School of Medicine

Research Summary

In 1999 UMKC School of Medicine led by Gary A. Salzman MD, FCCP in partnership with Truman Medical Center and Children’s Mercy Hospital established the UMKC Asthma Clinical Research Center (ACRC) funded by a $500,000 grant over five years from the American Lung Association (ALA). In 2004 UMKC was awarded increased funding from the American Lung Association of $750,000 over 5 years.  Recently funding was extended for another 3 years until 2012.  The American Lung Association- Asthma Clinical Research Centers (ALA-ACRC) has successfully completed five clinical trials with several additional trials under way or in preparation. Currently there are 17 clinical centers and a data coordinating center at Johns Hopkins University.

Why did the ALA fund this large network? Health care providers caring for patients with asthma need answers quickly to provide the best care for their patients. Clinical studies performed at one center or even three or four centers may take up to five years to enroll enough subjects to answer such important questions.

The ALA recognized that 17 clinical centers will be able to enroll a large number of subjects in a relatively short period of time so the studies’ results can be published and health care providers can have the answers they need to provide the best evidence-based care to their patients with asthma.

Another advantage of a large network of clinical centers is the ability to enroll subjects from diverse populations. The populations represented in the ALA-ACRC studies include the same type of patients encountered by health care providers across the country.
Five practical and clinically important questions addressed by the ALA-ACRC are summarized below.

Vaccine safety

Is the influenza vaccine safe for patients with asthma?
The ALA-ACRC Network’s first endeavor was the Study of Inactivated Influenza Vaccine in Asthmatics (SIIVA). Influenza causes substantial morbidity in adults and children with asthma. However, the rate of vaccination for patients with asthma has been low partly due to fears of increased exacerbations from the vaccine.

The purpose of SIIVA was to evaluate the safety of the influenza vaccine in patients with asthma. The trial enrolled 2,032 participants in a three-month period between September and November 2000. Results showed rates of asthma exacerbations between vaccine and placebo injections were equivalent in a diverse population of adults and children with asthma, including severe asthma.  The results were published in the New England Journal of Medicine.

Health care providers should encourage patients with asthma to be immunized. Not only is the vaccine safe in this population, but vaccination also reduces the morbidity and mortality associated with influenza in patients with asthma.

Add-on controller medications

Which add-on controller medications work well for patients with uncontrolled asthma?
The ALA-ACRC Network’s second clinical trial was the Effectiveness of Low Dose Theophylline as Add-On Therapy in Treatment of Asthma (LODO).  Current guidelines recommend adding a controller medication to the treatment regimen of poorly controlled patients with asthma. Theophylline, a relatively inexpensive asthma medication, and anti-leukotriene agents such as montelukast, are convenient choices because both are once-a-day medications taken by mouth.
The comparative effectiveness of these two add-on treatments for poorly controlled asthma is unknown. LODO is the first clinical trial to directly compare theophylline to both active (montelukast) and placebo control.

The study enrolled 489 adolescents and adults with poorly controlled asthma over an 11-month period between 2001 and 2002.  The primary outcome was the rate of episodes of poor asthma control (EPACs). An EPAC is a composite measure of asthma control including measures of asthma control, need for medical care, and lung function.

Results showed neither low-dose theophylline nor montelukast decreased the rate of EPACs in patients with poorly controlled asthma as compared to the placebo group.  Both treatments did, however, improve lung function as measured by spirometry.

In a sub-group of patients not taking inhaled corticosteroids (ICS), monotherapy low-dose theophylline resulted in both statistically and clinically significant improvements in asthma control and symptoms. Montelukast was less effective in patients not on an ICS. As such, low-dose theophylline may provide an effective, safe and low-cost treatment alternative for patients with poorly controlled asthma who can’t or won’t use ICS because of side effects, preference, or cost.

Step-down therapy

Which step-down therapy options work well for patients with mild asthma?

Current guidelines for the treatment of patients with mild persistent asthma are to establish control of symptoms using inhaled corticosteroids and then “step-down” therapy to the minimum needed to maintain control. Although step-down therapy has been studied in patients with moderate to severe asthma, it hasn’t been systematically evaluated in patients with mild asthma. This was the purpose of the Leukotriene Modifier or Corticosteroids or Corticosteroid-Salmeterol (LOCCS) trial.

A large number of patients with asthma have a mild form of the disease. Encouraging patient adherence to asthma treatment regimens continues to present challenges. Providing patients with convenient, efficacious alternative treatments associated with fewer side effects could enhance adherence and reduce unnecessary medication exposure.

This clinical trial compared three alternative treatments for patients whose asthma was well controlled on low-dose inhaled corticosteroids. The treatment groups were fluticasone (100 mg twice a day), fluticasone plus salmeterol (100/50 mg once daily) or montelukast (10 mg or 5 mg daily for adults and children, respectively). The study randomized 500 children and adults; participant follow-up was completed in July 2005.

Results showed patients with asthma well controlled on twice-daily inhaled fluticasone can be stepped-down to once daily fluticasone/salmeterol without increased rates of treatment failure.

Stepping-down to montelukast resulted in an increase in treatment failures and decreased asthma control. Notably, however, there were a high number of symptom-free days for patients in all treatment groups, including 79 percent of days for patients taking montelukast over a four-month follow-up period.  Hence, oral montelukast isn’t as effective as either low-dose ICS (twice a day) or a low-dose ICS with salmeterol (once daily), but montelukast still provided good asthma control for most patients. The results were published in the New England Journal of Medicine.

Patient education

Are the effects of patient education real or not?

The Trial of Asthma Patient Education (TAPE) was designed to evaluate the effect of patient education on the treatment response to both placebo and montelukast. The National Heart Lung Blood Institute-funded trial completed enrollment in 2005, eight months ahead of schedule.

Patients randomized to montelukast or placebo was randomized again to receive either an enhanced presentation of the study treatment or a neutral presentation. The enhanced presentation was designed to increase expectancy of therapeutic benefit.

We compared effects of the enhanced presentation independently in the montelukast and placebo groups. This comparison addressed the question — does increasing expectancy improve outcomes equally in active treatment and placebo groups?

The usual care group was compared to the placebo group receiving the neutral presentation to estimate the placebo effect. Results showed the placebo and education effects were small for measures of lung function. However, there were effects on symptom indices such as Asthma Control Score.

Furthermore, “nocebo” effects were observed on side effects, such that more patients reported headache in the placebo group after receiving information about possible side effects than those on placebo who didn’t receive similar information. These results address the specific question about the best ways to evaluate new therapies for asthma and, more generally, how the use of placebo may affect the results of clinical trials.

The main results of the trial are currently being prepared for publication as well as results from several sub-studies evaluating adherence and education effects.

GERD & asthma

Can treatment with a proton pump inhibitor (PPI) of gastroesophogeal reflux disease improve asthma control?

GERD is common in patients with asthma, even in patients who have no symptoms of heartburn. It’s predicted that GERD may contribute to poor control of asthma but its unknown if empiric treatment of GERD in patients with poorly controlled asthma can improve control.

Two complementary clinical trials funded by the NHLBI in adults and children were  conducted by the ALA-ACRC. Both trials examine whether treatment with a PPI for GERD will improve asthma control in patients with poorly controlled asthma despite relatively high doses of inhaled steroids. Subjects undergo esophageal pH monitoring for the accurate diagnosis of GERD and have methacholine challenge testing to determine changes in bronchial reactivity. The adult study was completed in 2009 and demonstrated no improvement in asthma control with high dose proton pump inhibitor treatments. The results were published in the New England Journal of Medicine.  The pediatric study will be completed in 2011.

The ALA-ACRC has provided answers to important clinical questions for health care providers working in the trenches caring for asthma patients every day. Investigators on the ALA-ACRC steering committee are planning several future studies to improve the quality of life for adults and children living with asthma.  We recently have acquired funding from the NIH for two additional studies.  One study evaluates the administration of Soy supplements to uncontrolled asthmatics to determine if there is improved asthma control.  The other study evaluates the treatment of allergic rhinitis/sinusitis on asthma control.

The UMKC ACRC is one 17 centers nationwide undertaking a multi-center research approach to discovering improved methods to manage asthma with the long term goal to find a cure for asthma.  UMKC joins Johns Hopkins, Duke, Washington University in St. Louis, and many other prestigious universities in the largest industry independent research consortium to ever study asthma.

UMKC Lung Research Center

The Lung Research Center at UMKC was started by Dr. Salzman in 2005 to expand on the successes in clinical asthma research to include collaboration with UMKC basic science researchers.  Areas of planned studies include metabolic bone disease related to the use of systemic corticosteroids, discovery of novel mechanisms of disease in sarcoidosis, lung injury related to fat embolism from long bone fractures, and the genetic characteristics of asthma.

The collaboration of the clinical and basic science investigators with expertise in many aspects of lung disease will lead to significant discoveries that will be taken from bench to bedside to improve the treatment for many types of lung disease.  The addition of an endowed chair in lung research will serve as a catalyst for the expansion of research activities and funding.  Building on the strong foundation of existing funding and the talent of existing faculty the UMKC Lung Research Center will obtain international prominence in the next five years.