhaled albuterol
Genotype eligibility (determined during screening)

Who cannot join

Smoker (total smoking history must be less than 10 pack years)
Significant unstable medical condition other than asthma
History of life-threatening asthma requiring treatment with intubation and mechanical ventilation in the past 10 years
Pregnant or lactating

Trial locations and contacts

7 sites in 1 country.

City, postcode or hospital

7 sites in 1 country

United States7 sites

Brigham & Women's Hospital
Boston, Massachusetts, 02115
National Jewish Medical & Research Center
Denver, Colorado, 80206
University of Wisconsin Madison
Madison, Wisconsin, 53792-3244
University of California, San Diego
San Diego, California, 92103
University of California, San Francisco
San Francisco, California, 94143-0130
Washington University
St Louis, Missouri, 63110
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27103

Other trials in United States

About this study

Read the detailed description

BACKGROUND:

The purpose of this study is to compare the effects of a long-acting beta agonist in patients with asthma receiving inhaled corticosteroids who express two distinct polymorphisms of the beta-2 adrenergic receptor.

DESIGN NARRATIVE:

Participants were homozygous for arginine or glycine at the 16th amino-acid position of the β-2 adrenergic receptor (B16 Arg/Arg or B16 Gly/Gly). Individuals were matched against their opposite genotype by forced expiratory volume in one second (FEV1) and race. Matched participants entered an 8-week run-in period. This is a 62-week crossover design where subjects receive the following therapies:

Beclomethasone HFA (240 µg twice a day (BID)) + as-needed (PRN) albuterol: 8-week run-in
Beclomethasone HFA (240 µg BID) + salmeterol (50 µg BID) + PRN ipratropium bromide + PRN albuterol: 18-week treatment period
Beclomethasone HFA (240 µg BID) + PRN albuterol: 8-week run-out
Beclomethasone HFA (240 µg BID) + placebo salmeterol + PRN ipratropium bromide + PRN albuterol: 18-week treatment period
Beclomethasone HFA (240 µg BID) + PRN albuterol: 10-week run-out

The order of treatments received during the two treatment periods is randomized.

Conditions: Asthma
Being tested: salmeterol, beclomethasone HFA
Medical subject headings: Asthma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

salmeterolDrug
Also called Serevent
50 micrograms (mcg) twice per day (BID) (Serevent 50 mcg diskus, GlaxoSmithKline (GSK), North Carolina)
beclomethasone HFADrug
Also called QVAR
240 mcg beclomethasone HFA (QVAR, Teva Pharmaceutical Industries)

Study groups in NCT00200967
Study group	Role	What they receive
B16 Arg/Arg	Experimental	B16 Arg/Arg genotype Sequence 1: inhaled salmeterol + inhaled beclomethasone hydroflouroalkane (HFA), followed by inhaled placebo salmeterol + inhaled beclomethasone HFA Sequence 2: inhaled placebo salmeterol + inhaled beclomethasone HFA, followed by inhaled salmeterol + inhaled beclomethasone HFA Receives: Drug: salmeterol; Drug: beclomethasone HFA
B16 Gly/Gly	Experimental	B16 Gly/Gly genotype Sequence 1: inhaled salmeterol + inhaled beclomethasone HFA, followed by inhaled placebo salmeterol + inhaled beclomethasone HFA Sequence 2: inhaled placebo salmeterol + inhaled beclomethasone HFA, followed by inhaled salmeterol + inhaled beclomethasone HFA Receives: Drug: salmeterol; Drug: beclomethasone HFA

What is being measured

The primary outcome is the main question the study is designed to answer.

Morning (AM) Peak Expiratory Flow (PEF) Rate
Change between placebo salmeterol and active salmeterol for AM PEF rate
Measured: Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period

Secondary outcomes (11)

Evening (PM) Peak Expiratory Flow (PEF) Rate
Change between placebo salmeterol and active salmeterol for PM PEF rate
Measured: Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Peak Expiratory Flow (PEF) Variability
Change between placebo salmeterol and active salmeterol for PEF variability, where PEF variability is defined as 100% x (PM PEF - AM PEF)/(PM PEF)
Measured: Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Asthma Symptoms
Change between placebo salmeterol and active salmeterol for asthma symptoms (0=absent, 1=mild, 2=moderate, 3=severe).
Measured: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Rescue Medication (Ipratropium and Albuterol) Use
Change between placebo salmeterol and active salmeterol for rescue medication use
Measured: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator
Change between placebo salmeterol and active salmeterol for Spirometry FEV1, pre-bronchodilator
Measured: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator
Change between placebo salmeterol and active salmeterol for Spirometry FVC, pre-bronchodilator
Measured: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator
Change between placebo salmeterol and active salmeterol for Spirometry PEF rate, pre-bronchodilator
Measured: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Exhaled Nitric Oxide (eNO)
Change between placebo salmeterol and active salmeterol for eNO
Measured: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Exhaled Breath Condensate (EBC)
Change between placebo salmeterol and active salmeterol for EBC
Measured: Clinic visits at weeks 0, 10, and 18 of each treatment period
Methacholine Provocative Concentration 20 (PC20)
Change between placebo salmeterol and active salmeterol for methacholine PC20
Measured: Clinic visits at weeks 0 and 18 of each treatment period
Asthma Control Questionnaire (ACQ)
Change between placebo salmeterol and active salmeterol for ACQ, where ACQ ranges from 0 (best asthma control) to 6 (worst asthma control).
Measured: Clinic visits at weeks 0 and 18 of each treatment period

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Dec 2004Feb 2008

First posted20 Sep 2005 (estimated)
Study startDec 2004
Primary completionFeb 2008
Study completionFeb 2008

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for AsthmaStudies of the same condition, open and under way.
More trials run by Milton S. Hershey Medical CenterThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 87 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00200967
Sponsor's protocol ID: 262
Other IDs: 5U10HL074231, U10HL074073, U10HL074204, U10HL074208, U10HL074212, U10HL074218, U10HL074225, U10HL074227
Status last verified: Dec 2017
First submitted: 12 Sep 2005
Last updated: 23 Jan 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, Ameredes BT, Castro M, Craig TJ, Denlinger L, Fahy JV, Jarjour N, Kazani S, Kim S, Kraft M, Lazarus SC, Lemanske RF Jr, Markezich A, Martin RJ, Permaul P, Peters SP, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Walter MJ, Wasserman SI, Israel E; National Heart, Lung and Blood Institute's Asthma Clinical Research Network. Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet. 2009 Nov 21;374(9703):1754-64. doi: 10.1016/S0140-6736(09)61492-6.
PubMed 19932356

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 23 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Asthma Clinical Research Network (ACRN) Trial - Long-Acting Beta Agonist Response by Genotype (LARGE)
ClinicalTrials.gov ID: NCT00200967
Acronym / sponsor ID: 262
Conditions: Asthma
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 87 participants (actual)
Lead sponsor: Milton S. Hershey Medical CenterUniversity, hospital or other
Collaborators: National Heart, Lung, and Blood Institute (NHLBI), Asthma Clinical Research Network
Study start: Dec 2004
Primary completion: Feb 2008 (actual)
Study completion: Feb 2008 (actual)
First posted: 20 Sep 2005 (estimated)
Results: Posted 2 Jun 2009

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

BACKGROUND:

DESIGN NARRATIVE:

Beclomethasone HFA (240 µg twice a day (BID)) + as-needed (PRN) albuterol: 8-week run-in
Beclomethasone HFA (240 µg BID) + salmeterol (50 µg BID) + PRN ipratropium bromide + PRN albuterol: 18-week treatment period
Beclomethasone HFA (240 µg BID) + PRN albuterol: 8-week run-out
Beclomethasone HFA (240 µg BID) + placebo salmeterol + PRN ipratropium bromide + PRN albuterol: 18-week treatment period
Beclomethasone HFA (240 µg BID) + PRN albuterol: 10-week run-out

The order of treatments received during the two treatment periods is randomized.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
B16 Arg/Arg	Experimental	Drug: salmeterol, Drug: beclomethasone HFAB16 Arg/Arg genotype Sequence 1: inhaled salmeterol + inhaled beclomethasone hydroflouroalkane (HFA), followed by inhaled placebo salmeterol + inhaled beclomethasone HFA Sequence 2: inhaled placebo salmeterol + inhaled beclomethasone HFA, followed by inhaled salmeterol + inhaled beclomethasone HFA
B16 Gly/Gly	Experimental	Drug: salmeterol, Drug: beclomethasone HFAB16 Gly/Gly genotype Sequence 1: inhaled salmeterol + inhaled beclomethasone HFA, followed by inhaled placebo salmeterol + inhaled beclomethasone HFA Sequence 2: inhaled placebo salmeterol + inhaled beclomethasone HFA, followed by inhaled salmeterol + inhaled beclomethasone HFA

Who may qualify

Ages: 18 to 90 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

Male or female, ages 18 and older
Clinical history consistent with asthma
For subjects regularly using inhaled corticosteroids, FEV1 50% of predicted, methacholine PC20 FEV1 16 mg/ml or 12% and 200 ml, improvement in FEV1 after 2 puffs of inhaled albuterol
For subjects not regularly using inhaled corticosteroids, FEV1 40% of predicted, methacholine PC20 FEV1 8 mg/ml or 12% and 200 ml, improvement in FEV1 after 2 puffs of inhaled albuterol
Genotype eligibility (determined during screening)

Key exclusion criteria (4 listed)

Smoker (total smoking history must be less than 10 pack years)
Significant unstable medical condition other than asthma
History of life-threatening asthma requiring treatment with intubation and mechanical ventilation in the past 10 years
Pregnant or lactating

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
salmeterolAlso: Serevent50 micrograms (mcg) twice per day (BID) (Serevent 50 mcg diskus, GlaxoSmithKline (GSK), North Carolina)	Drug	B16 Arg/Arg, B16 Gly/Gly
beclomethasone HFAAlso: QVAR240 mcg beclomethasone HFA (QVAR, Teva Pharmaceutical Industries)	Drug	B16 Arg/Arg, B16 Gly/Gly

Primary outcome

Morning (AM) Peak Expiratory Flow (PEF) Rate
Time frame: Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Change between placebo salmeterol and active salmeterol for AM PEF rate

11 secondary outcomes

Evening (PM) Peak Expiratory Flow (PEF) Rate
Time frame: Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Peak Expiratory Flow (PEF) Variability
Time frame: Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Asthma Symptoms
Time frame: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Rescue Medication (Ipratropium and Albuterol) Use
Time frame: Recorded daily on a diary card, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Spirometry Forced Expiratory Volume in One Second (FEV1), Pre-bronchodilator
Time frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Spirometry Forced Vital Capacity (FVC), Pre-bronchodilator
Time frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Spirometry Peak Expiratory Flow (PEF) Rate, Pre-bronchodilator
Time frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Exhaled Nitric Oxide (eNO)
Time frame: Clinic visits at weeks 0, 2, 6, 10, 14, and 18 of each treatment period
Exhaled Breath Condensate (EBC)
Time frame: Clinic visits at weeks 0, 10, and 18 of each treatment period
Methacholine Provocative Concentration 20 (PC20)
Time frame: Clinic visits at weeks 0 and 18 of each treatment period
Asthma Control Questionnaire (ACQ)
Time frame: Clinic visits at weeks 0 and 18 of each treatment period

Results and safety

Results posted to the registry on 2 Jun 2009, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
B16 Arg/Arg	42	36
B16 Gly/Gly	45	44

Primary outcome: Morning (AM) Peak Expiratory Flow (PEF) Rate

Time frame: Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period. Least squares mean (95% Confidence Interval). Unit: liters per minute

Measure	B16 Arg/Arg n = 42	B16 Gly/Gly n = 45
Value	-21 (-31 to -12)	-22 (-32 to -11)

B16 Arg/Arg vs B16 Gly/Gly: Mean Difference (Final Values): 0 (95% CI -14 to 14), p = 0.99, Mixed Models Analysis

Population analysed: An intention-to-treat (ITT) paradigm was invoked in which the available data (without any imputation for missing data) on all randomized participants were included.

11 secondary outcomes are reported in the full results.

Adverse events

Time frame: 1 year. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
B16 Arg/Arg	1 of 42 (2.4%)	20 of 42 (47.6%)	Not reported
B16 Gly/Gly	4 of 45 (8.9%)	20 of 45 (44.4%)	Not reported

Limitations and caveats (from the sponsor): The study used a moderately high dose of ICS. Genotype-specific effects may be evident at lower doses of ICS often used in combination therapy. Also, short-acting β2-agonists have been shown to have genotype-specific effects on asthma outcomes.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 23 Jan 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 19932356Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, Ameredes BT, Castro M, Craig TJ, Denlinger L, Fahy JV, Jarjour N, Kazani S, Kim S, Kraft M, Lazarus SC, Lemanske RF Jr, Markezich A, Martin RJ, Permaul P, Peters SP, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Walter MJ, Wasserman SI, Israel E; National Heart, Lung and Blood Institute's Asthma Clinical Research Network. Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet. 2009 Nov 21;374(9703):1754-64. doi: 10.1016/S0140-6736(09)61492-6.
Asthma Clinical Research Network (ACRN) WebsiteLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Homer Boushey principal investigator

University of California, San Francisco

Mario Castro principal investigator

Washington University School of Medicine

Vernon M. Chinchilli, PhD principal investigator

Milton S. Hershey Medical Center

7 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing salmeterol and beclomethasone HFA in people with Asthma, run by Milton S. Hershey Medical Center at 7 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Jun 2009). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Morning (AM) Peak Expiratory Flow (PEF) Rate (time frame: Measured daily using a hand-held peak flow meter, and then averaged between weeks 0, 2, 6, 10, 14, and 18 of each treatment period). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00200967, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jan 2018.