SYMBICORT FAQs- COPD

COPD

Q: Why is PATHOS carried out in Sweden? Are results of this study relevant only to the healthcare
system in
Sweden?
PATHOS6 was carried out in Sweden because this is a country with a high-quality storage system for
electronic medical files. The data of the study were collected from electronic data records of primary
health care centers and linked with the mandatory Swedish national registers. The data linkage was done
by relying on the social insurance numbers of the patients. These data are thus well suited for
retrospective, observational registry, "Real World Evidence" study. Researchers monitored the patients
treatment to get solid and unique information. This helped researchers find out the correlation between
COPD treatment strategies with clinical outcomes such as hospital admissions, emergency visits,
antibiotics and oral steroids usage.
The results from PATHOS are not only relevant to the health care system in Sweden. COPD treatment
strategies and the use of ICS/LABA in COPD treatment are not applicable to only Sweden but are
applicable to all places around the world. Therefore, the effect of the therapy used in PATHOS for treating
clinical exacerbations is relevant not only to the health care system in Sweden but to all other health care
systems.
Q: The population characteristics of PATHOS differ from the population of COPD living in Asia. Does
this difference in population distribution affect the research results?
PATHOS6 is a Real World Evidence study, so an obvious value of this study is that it may reflect the reality
demographic distribution of COPD patients in Sweden. Due to the cultures influence, most European
countries have higher proportion of female
COPD patients than male. This is different from the demographic distribution of COPD in Asia. However,
while analyzing patients groups based on age, sex, treatment duration, etc., the authors found that these
factors did not influence the study results. In other words, both groups of patients, male and female,
showed similar results to those of the general population. Therefore, the results from the PATHOS study
are consistent with the population in other countries and are not affected by demographic characteristics.
Q: PATHOS is not a Randomized Controlled Trial. Therefore, Budesonide/Formoterol may show higher
effectiveness because it is used on less severe COPD patients. Is it possible that physicians in the
study perceived Fluticasone/Salmeterol to be a better fit for treating more severe COPD patients?
PATHOS6 study analyzed a database of 9893 patients using ICS/LABA (7,155 patients using Budesonide
/Formoterol and 2738 patients using
Fluticasone/Salmeterol). The patients in both groups were "matched" (paired up) at the beginning of the
study to ensure that two groups had similar characteristics. After matching, the study had 2734 pairs of
Seretide-Symbicort patients with similar characteristics. The "matching" analysis (pairing) minimized the
confounding factors of non- random assignment of patients to treatments.

Q: How does one know that all factors causing variation to the results of the study have been
removed by the method of score-matching? Can the 31 variables chosen for score-matching
ensure that the severity of COPD is equivalent between the two groups? Did this study provide
information about the GOLD classification of COPD patients?
The parameters used to "match" (pair up) patients in the PATHOS6 study must satisfy 2 criteria (1) can
be collected from the medical records, and (2) were found to be important parameters that can affect
the study results. PATHOS study used 31 different variables. The important parameters that affected
the exacerbation risk were recorded in Sweden while monitoring the patients and thus, may be used
for matching. These 31 variables reflected most of the COPD burden faced by patients in the study.
The "matching" analysis minimized the confounding factors which can affect the results of the study.
The PATHOS study was published in 2 journals:

(1) Internal Medicine Journal acknowledged the comparable results between the
exacerbation rate in two groups of COPD patients using two different types of
ICS/LABA

(2) BMJ acknowledged the comparable results between the incidence of pneumonia in
two groups of COPD patients using two different types of ICS / LABA
These two results used the same research method, the same matching method, the same variables
and database. However, the authors only used part of the database when published on each journal
according to the requirements of respective Evaluation and Approval Council of each journal. This is
why the numbers of variables differ in 2 reputable journals. A total of 26 variables were mentioned in
these journals. However, in this study, the authors used 31 pairs of variables for matching and
analysis (However, a few variables were not mentioned in the full text).
Q: The table analyzing the characteristics of patients at the start of the study records only around
20% of the patients possessing FEV1 data. Does this affect the result of the study?
Although the use of spirometers at primary healthcare centers in Sweden has grown tremendously in the
past decade and is increasingly popular, there is no routine procedure for storing electronic data of
respiratory function of each patient. The data were stored in different places for different centers under
different forms in the medical record systems, be it personal computer or paper records. Therefore, it was
not possible to retrieve electronic data of FEV1 for all patients.
The matching method used in the study was a 1:1 matching in order to create two groups of patients using
Symbicort vs. Fluticasone/Salmeterol with similar propensity scores, implying similar burden of COPD.
When the authors analyzed only the group of patients with FEV1 data who were matched between the two
groups, they saw similar results when compared to the general population of 5468 patients (including
patient groups with and without FEV1 data). Whether or not FEV1 data was included, results of the
PATHOS6 study would still be unchanged. Therefore, the lack of information on FEV1 does not affect the
published results of this study.

Q: In the study, the physicians in charge were primary care physicians and not respiratory
specialist physicians. Does this affect the result of the study?

The process of gathering information in the PATHOS6 study was carried out as follows:

Starting with the data from 76 primary healthcare centers, the authors found 21361 patients with COPD.
They then retrieved all the information of these patients through social insurance books of the Department
of Health and Social Welfare Department, including details of treatment, diagnostic parameters, drugs use,
cause hospitalization, mortality, ... At the same time, they linked the patients data with those of major
hospitals (in the case where patients were transferred to a different hospital) . All data collected was sent to
the research center of the University of Uppsala-Sweden to be processed. Therefore, the study results of
PATHOS not only assessed the effectiveness of treatment in one group of primary care physicians but
during the 11 years tracking COPD patients through their history of treatment, starting from the primary
care centers.
Q: Were diagnoses of patients with pneumonia in the study supported by pulmonary x-ray?

Not only PATHOS but all previous RCTs on COPD classified pneumonia as an adverse event. Therefore,
the diagnosis of pneumonia can be based on clinical examination of a doctor or on pulmonary x-ray. In
PATHOS study, more than 67% of pneumonia cases were diagnosed from the hospital with X-ray method,
which is one of the routine diagnostic procedures for diagnosing pneumonia.
Q: How do you explain the difference between ICS dose used in the study and ICS recommened
dose?

The results of the study show that in real-life therapy, the two ICS/LABA drugs are used at doses different
than recommended doses. However, the average dose of Budesonide found in the research survey was
568g/day and 783 g/day for Fluticasone. This showed that 80-90% of patients in the 2 groups followed
the recommended dose.

Q: PATHOS study showed that Symbicort group used on average 568 g Budesonide/day and
Fluticasone/Salmeterol group used on average 783 g Fluticasone/day. Is this difference the cause of a
higher rate of pneumonia in the Fluticasone/Salmeterol group?
PATHOS6 is a Real World Evidence study, which recorded real-life medical practices in the community
regarding treatment doses and clinical outcomes, including factors causing increase/decrease of doses
depending on the patient's condition and clinical examination of doctors. According to the products
prescribing information, the recommended dose of
Budesonide in Symbicort is 640 g/day and of Fluticasone in
Fluticasone/Salmeterol is 1000 g/day. Thus, the doses used in PATHOS were relatively consistent with
the prescribing information of these 2 products.
On the other hand, with the aforementioned doses, the efficacy in reducing exacerbation risk of Symbicort
was 26% higher than that of
Fluticasone/Salmeterol. This confirmed the advantage of using Symbicort in treating COPD because its
ICS was used at a lower dose yet its therapeutic efficacy was better with higher safety.
Q: What are the differences between Real World Evidence (RWE) and Randomized Controlled Trial
(RCT)?

Randomized clinical trial is often the gold standard in which the effectiveness and safety of drugs are
shown. However, these studies are often designed with strict control and thus they are limited and protected
from the impact of actual treatment variables. Thus, they cannot answer problems related to actual health
care processes in everyday life. The limitations of randomized clinical trials include: removal of previous
therapies, short follow-up time, small study population, quitting of patients, excluding patients with
associated diseases, conditions for adherence too strict, unrealistic and incapable of detecting rare adverse
events (<1%) or of drug interactions due to restriction applied on patients to not use multiple drugs
simultaneously.

"Real World Evidence" studies can bring about benefits of costs and reflect the reality of daily therapy that
randomized trials cannot. These studies will provide better information about the use of drugs in everyday
treatment, real-life situations, etc.

Please note that we are not proposing that RWEs can replace RCTs; RCTs are considered to be the Gold
Standard however data represented through RWEs may be more closer to the real world practice.

Q: PATHOS study showed the difference between the two groups Budesonide/Formoterol and
Fluticasone/Salmeterol in their effectiveness on controlling exacerbation and safety in treating
pneumonia. How do you explain this difference?
Explanation for the differences in pneumonia:
The problem of pneumonia in COPD patients when using ICS/LABA has existed since long. Before PATHOS,
there were at least 5 randomized clinical trials (RCTs) showing Fluticasone/Salmeterol increased the risk of
pneumonia compared to placebo-group and other bronchodilators.6

According to the authors of PATHOS, the difference of pneumonia risk in COPD patients using ICS/LABA
containing budesonide or fluticasone may be related to the pharmacological properties of these two ICS.
When inhaled, corticosteroids will stay at high concentrations in the lungs and increase the risk of pneumonia
due to its immunosuppressive properties. Immunosuppressive potency of Fluticasone is about
10 times higher than that of Budesonide, which in ex vivo inhibits alveolar macrophages from activating the
intrinsic immune system against invading bacteria7. This may be one reason to explain the higher risk of
pneumonia in the group of Fluticasone/Salmeterol compared to the group of Budesonide/Formoterol. In
addition, differences in pharmacodynamic properties and pharmacological activities related to solubility
properties (water-based or oil-based) can lead to differences in the risk of pneumonia between Budesonide
and Fluticasone8. In patients with severe COPD, Fluticasone molecule with relatively high oil make-up will last
longer in the mucous membrane and alveolar epithelial cells compared with Budesonide9. This can cause
stronger and longer local immunosuppression after using Fluticasone compared with Budesonide, increasing
local bacterial growth and leading to pneumonia.
Explanation for the differences in the rate of exacerbation:
The authors of PATHOS6 hypothesized an explanation for the differences in the rate of exacerbation
between the two groups
Budesonide/Formoterol and Fluticasone/Salmeterol. According to this hypothesis, there is a significant
amount of bacteria in the lower respiratory tract in patients with well-controlled COPD. The bacteria may
contribute to stimulating airway inflammation, leading to the start of an exacerbation.

On the other hand, we know that the immunosuppressive potency of

Fluticasone is about 10 times higher than that of Budesonide. Therefore, Fluticasone may facilitate
favourable conditions for bacteria in the lower respiratory tract of patients to develop stronger, affecting the
rate of exacerbation.
SYMBICORT

Q: Formoterol is a full agonist while Salmeterol is a partial agonist. What is the difference?
A partial agonist can activate the respective receptors but cannot promote the maximum effect like a full
agonist even after saturation of receptors (according to Trn Th Thu Hng, Pharmacokinetics, 2006). In
other words, a full agonist leads to a tight and clear relationship between the dose and the response
whereas a partial agonist does not.

Q: Fluticasone shows higher ICS potency which can help moderate-severe asthma patients to
achieve asthma control faster.
Higher potency does not equate to high efficacy. Potency is how much drug concentration to produce an
action. But when looking into clinical studies, indicated dosage shows better efficacy with Symbicort.

ULTIBRO FAQs SPARK study - Ultibro

References:
INSPIRE Study- Wedzicha J., et al, Am J Crit Care Med 2008; 177:19-26
GINA 2014
COMPASS Study- Kuna P., et al, Int J Clin Pract, May 2007, 61, 5, 725736
AHEAD- Bosquet J., et al, J Resp Med, .2007.07.014
COSMOS- Vogelmeier C., et al, Eur Resp J, 2005 Vol 26 no. 5
PATHOS study 2013
Thorax 2006, 61:164-168
Respiratory Med (2008) 102, 1099-1108
Sin et al, The Lancet, Volume 374, Issue 9691
Nannini LJ, the Cochrane Library, 2012, Issue 9
SPARK Study- Wedzicha J., et al, Lancet Respir Med 2013; 1:199-209