Are Safer and more Effective Therapeutic Asthma and COPD Medications on the Horizon?
Companies to Watch
Apellis Pharmaceuticals in collaboration with leading U.S. universities believes that safer and more effective therapeutic Asthma and COPD medications are on the horizon and it aims to bring a new class of anti-inflammatory drugs to the market to address chronic inflammatory diseases in areas of significant unmet need such as asthma and chronic obstructive pulmonary disease (COPD).
Severe Asthma and COPD
According to the Apellis Pharmaceuticals website, Asthma affects 7% of the population of the United States and a total of 300 million people worldwide. In 2009 asthma represented a $12.7B market. The standard-of-care in asthma is dominated by corticosteroids, beta-agonists and to a lesser extent leukotriene inhibitors and anti-IgE antibodies. While these drugs control asthma in a majority of patients, there remains a significant unmet medical need for safer and more effective therapeutics. Especially in severe asthma there is a tendency to have poor control with corticosteroids. Due to the continued immune aggression on the lungs, patients with severe asthma account for ~50% of asthma-related healthcare costs and are at greater risks of complications, including the development of COPD and death.
COPD is the third-leading cause of death in the USA after heart disease and cancer. In spite of the large number of people affected (~14 million people have been diagnosed withGrade II-IV COPD) and its enormous cost (the NIH estimated the cost of COPD to the healthcare system to be $42.6B in 2007) there are no treatments that effectively treat COPD. The standard of care is almost exclusively symptomatic (suppressing inflammation and opening the airways) but no drug has been successful in slowing or halting the immune process that slowly destroys the airways (chronic bronchitis) and lung tissues (emphysema).
Apellis explores novel mechanisms to modify these diseases by inhibiting complement activation and has assembled an innovative and multi-faceted drug pipeline through a combination of selective in-licensing and internal research and development. As an important component of its long-term strategy, Apellis also engages in and catalyses the development of broad-ranging and complementary technologies such as drug delivery systems and diagnostic tools through collaborations and grant-funded programs.
If confirmed, the most important distinguishing feature of complement inhibition would be its exceptional ability to change the immunological micro-environment and thus resolve the immune process at work in these pulmonary diseases. APL-1 might thus halt or reverse anatomic remodeling of the lungs, the principle cause of irreversible loss of respiratory capacity, morbidity and mortality in severe asthma and COPD.
Study Sheds Light on Late Phase of Asthma Attacks Could Lead to Better treatments for the Disease
New research led by scientists from Imperial College London explains why around half of people with asthma experience a ‘late phase’ of symptoms several hours after exposure to allergens. The findings, published in the journal Thorax, could lead to better treatments for the disease.
An estimated 300 million people suffer from asthma, and the prevalence is rising. Symptoms are commonly triggered by allergens in the environment, such as pollen and dust mites. These stimuli can cause the airways to tighten within minutes, causing breathing difficulties which range from mild to severe. Many sufferers also experience a ‘late asthmatic response’ three to eight hours after exposure to allergens, causing breathing difficulties which can last up to 24 hours.
In the early asthmatic response, the allergen is recognised by mast cells, which release chemical signals that cause the airways to narrow. In contrast, the mechanism behind the late phase has remained unclear.
In research on mice and rats, the Imperial team have now found evidence that the late asthmatic response happens because the allergen triggers sensory nerves in the airways. These nerves activate reflexes which trigger other nerves that release the neurotransmitter acetylcholine, which causes the airways to narrow. If the findings translate to humans, it would mean that drugs that block acetylcholine – called anticholinergics – could be used to treat asthma patients that experience late phase responses following exposure to allergens.
Steroids are the main treatments for asthma prescribed now, but they are not effective for all patients. A recent clinical trial involving 210 asthma patients found that the anticholinergic drug tiotropium improved symptoms when added to a steroid inhaler, but the reason for this was unexplained.
“Many asthmatics have symptoms at night after exposure to allergens during the day, but until now we haven’t understood how this late response is brought about,” said Professor Maria Belvisi, from the National Heart and Lung Institute at Imperial College London, who led the research. “Our study in animals suggests that anticholinergic drugs might help to alleviate these symptoms, and this is supported by the recent clinical data. We are seeking funding to see if these findings are reproduced in proof of concept clinical studies in asthmatics.”
The researchers hypothesised that sensory nerves were involved after observing that anaesthesia prevented the late asthmatic response in mice and rats. They succeeded in blocking the late asthmatic response using drugs that block different aspects of sensory nerve cell function, adding further evidence for this idea.
After establishing that sensory nerves detect the allergen, the researchers tested the effect of tiotropium, an anticholinergic drug that is used to treat chronic obstructive pulmonary disease. Tiotropium blocks the receptor for acetylcholine, which is released by nerves in the parasympathetic nervous system. Tiotropium also blocked the late asthmatic response, suggesting that parasympathetic nerves cause the airways to constrict.
The study was funded by the Medical Research Council (MRC). Professor Stephen Holgate, MRC funding board chair and an expert on asthma, said: “Unravelling the complex biology of asthma is vitally important, as it is an extremely dangerous condition which exerts lifelong damaging effects. The Medical Research Council is committed to research that opens doors to improving disease resilience, particularly in conditions which attack our body over the long-term. Studies like this are making really important progress and whilst we must always be cautious when taking findings from rodents into humans, these are very interesting and potentially important results.”
Sam Wong
Research Media Officer
Imperial College London
Email: sam.wong@imperial.ac.uk
Tel: +44(0)20 7594 2198
Out of hours duty press officer: +44(0)7803 886 248
A New Asthma Treatment Option Drug called Lebrikizumab Shows Results Needs Further Review Says Asthma Specialist
News reports reflect that For asthma patients who continue to suffer from symptoms even after taking their inhaled steroids, a new drug called lebrikizumab may be a treatment option, and a simple blood test can determine the effectiveness of the drug, according to a consortium of researchers including a Baylor College of Medicine asthma expert in a report that appears in The New England Journal of Medicine
Dr. Nick Hanania, associate professor of medicine and director the BCM Asthma Clinical Research Center and colleagues studied whether lebrikizumab, an antibody to interleukin-13, a protein that plays a major role in the inflammation in the airways of asthmatics, would block the effects of the protein and have an effect on lung function or flare ups in asthmatics.
The phase II clinical trial looked at 219 adults with asthma who were already taking inhaled steroids and continued to suffer from asthma symptoms. After 12 weeks, those who received the once-a-month injection of lebrikizumab had better lung function as measured by a test called forced expiratory volume than those who received a placebo. However, there were no significant effects of this drug on asthma flare ups over the six months of the study.
Researchers also found that patients in the study who had a higher blood level of a biomarker periostin, a protein that reflects high interleukin-13 activity and causes a type of inflammation in asthma patients called eosinophilic inflammation, responded better to the drug than those who had lower levels of this biomarker. These findings suggest that a simple blood test can determine which asthma patients may have a positive response to the study medication.
“This information will be very helpful in the future in better defining the role of periostin in asthma and in differentiating the phenotypes, or the characteristics, of asthma,” said Hanania. “We know that not all asthmatics are the same as there are different types of airway inflammation in this disease, and we have never had a simple test that could help us identify who would and wouldn’t respond to agents like this new drug until now.”
Hanania also notes that the safety of the drug was promising compared to the placebo.
“This is a step forward in treating asthma patients,” said Hanania. “These findings could help the well being and quality of life for those on inhaled steroids who continue to suffer from asthma symptoms. Such symptoms can cause increased hospitalizations and emergency room visits, which result in a high cost for patients and the health care system.”
Lebrikizumab will need to be studied in a larger number of patients before it can be reviewed and approved by FDA and become available to patients.
Others who took part in this study include Dr. Jonathan Corren of Allergy Medical Clinic and Genentech; Dr. Robert F. Lemanske, Jr. of the University of Wisconsin School of Medicine and Public Health; Dr. Phillip E. Korenblat of the Clinical Research Center in St. Louis.Dr. Merdad V. Parsey of 3-V Biosciences; and Drs. Joseph R. Arron, Jeffrey M. Harris, Heleen Scheerens, Lawren C. Wu, Zheng Su, Sofia Mosesova, Mark D. Eisner, Sean P. Bohen and John G. Matthews of Genentech.
Funding for this study came from Genentech, a member of Roche group.
A U.S. Asthma Genetics Consortium Reveals a Novel Asthma Gene in African-Americans
NewBlaze.com is reporting that a new national collaboration of asthma genetics researchers has revealed a novel gene associated with the disease in African-Americans, according to a new scientific report.
By pooling data from nine independent research groups looking for genes associated with asthma, the newly-created EVE Consortium identified a novel gene association specific to populations of African descent. In addition, the new study confirmed the significance of four gene associations recently reported by a European asthma genetics study.
The findings, published in Nature Genetics, are a promising first step for a new national scientific effort to hunt for the genetic roots of asthma.
“We now have a really good handle on at least five genes that anyone would be comfortable saying are asthma risk loci,” said Carole Ober, PhD, co-chair of the EVE Consortium, senior author of the study, and Blum-Riese Professor of human genetics and obstetrics/gynecology at the University of Chicago. “I think it’s an exciting time in asthma genetics.”
“Asthma rates have been on the rise in recent years, with the greatest rise among African Americans,” said Susan B. Shurin, M.D., acting director of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health, which co-funded the study. “Understanding these genetic links is an important first step towards our goal of relieving the increased burden of asthma in this population.”
Genome-wide association studies, or GWAS, are a popular method used by geneticists to find genetic variants associated with elevated risk for a particular disease. Genetic data from a group of patients with the target disease are compared to data from a control group without the disease, and researchers look for variants that appear significantly more often in the disease group.
But the ability, or power, of GWAS to find disease-associated variants is dependent on the number of participants enrolled in a study. To find variants involved in complex diseases, thousands of participants may be necessary – a logistical and financial demand often beyond the capacity of an individual research team.
“It has become clear to geneticists studying nearly every common disease that GWAS are often under-powered, and unless you pull together many researchers doing the same thing you’re just not going to have the power to find genes,” said Dan Nicolae, PhD, associate professor of medicine, statistics, and human genetics at University of Chicago, co-chair of the consortium and another senior author of the study. “That was the motivation for nine groups of investigators coming together to form EVE.”
Spurred by support from the NHLBI and the National Institutes of Health, research groups from the nine institutions discussed pooling their GWAS data to create a larger, shared dataset. But it wasn’t until they received a $5.6 million grant from the American Recovery and Reinvestment Act of 2009 that the EVE Consortium could officially form and hire the necessary personnel to execute the collaboration.
“It would never have been possible without the grant, this was a huge amount of work,” said Nicolae, “The key was the ARRA funding that allowed us to move it faster.”
In addition to increased power to find variants associated with asthma risk, the EVE dataset comprised a more ethnically diverse population than similar efforts in other countries by including European Americans, African Americans/African Caribbeans, and Latinos.
“We believe that this heterogeneity is important,” Ober said. “There are differences in asthma prevalence in these three groups, so it’s important to understand whether these are caused by environmental exposures or by differences in genetic risk factors.”
The diverse sample enabled the researchers to discover a novel genetic association with asthma observed exclusively in African-Americans and African-Caribbeans. The polymorphism, located in a gene called PYHIN1, was not present in European-Americans and may be the first asthma susceptibility gene variant specific to populations of African descent.
Four more gene variants were found significant for asthma risk by the meta-analysis: the 17q21 locus, and IL1RL1, TSLP, and IL33 genes. All four of these sites were concurrently identified in a separate dataset by the GABRIEL Study of more than 40,000 European asthma cases published last year in the New England Journal of Medicine. Confirming these associations in the more diverse EVE population offers additional evidence that the gene variants are significant across ethnicities, the researchers reported.
“We were able to show that almost all of the genes other than PYHIN1 are trans-ethnic and important in all of the groups,” Ober said.
The Nature Genetics study is only the first fruit of the EVE Consortium mission to understand the genetics of asthma. A deeper meta-analysis looking at a longer list of gene variants is currently underway, and individual groups within the consortium are using the pooled dataset to answer additional questions. Topics of interest include gene-environment interactions, genetic associations with asthma-associated phenotypes such as allergies and lung function, and the role of tissue-specific gene expression.
“What you see here in this paper is only the beginning,” Nicolae said. “The foundation was to make people work together, share the data, and share research ideas, and that will generate a lot of research down the road.”
The paper, “Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations” by Dara Torgerson et al., will be published online July 31, 2011 by Nature Genetics.
In addition to Ober and Nicolae, lead investigators of groups participating in the consortium include W. James Gauderman and Frank D. Gilliand of University of Southern California; Eugene R. Bleecker and Deborah A. Meyers of Wake Forest University; Benjamin A. Raby and Scott T. Weiss of Harvard Medical School; Stephanie J. London of the National Institute of Environmental Health Sciences; Esteban G. Burchard of University of California, San Francisco; Fernando D. Martinez of University of Arizona; L. Keoki Williams of Henry Ford Health System; and Kathleen C. Barnes of Johns Hopkins University. For a complete list of authors and funding agencies, see Nature Genetics (DOI: 10.1038/ng.888).
Can Antibiotics Cure Asthma? Pioneering Research Show’s Promise
The first in a series.
It is estimated that over 300 million people worldwide, including almost 24 million American children and adults have Asthma. It is also estimated that a sizable percentage of that population suffers from severe asthma many of whom do not respond well to conventional treatment.
To learn more about current research to address this disease, the World Asthma Foundation reached out to Dr. David Hahn, family practitioner and research pioneer from Madison Wisconsin U.S.A. Dr. Hahn has twenty plus years of research reflecting that severe Asthma may be linked to a respiratory bacterium known as Chlamydia pneumoniae.
Asthma in the US is on the Rise Says U.S. Centers for Disease Control
Growing every year
Introduction
Asthma is a lifelong disease that causes wheezing, breathlessness, chest tightness, and coughing. It can limit a person’s quality of life. While we don’t know why asthma rates are rising, we do know that most people with asthma can control their symptoms and prevent asthma attacks by avoiding asthma triggers and correctly using prescribed medicines, such as inhaled corticosteroids.
The number of people diagnosed with asthma grew by 4.3 million from 2001 to 2009. From 2001 through 2009 asthma rates rose the most among black children, almost a 50% increase. Asthma was linked to 3,447 deaths (about 9 per day) in 2007. Asthma costs in the US grew from about $53 billion in 2002 to about $56 billion in 2007, about a 6% increase. Greater access to medical care is needed for the growing number of people with asthma.
Latest Findings
Asthma is increasing every year in the US.
Too many people have asthma.
The number of people with asthma continues to grow. One in 12 people (about 25 million, or 8% of the population) had asthma in 2009, compared with 1 in 14 (about 20 million, or 7%) in 2001.
More than half (53%) of people with asthma had an asthma attack in 2008. More children (57%) than adults (51%) had an attack. 185 children and 3,262 adults died from asthma in 2007.
About 1 in 10 children (10%) had asthma and 1 in 12 adults (8%) had asthma in 2009. Women were more likely than men and boys more likely than girls to have asthma.
About 1 in 9 (11%) non-Hispanic blacks of all ages and about 1 in 6 (17%) of non-Hispanic black children had asthma in 2009, the highest rate among racial/ethnic groups.
The greatest rise in asthma rates was among black children (almost a 50% increase) from 2001 through 2009.
Asthma Action Plan Stages
Green Zone: Doing Well
No cough, wheeze, chest tightness, or shortness of breath; can do all usual activities. Take prescribed longterm control medicine such as inhaled corticosteroids.
Yellow Zone: Getting Worse
Cough, wheeze, chest tightness, or shortness of breath; waking at night; can do some, but not all, usual activities. Add quick-relief medicine.
Red Zone: Medical Alert!
Very short of breath; quick-relief medicines don’t help; cannot do usual activities; symptoms no better after 24 hours in Yellow Zone. Get medical help NOW.
Asthma has a high cost for individuals and the nation.
Asthma cost the US about $3,300 per person with asthma each year from 2002 to 2007 in medical expenses, missed school and work days, and early deaths.
Medical expenses associated with asthma increased from $48.6 billion in 2002 to $50.1 billion in 2007. About 2 in 5 (40%) uninsured people with asthma could not afford their prescription medicines and about 1 in 9 (11%) insured people with asthma could not afford
their prescription medicines.
More than half (59%) of children and one-third (33%) of adults who had an asthma attack missed school or work because of asthma in 2008. On average, in 2008 children missed 4 days of school and adults missed 5 days of work because of asthma.
Better asthma education is needed.
People with asthma can prevent asthma attacks if they are taught to use inhaled corticosteroids and other prescribed daily long-term control medicines correctly and to avoid asthma triggers. Triggers can include tobacco smoke, mold, outdoor air pollution, and colds and flu.
In 2008 less than half of people with asthma reported being taught how to avoid triggers. Almost half (48%) of adults who were taught how to avoid triggers did not follow most of this advice.
Doctors and patients can better manage asthma by creating a personal asthma action plan that the patient follows.
Who’s At Risk?
Asthma by age and sex US, 2001-2009
>
Percentages are age-adjusted
SOURCE: National Center for Health Statistics; 2010.
Asthma self-management education by age, US, 2008
SOURCE: National Health Interview Survey, 2008, asthma supplement.
U.S. State Info
Adults with asthma in the US, 2009
What Can Be Done
Federal, state, and local health officials can:
Track asthma rates and the effectiveness of control measures so continuous improvements can be made in prevention efforts.
Promote influenza and pneumonia vaccination for people with asthma.
Promote improvements in indoor air quality for people with asthma through measures such as smoke-free air laws and policies, healthy schools and workplaces, and improvements in outdoor air quality.
Health care providers can:
Determine the severity of asthma and monitor how much control the patient has over it.
Make an asthma action plan for patients. Use this to teach them how to use inhaled corticosteroids and other prescribed medicines correctly and how to avoid asthma triggers such as tobacco smoke, mold, pet dander, and outdoor air pollution.
Prescribe inhaled corticosteroids for all patients with persistent asthma.
People with asthma and parents of children with asthma can:
Receive ongoing appropriate medical care.
Be empowered through education to manage their asthma and asthma attacks.
Avoid asthma triggers at school, work, home, and outdoors. Parents of children with asthma should not smoke, or if they do, smoke only outdoors and not in their cars.
Use inhaled corticosteroids and other prescribed medicines correctly.
Schools and school nurses can:
Use student asthma action plans to guide use of inhaled corticosteroids and other prescribed asthma medicines correctly and to avoid asthma triggers.
Make students’ quick-relief inhalers readily available for them to use at school as needed.
Take steps to fix indoor air quality problems like mold and outdoor air quality problems such as idling school buses.
Employers and insurers can:
Promote healthy workplaces by reducing or eliminating known asthma triggers.
Promote measures that prevent asthma attacks such as eliminating co-payments for inhaled corticosteroids and other prescribed medicines.
Provide reimbursement for educational sessions conducted by clinicians, health educators, and other health professionals both within and outside of the clinical setting.
Provide reimbursement for long-term control medicines, education, and services to reduce asthma triggers that are often not covered by health insurers.
ucation, and services to reduce asthma triggers that are often not covered by health insurers.
Asthma and Chlamydia Pneumoniae Link Says Study from Massachusetts University
Recent press reports and research reflect that American researchers have recently linked a particular type of bacteria, Chlamydia pneumoniae, with very bad cases of the respiratory condition and Asthma. Chlamydia pneumoniae is not related to a sexually transmitted disease.
The Chlamydia pneumoniae (C. pneumoniae) organism, first described in 1988, is not the sexually-transmitted type that first comes to mind to most people. It is an airborne organism that you get from breathing after a person carrying the organism has coughed.
“They float around as droplet nuclei, similar to TB. People cough and up come these infectious bodies. They float around a room. You breathe. In they come and now you’ve got your own.”
Eduard Drizik, a microbiologist at Massachusetts University in the US, led the study which looked at whether the presence of antibodies specific to fighting C. pneumonia could predict the severity of a patient’s asthma.
Video Microbiology: Chlamydia and Asthma Courtesy of the Amereican Society of Microbiology
Presenting the study to the annual conference of the American Society for Microbiology in New Orleans on Monday, Drizik said: “We conclude that a subset of severe asthmatics harbor infectious C. pneumoniae in their lungs, resulting in antibody production and increased asthma severity.”
He explained: “Of the asthma patients analysed, 55 per cent had Chlamydia-specific antibodies in their lungs compared to 12 per cent of blood donor controls.”
Patients with severe asthma who were treated with antibiotics saw their symptoms significantly improve, while in some they completely disappeared.
Drizik said doctors “should therefore fully explore the involvement of microbes in difficult to treat asthma cases, since there might be a cure for some types of asthma after all”.
The study comes after work which found that asthma can be caused by chronic inflammation.
Inflammation is often a sign of infection, which has led microbiologists to search for potential bacterial culprits.
Related News
Clinical Trial Information
AZMATICS: AZithroMycin/Asthma Trial In Community Settings
This study has been completed.
First Received on December 15, 2005. Last Updated on April 12, 2011 History of Changes
Sponsor: University of Wisconsin, Madison
Collaborators:
American Academy of Family Physicians
Wisconsin Academy of Family Physicians (WAFP)
Dean Foundation
Pfizer
Information provided by: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT00266851
Purpose
The purpose of this study is to assess the effectiveness of the azalide macrolide azithromycin in adults with persistent asthma.
Research Question: Will a 12-week treatment with the antibiotic, azithromycin, result in a statistically significant and clinically meaningful improvement in overall asthma symptoms and other patient-oriented asthma outcomes one year after initiation of treatment of adult primary care patients with asthma?
Experimental Design: The investigators propose a one-year randomized, placebo-controlled, blinded (investigator, patient, data collector, data analyst) trial of 12 weekly doses of azithromycin/placebo as adjunctive therapy (in addition to usual care) in 100 adult asthma patients recruited from practice-based research networks (e.g., Wisconsin Research and Education Network (WREN) and others). This “practical clinical trial” will (1) enroll a representative sample of asthma patients encountered in the practices of primary care physicians, (2) employ standard clinical trial methodology to ensure internally valid results and (3) measure outcomes important to patients, so that the results will be valid and applicable to the kinds of asthma patients encountered by family physicians and other primary care providers.
Active study sites – Wisconsin: Augusta, Cross Plains, La Crosse, Marshfield, Milwaukee, Madison, Mauston, Rice Lake, Tomah, Wausau; Colorado: Monument; Illinois: Peoria; Nevada: Reno; North Carolina: Granite Falls; North Dakota: Minot; Ohio: Cleveland, Berea; Oklahoma: Ardmore, Claremore, Edmond, Lawton, Oklahoma City, Stroud, Tulsa, Weatherford; Rhode Island: East Providence
Condition Intervention Phase
Asthma
Drug: Azithromycin
Drug: Placebo
Phase III
Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: AZMATICS: Azithromycin Asthma Trial In Community Settings
Resource links provided by NLM:
MedlinePlus related topics: Asthma
Drug Information available for: Azithromycin
U.S. FDA Resources
Further study details as provided by University of Wisconsin, Madison:
Primary Outcome Measures:
Overall asthma symptoms, as measured by a 5-point scale [ Time Frame: 2006-2010 ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
Asthma control [ Time Frame: 2006-2010 ] [ Designated as safety issue: No ]
Asthma-specific quality-of-life [ Time Frame: 2006-2010 ] [ Designated as safety issue: No ]
Asthma exacerbations [ Time Frame: 2006-2010 ] [ Designated as safety issue: No ]
Enrollment: 97
Study Start Date: January 2006
Study Completion Date: November 2010
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Azithromycin: Active Comparator
Active adjunctive treatment
Intervention: Drug: Azithromycin
Drug: Azithromycin
600 mg x 3 days, then 600 mg weekly x 11 weeks
Other Name: Zithromax
Placebo: Placebo Comparator
Adjunctive placebo
Intervention: Drug: Placebo
Drug: Placebo
Matching placebo
Detailed Description:
1.0 PROTOCOL SYNOPSIS
Approximately 100 eligible adult patients with physician-diagnosed asthma will be randomized to 12-week treatment with azithromycin, a widely marketed azalide antibiotic with an excellent safety profile, or identical placebo as adjunctive therapy for usual care for asthma. The following patient-reported data will be collected via Zoomerang™ (a commercially-available data collection tool) periodically until one year after randomization: (1) study medication adherence and side effects weekly until 12 weeks, (2) asthma control and exacerbations every 6 weeks until 12 months, and (3) asthma quality of life and asthma controller medication changes every 3 months until 12 months. The primary hypothesis is that azithromycin will significantly improve asthma control (decrease symptoms and medication use) by 3 months (end treatment) and the improvement will continue to 12 months (end study). The primary outcome variable is overall asthma symptoms. Secondary outcomes are asthma medication use, quality of life and exacerbations. We will examine the predictive value of baseline patient characteristics including age, sex, smoking, co-morbid respiratory diagnoses and degree of airflow limitation. We will also examine for any imbalances between study groups in controller medication use, other antibiotic prescriptions and acute respiratory illnesses during the one-year study period.
We will enroll subjects from the practices of Wisconsin Research and Education Network (WREN) members, UW Department of Family Medicine physicians, Dean Medical Center primary care physicians, and from other practice-based research networks (PBRNs), medical group practices and individual primary care practices throughout North America.
Patients with physician-diagnosed asthma aged 18 and older will be identified at point-of-service (office, urgent care, emergency room or hospital), by administrative data base review, or by physician recall. Most subjects will be the patients of study physicians. Other physicians in the group practice may refer subjects. Subjects also may be self-referred after responding to posters placed in the clinics. Some sites may elect to identify cases by medical record or database review, in which case only the personal physician may initiate patient contacts.
Treatment is azithromycin tablets, 600 milligrams orally once daily for 3 days, then 600 milligrams once weekly for an additional 11 weeks (total dose 8400 milligrams) or identical placebo, in addition to usual care for asthma.
Eligibility
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: Yes
Criteria
Inclusion Criteria:
Age 18 and older (and at least 50 kg/110 pounds)
The lower weight limit was chosen to avoid exposure to greater than 12 mg/kg/day of azithromycin (a currently recommended dose for children)
We specify no upper age limit because asthma occurs throughout the age range and because asthma in the elderly is particularly severe and warrants inclusion.
Physician-diagnosed asthma
At the time of randomization, eligible subjects must either:
be having a documented asthma exacerbation OR
be reporting at least mild persistent asthma symptoms, as defined by GINA (Global Initiative for Asthma)
Subjects must also have asthma symptoms for at least six months prior to randomization
Documentation of objective evidence of reversible airway obstruction, either spontaneously or after treatment, is required prior to randomization. This requirement can be met by documentary evidence, within 2 years of randomization, of either:
a 12% or greater (and ?200 mL) change in FEV1 OR
a 25% or greater (and >60 L/min) change in PEFR either spontaneously or as a result of treatment
Exclusion Criteria:
Not English literate or without email and internet access
Macrolide allergy
Pregnancy or lactation
Females of childbearing potential must agree to use an acceptable form of contraception during the treatment period
Chronic use of macrolides, tetracyclines or quinolones Chronic use is defined as 4 or more weeks of continuous use within 6 months of randomization
Asthma symptoms for less than 6 months prior to randomization Asthma symptoms must be present for at least 6 months to exclude patients without true chronic asthma
Unstable asthma requiring immediate emergency care All patients with asthma exacerbations will receive usual urgent or emergency care for asthma and must be improving or stable in the judgment of the treating physician prior to being enrolled
Specified co-morbidities likely to interfere with study assessments or follow up. Excluded comorbidities include:
cystic fibrosis
obstructive sleep apnea requiring CPAP
cardiomyopathy
congestive heart failure
terminal cancer
alcohol or other drug abuse
or any other serious medical condition that, in the opinion of the study physician, would seriously interfere with or preclude assessment of study outcomes or completion of study assessments
Specified medical conditions for which macrolide administration may possibly be hazardous
Patients with acute or chronic hepatitis, cirrhosis or other liver disease, chronic kidney disease, or history of prolonged cardiac repolarization and QT interval or torsades de pointes, are excluded
Specified medications for which close monitoring has been recommended in the setting of macrolide administration Patients taking digoxin, theophylline, warfarin, ergotamine or dihydroergotamine, triazolam, carbamazepine, cyclosporine, hexobarbital or phenytoin are excluded.
If any of these medications are started after randomization and before completion of the 12-week treatment phase, study medication will be discontinued and the patient may remain in the study.
The intent of this protocol is to enroll a broadly generalizable sample of adult patients with physician-diagnosed asthma, either stable persistent or in exacerbation.
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00266851
Locations
United States, Illinois
ANSR
Peoria, Illinois, United States, 61602
United States, Kansas
AAFP National Research Network
Kansas City, Kansas, United States, 66211
United States, Ohio
RAP – Cleveland Clinic
Cleveland, Ohio, United States, 44130
United States, Oklahoma
University of Oklahoma Health Sciences Center (OUHSC) and Oklahoma Physicians Resource/Research Network (OKPRN)
Oklahoma City, Oklahoma, United States, 73104
United States, Wisconsin
Wisconsin Research and Education Network (WREN)
Madison, Wisconsin, United States, 53713
Sponsors and Collaborators
University of Wisconsin, Madison
American Academy of Family Physicians
Wisconsin Academy of Family Physicians (WAFP)
Dean Foundation
Pfizer
Investigators
Principal Investigator: David L Hahn, MD, MS Wisconsin Research and Education Network (WREN)
More Information
Additional Information:
Patient perspective/literature review This link exits the ClinicalTrials.gov site
Infectious asthma research/annotated bibliography This link exits the ClinicalTrials.gov site
Publications:
Hahn DL, Plane MB. Feasibility of a practical clinical trial for asthma conducted in primary care. J Am Board Fam Pract. 2004 May-Jun;17(3):190-5.
Hahn DL. Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial. J Fam Pract. 1995 Oct;41(4):345-51.
Hahn DL. Chlamydia pneumoniae, asthma, and COPD: what is the evidence? Ann Allergy Asthma Immunol. 1999 Oct;83(4):271-88, 291; quiz 291-2. Review.
Hahn DL, Plane MB, Mahdi OS, Byrne GI. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials. 2006 Jun;1(2):e11. Epub 2006 Jun 30.
Responsible Party: Dean Medical Center ( David L Hahn )
ClinicalTrials.gov Identifier: NCT00266851 History of Changes
Other Study ID Numbers: H-2005-0258
Study First Received: December 15, 2005
Last Updated: April 12, 2011
Health Authority: United States: Institutional Review Board
Keywords provided by University of Wisconsin, Madison:
Randomized clinical trial
Asthma
Adults
Azithromycin
The U.S. National Library of Medicine and National Institutes of Health is reporting that U.S. health regulators have ordered drugmakers to conduct clinical trials involving a total of 53,000 patients to test the safety of a controversial class of inhaled asthma drugs that are already on the market.
The trials are being required to demonstrate the safety of medicines known as long-acting beta-agonists (LABAs) when used in combination with inhaled steroids, another class of asthma drugs, the U.S. Food and Drug Administration said on Friday.
LABAs to be studied are AstraZeneca’s Symbicort, GlaxoSmithKline’s Advair Diskus, Merck & Co’s Dulera, and Novartis AG’s Foradil.
LABAs have long been under FDA scrutiny as they can increase the risk of severely worsening asthma symptoms that can lead to hospitalizations and death.
The drugs work by relaxing the muscles of the airways to help people breathe easier and are also used to treat the serious lung condition, chronic obstructive pulmonary disease
(COPD).
The FDA expects to receive results in 2017 for the studies that will begin later this year.
In four of the trials sought by the FDA, each of the LABAs plus a corticosteroid will be compared with the steroid alone in patients 12 years of age and older. Those studies are expected to include a total of 46,800 patients.
Some of these drugs. such as Advair and Symbicort, are combination drugs that include a LABA with a corticosteroid.
The agency has also asked for a trial of 6,200 younger patients, aged 4 to 11, using Glaxo’s Advair Diskus.
The huge size of the studies signals that FDA wants to be completely sure about the safety profile of these drugs as they are used so widely, Morningstar analyst Damien Conover said.
Such a large study population might pose some financial challenges for the drugmakers, he said.
“Glaxo is complying with the FDA request to implement the Phase 4 study,” Glaxo spokeswoman Lisa Behrens said of the post-marketing trial.
AstraZeneca said it was finalizing study protocol with the agency and supports efforts to address any questions regarding use of its drug.
Novartis said it was reviewing the post-marketing requirements issued by the FDA, while Merck said it would have a comment shortly.
The FDA last June issued warnings on LABAs, saying they should never be used on their own to treat asthma and called on drugmakers to conduct further studies to better understand the safety of LABAs when used with inhaled steroids.
Why Are Asthma Rates Soaring? Researchers once blamed a cleaner world. Now they are not so sure
Research into varying causes of asthma may eventually lead to new ideas on how to manage the condition.
According to an article published in the Scientific American, Asthma rates have been surging around the globe over the past three decades, and for a long time researchers thought they had a good idea of what might be fueling the increase: the world we live in is just a little too clean. According to this notion—known as the hygiene hypothesis—exposure in early childhood to infectious agents programs the immune system to mount differing highly effective defenses against disease-causing viruses, bacteria and parasites. Better sanitary conditions deprive the immune system of this training, so that for reasons that are still unclear, the body pounces on harmless particles—such as dust and ragweed—as if they were deadly threats. The resulting allergic reaction leads to the classic signs of asthma: chronic inflammation or swelling of the airways and acute spasms of those passageways.
Or so the thinking went. Although a lot of data support the hygiene hypothesis for allergies, the same cannot be said for asthma. Contrary to expectations, asthma rates have skyrocketed in urban areas in the U.S. that are not particularly clean. Moreover, the big increase in asthma rates in developed countries did not kick off until the 1980s—well after general sanitary conditions in the richer parts of the world had improved. And some studies are beginning to show that far from protecting children from asthma, respiratory infections in early childhood may actually be a risk factor for it.
The collapse of the hygiene hypothesis as a general explanation for the startling jump in asthma rates has led physicians and scientists to a new realization: asthma is a much more complex condition than anyone had truly appreciated. Indeed, it may not be even be a single disease. Studies now suggest that only half of asthma cases have an allergic component.
The prevention and treatment implications are significant. If, for instance, it is true that allergy is not a fundamental cause of asthma in many people, then an alternative mix of treatments may be more effective for those individuals. To root out asthma’s cause (or causes) and properly treat the burgeoning number of people who are affected—300 million globally at last count—scientists will have to come to grips with the biology of its various forms.
Balancing Act
The hygiene hypothesis was first described in 1989 by David P. Strachan, a British epidemiologist who was studying hay fever. The more children in a family, he noticed, the lower the rates of hay fever and eczema, an allergic skin condition. Children in large families tend to swap colds and other infections more often than children with fewer siblings. Could it be that increased exposure to pathogens from their many siblings was protecting children from large families against allergies?
That same year Erika von Mutius, an epidemiologist at Munich University, was looking into the effect of air pollution on asthma in what was then East and West Germany. Children from dirtier East Germany, she was shocked to find, had dramatically less asthma than their West German counterparts living in cleaner, more modern circumstances. The East German children, unlike their Western counterparts, had spent more time in day care and thus had likely been exposed to many more viruses and bacteria. “That was astonishing,” she recalls, and led to “a major shift” in thinking.
These findings sparked intense debate among scientists. What is it about unhygienic living that might protect against asthma? One of the more popular explanations in the following decades entailed a balance between the immune cells that are involved in the body’s reaction to most viruses and bacteria and those that are involved in the reaction to most parasites and allergens. These two groups of cells produce chemicals that inhibit each other. Early-childhood exposure to bacteria and viruses would cause the infection-related cells to become active, keeping the allergy- and parasite-related cells in check. Without that interplay, the allergy-related cells would later become overreactive, starting an allergic chain reaction that became chronic and ended in constricted airways, asthmatic spasms and labored breathing.
Inconvenient Facts
There was only one problem. As more data came in, they failed to tell the same story as the hygiene hypothesis. Children in Latin America with high rates of supposedly protective infection have even higher rates of asthma than children in western Europe. Inner-city children in Chicago and New York have quite high rates of asthma, despite unhygienic living. And the rates of asthma varied among countries with very similar histories of cleanliness—indicating that there was more to it than tidiness. For example, by 2004 Sweden’s asthma cases had increased to 10 percent, according to one international study, while the number of cases in the U.K. had soared to 20 percent.
In addition, research showed that the relation between asthma and allergy is not at all straightforward. Some cases of asthma are indeed triggered by allergies, although the consensus among researchers over the past decade is that the connection is probably not as clear-cut as the hygiene hypothesis would suggest. Still other layers of immune regulation must be involved. Maria Yazdanbakhsh, a parasitologist at Leiden University in the Netherlands, has shown that people infected with parasitic worms have very high levels of the allergy-related immune cells but very low rates of asthma, disproving a direct connection between allergy and asthma in these cases at least.
What is more, a landmark review of asthma studies in 1999 by Neil Pearce, now at the London School of Hygiene and Tropical Medicine, demonstrated that at least half of asthma cases in the general population have no connection to allergic reactions at all. These could never be explained by the hygiene hypothesis.
In fact, the same factors that the hygiene hypothesis suggests protect people from developing allergic asthma may cause them to develop nonallergic asthma. “We think that dirt protects against allergic asthma, as foretold by the hygiene hypothesis, but increases the risk of having a nonallergic form,” says Laura Rodrigues of the London School of Hygiene and Tropical Medicine, who studies asthma in Latin America. Pollutants in the air can irritate the airways and cause inflammation that leads to constricted breathing. Childhood colds, which the hygiene hypothesis suggested might help prevent development of asthma, can actually be a risk factor for asthma, especially if severe, says James E. Gern, a pediatrician who studies colds and asthma at the University of Wisconsin–Madison. “Early-life infections are an indicator of asthma risk rather than protective in any way,” he says.
Besides the hygiene hypothesis, what can explain the increase in asthma rates? Other suggested causes include a rise in sedentary lifestyle, which could affect lung strength, and the rise in obesity, which increases inflammation throughout the body. A reworking of the hygiene hypothesis that focuses on changes in the normal nondisease-causing bacteria that live inside and on the body (in the intestines or the airways or on the skin) has promise. Studies by von Mutius and others have shown that children who live on farms where cows or pigs are raised and where they drink raw milk almost never have asthma, allergic or otherwise. Presumably because the children drank unpasteurized milk and handled livestock, they have different strains of normal bacteria in their airways that are somehow more protective than those found in city kids.
But the short answer to the question of why asthma has increased, according to Pearce, von Mutius, Rodrigues and many others, is, “We don’t know.” Pearce, in particular, wonders whether modernization in general or westernization in particular may play a role. “There is something about westernization that means people’s immune systems function in a different way,” he says. “But we don’t know what the mechanism is.”
Getting at the true underlying cause of the climb will require better ways of distinguishing among various possible types of asthma. Major asthma research networks supported by the National Institutes of Health have begun recording the details of thousands of individuals’ symptoms and treatments. As the results are gathered and analyzed, researchers hope to identify clusters of asthma cases that have different causes and respond to different treatments. The hope is that “if you come in with these characteristics in asthma, we can anticipate what the prognosis is going to be and what the most effective treatment for you is going to be,” says William W. Busse of the University of Wisconsin School of Medicine and Public Health, who is part of one such network.
It will take years to understand fully whether microbial exposure, lifestyle changes or the obesity epidemic is more important in explaining the continuing increase in asthma rates. But one thing is clear: the hygiene hypothesis was just the beginning.
To subscribe to the Scientific American and for more information about the Asthma article visit http://www.scientificamerican.com/article.cfm?id=why-are-asthma-rates-soaring&page=3
Researchers in South Australia are claiming a breakthrough in the understanding of asthma say news sources.
They have found a protein which stops the absorption of the essential mineral, zinc, which may help control symptoms.
According to researchers, zinc can protect humans against any pollutants that are inhaled.
However, experts have found that in asthmatics zinc does not have the same effect because the molecules that usually carry it through the body are missing.
Work has begun to find a way to correct the deficiency.
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