Dear Reader, What was the study about? Why was the research needed? BI NCT

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1 Dear Reader, Sponsors of clinical studies create study reports. A study report describes how the study was done and what the results of the study were. This is a summary of such a report. It is meant for the general reader. Complex medical explanations have been avoided as much as possible. You may be interested in this summary because you want to learn about treatment options for lung diseases such as Chronic Obstructive Pulmonary Disease (COPD). This summary describes the results of a single study. The results cannot be assumed to apply for everybody. This study started in March 2014 and ended in October Its lay title was "To evaluate the effect of inhaled medication together with exercise and activity training on exercise capacity and daily activities in patients with chronic lung disease with obstruction of airways". The sponsor was Boehringer Ingelheim. What was the study about? This study compared 4 treatments for COPD. One treatment involved inhaling 2 medicines (tiotropium and olodaterol) and starting to exercise. The other 3 treatments involved inhaling 2 medicines (tiotropium and olodaterol), 1 medicine (tiotropium), or no medicine (placebo; a placebo is inactive and is not expected to have an effect on the disease). As part of their treatments, patients in all treatment groups were encouraged to make lifestyle changes; they took part in a special (behaviour modification) programme where they: attended classes about COPD, learned about the importance of exercise and activity training, made goals related to physical activity, and received a device to count steps to help them monitor their physical activity. At the end of the study, the treatments including medicines were compared with the treatment including placebo. Researchers wanted to know if patients who took treatments including medicines were more physically fit (in terms of exercise capacity) than patients who took the treatment including placebo. Why was the research needed? COPD is a disease that makes it difficult to breathe. It causes wheezing, shortness of breath, and chest tightness. Patients often have a cough that produces mucus. COPD is usually caused by smoking cigarettes. Many people with COPD find it hard to stay physically active because it makes them feel out of breath. However, it is important for patients with COPD to stay active (or become even more active) in day-to-day life and exercise. Otherwise, their symptoms might get worse. Researchers wanted to find out what treatments help patients increase physical fitness. All patients in this study had COPD and were current or ex-smokers. Page 1 of 7

2 Which medicines were studied? Researchers studied 2 medicines that widen the airways. Tiotropium: a so-called long-acting anticholinergic Olodaterol: a so-called long-acting beta-agonist Both medicines are used separately or combined together (a fixed-dose combination) for the treatment of COPD. These medicines come as a solution that needs to be inhaled using a special inhaler called the RESPIMAT. This inhaler converts the solution into a soft mist. Patients breathe in this soft mist to take the medicines. What did the researchers want to know? Researchers wanted to know if patients who took treatments including medicines were more physically fit than patients who took the treatment including placebo. To find this out, they measured: The time (endurance time) patients could briskly walk during a fitness test (endurance shuttle walk test at 85% of predicted maximum oxygen consumption) before they needed to stop due to symptoms. During this test, each patient walked a constant speed. This speed was directly related to the individual patient's maximum speed. Even though some patients walked faster and others walked slower, all patients walked at the same relative speed. Researchers were particularly interested in the fitness tests taken after 8 and 12 weeks of treatment. The time patients spent walking per day and how hard they pushed themselves while walking (intensity). Researchers were particularly interested in what happened during Week 12. Patients' symptoms and ability to complete certain activities. Researchers measured this by asking patients to fill out special questionnaires. Researchers were particularly interested in what happened after 12 weeks of treatment. Patients answered questions about: o Breathlessness during everyday activities (Modified Medical Council Dyspnoea Scale) o The impact of COPD symptoms on everyday life (Chronic Respiratory Questionnaire- Self Administered, Standardised), and o How easy it is to do certain activities (Functional Performance Inventory Short Form) In addition, researchers collected information on the side effects of all treatments. Who participated in the study? Patients with COPD took part in the study. All had to be current or ex-smokers between the ages of 40 and 75. Overall 303 patients were treated; 200 were men and 103 were women. On average patients were 65 years old. The youngest patient was 41 years and the oldest patient was Page 2 of 7

3 75 years. Patients were White (295), African American (6), Asian (1), and Native Hawaiians/Pacific Islanders (1). Patients were from 11 different countries (Australia, Austria, Belgium, Canada, Denmark, Germany, New Zealand, Poland, Portugal, United Kingdom, and United States). How was this study performed? Patients were divided into 4 groups of similar size. It was decided by chance who got into which group (randomised). Each of the groups received only one of the 4 treatments. Patients in the group that received exercise training knew what treatment they received; this is because they were the only group that received exercise training. The patients in the other groups did not know which medicine they received. Also their doctor did not know this. This is called 'partial doubleblind design'. The 4 different groups had the following treatments: Combination 1: Patients took 2 puffs of combined tiotropium and olodaterol using the RESPIMAT inhaler every day (5 µg tiotropium/5 µg olodaterol per day) and were encouraged to make lifestyle changes. They did this for 12 weeks. Patients also attended exercise classes 3 times per week for 8 weeks. Combination 2: Patients took 2 puffs of combined tiotropium and olodaterol using the RESPIMAT inhaler every day (5 µg tiotropium/5 µg olodaterol per day) and were encouraged to make lifestyle changes. They did this for 12 weeks. Tiotropium: Patients took 2 puffs of tiotropium using the RESPIMAT inhaler every day (5 µg tiotropium per day) and were encouraged to make lifestyle changes. They did this for 12 weeks. Placebo: Patients took 2 puffs of placebo using the RESPIMAT inhaler every day and were encouraged to make lifestyle changes. They did this for 12 weeks. The chart below provides a summary of the different treatments and their components. Tiotropium only Tiotropium+ Olodaterol Combination 1 Combination 2 Tiotropium Placebo Lifestyle changes Exercise Except for having different treatments, all patients followed the same procedures: Patients stayed in regular contact with their doctor. Patients took tests to find out how fit they were at doctor visits. At doctor visits, the patients also answered questions about their health and fitness. Page 3 of 7

4 All patients took classes to support their lifestyle changes. They took these classes during the first, second, fifth, eighth, and eleventh weeks of the study. Patients wore activity monitors during the ninth and the twelfth weeks of treatment to keep track of their activities during everyday life. The doctors looked after each patient and checked results. They also discussed any health problems with the patients and performed further medical tests when needed. What were the results of this study? This study compared 4 treatments for COPD. Researchers wanted to know if patients who took treatments including medicines were more physically fit than patients who took the treatment including placebo. Researchers used several different methods to answer this question. To be sure that the results they got were reliable, researchers tested whether the results could have come about by chance. This was done by using statistical tests. Some of these statistical tests involved the calculation of so-called p-values. In this study, a small p-value (p less than 0.05) shows that the differences between the treatments are unlikely due to chance. Larger p-values show that differences between the treatments are possibly due to chance. This study showed that patients who took combinations 1 and 2 were more physically fit than those who took placebo. No difference was found between patients who took tiotropium and placebo in terms of physical fitness. The results are discussed in further detail below. How long did patients take each medicine? Patients took the medicines for about 86 days (median). This was similar across all 4 treatment groups. Was there a difference between the treatments in time patients could briskly walk during a fitness test before they needed to stop due to symptoms? Yes, there was a difference between the treatments in terms of time patients could walk before they needed to stop due to symptoms at Week 8. Patients who took combination 1 could walk for a longer time (46% longer) before they needed to stop due to symptoms than patients who took placebo. Patients who took combination 2 could also walk for a longer time (29% longer) before they needed to stop due to symptoms than patients who took placebo. These results were unlikely to have come about by chance (p= for combination 1 comparison to placebo; p= for combination 2 comparison to placebo). Patients who took tiotropium could only walk a little longer (4% longer) before they needed to stop due to symptoms than patients who took placebo. It is possible that the difference between treatment with tiotropium and treatment with placebo was due to chance (p= for tiotropium comparison to placebo). These results and the results for Week 12 are illustrated in the graph on the next page. Page 4 of 7

5 Was there a difference between the treatments in time patients spent walking per day and how hard they pushed themselves while walking? No. The differences between the treatments containing medicines and the treatment containing placebo were small. They were possibly due to chance. Was there a difference between the treatments in terms of symptoms and ability to complete certain activities? Yes, in this study some differences between the treatments were seen in terms of symptoms and ability to complete certain activities after 12 weeks of treatment: Patients who took combination 1 or combination 2 were not as breathless during everyday activities (Modified Medical Council Dyspnoea Scale) as patients who took placebo; this was not likely due to chance. The difference in breathlessness during everyday activities between patients who took tiotropium and patients who took placebo was possibly due to chance. COPD symptoms (Chronic Respiratory Questionnaire-Self Administered, Standardised) related to breathlessness and feeling tired had less of an impact on everyday life for patients who took combination 1 or combination 2 than for patients who took placebo; this was not likely due to chance. The difference between patients who took tiotropium and patients who took placebo for these specific symptoms was possibly due to chance. COPD symptoms related to mood and feeling in control of COPD had a similar impact on everyday life for patients who took treatments containing medicines and the treatment containing placebo; any differences between the treatments for these specific symptoms were possibly due to chance. Patients in the combination 2 treatment group found that it was easier to do certain activities (Functional Performance Inventory Short Form) than patients in the placebo treatment group; this was not likely due to chance. The differences between the combination 1 and placebo group and tiotropium and placebo group, however, were possibly due to chance. Page 5 of 7

6 Which side effects did patients have? A side effect is any medical problem seen during a study. Some side effects are caused by the study medicines or by other medicines taken by the patient. Others are caused by the disease. Some have yet a different cause. Side effects might happen only 1 time, for 1 patient, and last for a very short period of time. Other side effects might happen many times, for many patients, and last for a longer period of time. Researchers keep track of all medical problems patients have during a study. In this study very few patients had side effects that doctors believed were caused by the study medicines. Such side effects were generally related to COPD or how the medicines work to widen the airways. Most side effects that were likely related to the study medicines had a mild or moderate intensity. The table below shows the side effects likely caused by study medicines that were seen in more than 1 patient overall. Combination 1 (76 patients) Combination 2 (76 patients) Tiotropium (76 patients) Placebo (75 patients) Patients who had side effects related to the study medicines 2 patients (2.6%) 3 patients (3.9%) 6 patients (7.9%) 4 patients (5.3%) Dry throat 1 patient 1 patient 3 patients (3.9%) 0 patients Flare-up of COPD (COPD) 0 patients 1 patient 1 patient 3 patients (4.0%) Some patients left the study because of side effects. The percentage of patients who left the study because of side effects was similar in all groups. Overall, 5 patients (6.6%) in the combination 1 group, 4 patients (5.3%) in the combination 2 group, 5 patients (6.6%) in the tiotropium group, and 4 patients (5.3%) in the placebo group left the study because of side effects. A higher percentage of patients in the combination 1 (10.5%) and tiotropium (14.5%) groups than in the combination 2 (3.9%) and placebo (5.3%) groups had serious side effects. One patient in the placebo group had a serious side effect that was believed to be caused by the study medicines. No patients in the combination 1, combination 2, or tiotropium groups had serious side effects believed to be caused by the study medicines. Patients who had serious side effects had to go to the hospital or stay in the hospital. Their side effects needed urgent attention by a doctor, or were life-threatening. In some cases, patients died from serious side effects. Page 6 of 7

7 During the trial, 2 patients died. One patient who died was in the placebo group. The other patient who died was in the combination 2 group. The study doctor did not believe that their deaths were related to the study medicines. What else is important to know? Comments on the study This summary only shows results from this study. Other studies may have different results. This summary was written in July Important notice This study does not represent all the knowledge about the medications studied. Patients should not change their current therapy based on their understanding of the results from any single study. Patients should talk with their physician before making any changes in their therapy. Are there follow-up studies? No follow-up studies are planned. Where can I find more information? The protocol number of the study is The full title of the study is: An exploratory, 12 week, randomised, partially double-blinded, placebo-controlled, parallel group trial to explore the effects of once daily treatments of orally inhaled tiotropium + olodaterol fixed dose combination or tiotropium (both delivered by the Respimat inhaler), supervised exercise training and behaviour modification on exercise capacity and physical activity in patients with Chronic Obstructive Pulmonary Disease (COPD) [PHYSACTO TM ] Please visit the following website to find a scientific summary of the study results: You can find more details at by searching for the NCT number () at Page 7 of 7