The Role of Physical Activity, Malnutrition and Sarcopenia for the Prediction of Acute Exacerbations and the Evolution of COPD Assessment Test (CAT) in Patients With COPD
Conditions: COPD
Sponsor: Cantonal Hospital of St. Gallen

s wi s s e t h i c s  
Schweizerische Ethikkommissionen für die Forschung am Menschen 
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Commissioni etiche svizzere per la ricerca sull'essere umano 
Swiss Ethics Committees on research involving humans 
 
Project plan template 
Human research other than clinical trials 
 
v1.0, 17.05.2018 
The role of physical activity, malnutrition and sarcopenia for the 
prediction of acute exacerbations and the evolution of COPD 
assessment test (CAT) in patients with COPD 
 
 
 
 
Research legislation: 
 Ordinance on human research with the exception of Clinical trials 
(HRO) [1]. 
 
 
Type of Research Project: 
Research project involving human subjects (clinical cohort study) 
 
 
Risk Categorisation:  
Category A 
 
 
Project Leader: 
 Maximilian Bösch, PhD, Clinical Project Leader, Lungenzentrum 
St. Gallen, Kantonsspital St. Gallen, Rorschacherstrasse 95, 9007 
St. Gallen, Phone: +41 71 494 7143, Fax: +41 71 494 6118, Email: 
Maximilian.Boesch@kssg.ch 
 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS 
3 
GLOSSARY OF ABBREVATIONS 
4 
1 BACKGROUND AND PROJECT RATIONALE 
5 
2 PROJECT OBJECTIVES AND DESIGN 
5 
2.1 Hypothesis and primary objective 
5 
2.2 Primary and secondary endpoints 
5 
2.3 Project design 
5 
3 PROJECT POPULATION AND STUDY PROCEDURES 
6 
3.1 Project population, inclusion and exclusion criteria 
6 
3.2 Recruitment, screening and informed consent procedure 
6 
3.3 Study procedures 
6 
3.4 Withdrawal and discontinuation 
6 
4 STATISTICS AND METHODOLOGY 
6 
4.1. Statistical analysis plan 
6 
4.2. Handling of missing data 
7 
5 REGULATORY ASPECTS AND SAFETY 
7 
5.1 Local regulations / Declaration of Helsinki 
7 
5.2 Notification of safety and protective measures (HRO Art. 20) 
7 
5.3 Serious events (HRO Art. 21) 
7 
5.4 Radiation 
7 
5.5 Amendments 
7 
5.6 End of project 
7 
5.7 Insurance 
8 
6 FURTHER ASPECTS 
8 
6.1 Overall ethical considerations 
8 
6.2 Risk-Benefit Assessment 
8 
6.3 Rationale for the inclusion of vulnerable participants 
8 
7 QUALITY CONTROL AND DATA PROTECTION 
8 
7.1 Quality measures 
8 
7.2 Data recording and source data 
8 
7.3 Confidentiality and coding 
8 
7.4 Retention and destruction of study data and biological material 
9 
8  FUNDING / PUBLICATION / DECLARATION OF INTEREST 
9 
9 REFERENCES 
9 
10 LITERATURE CITED 
9 
Appendix 1: Schedule of assessments 
10 
 
 

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GLOSSARY OF ABBREVATIONS 
 
AECOPD 
Acute exacerbations of COPD 
BASEC 
Business Administration System for Ethical Committees 
BIA 
Bioelectrical impedance analysis 
BMI 
Body mass index 
CAT 
COPD assessment test 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case report form 
CRP 
C-reactive protein 
DXA 
Dual-energy X-ray absorptiometry 
FEV1 
Forced expiratory volume in 1 second 
FFMI 
Fat free mass index 
FOPH 
Federal Office of Public Health 
FVC 
Forced vital capacity 
HGS 
Hand grip strength 
HRA 
Human Research Act 
HRO  
Ordinance on Human 
SO 
Sarcopenic obesity 
THC 
Telehealth care 
 
 
 
 
 

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1 
BACKGROUND AND PROJECT RATIONALE  
A low body mass index (BMI) has been described as an independent risk factor for mortality in 
subjects with chronic obstructive pulmonary disease (COPD), while the association was 
strongest in patients with severe COPD 1. Additionally, weight loss in the course of the disease 
was associated with increased mortality 2. 
A low fat free mass index (FFMI) was also associated with increased overall and COPD-related 
mortality, even in subjects with normal BMI 3. FFMI seems to be a better predictor of disease 
severity regarding the degree of chronic dyspnea, forced expiratory volume in 1 second (FEV1), 
FEV1/forced vital capacity (FVC) ratio and stage of disease than BMI 4. Patients with the 
constellation of abdominal obesity, normal weight and low muscle mass have an increased 
cardiometabolic risk 5. FFMI also correlates with quality of life 6. Sarcopenic obesity (SO) is 
associated with worse physical performance and higher systemic inflammatory burden 
compared with other body composition phenotypes in COPD 7. Sarcopenia affects 15% of 
patients with stable COPD and impairs function and health status. Sarcopenia does not impact 
on response to pulmonary rehabilitation (PR), which can lead to a reversal of the syndrome in 
select patients 8. Body composition evaluation is useful for the assessment of COPD patients 
referred to pulmonary rehabilitation and should be routinely performed 9. A well-balanced diet is 
beneficial to all COPD patients, not only for its potential pulmonary benefits, but also for its 
proven benefits in metabolic and cardiovascular risk 10. 
If our hypothesis proves to be true, the clinical consequence would be the need to 
systematically include nutritional assessment / therapy and other measures to reduce 
malnutrition and sarcopenia in the clinical routine of treating COPD patients to reduce overall 
risk of acute exacerbation of COPD (AECOPD) and improve quality of life. 
The study is of risk category A since there are no relevant risks for participating patients (the 
study poses no additional risks to the patients compared to routine care). 
2 
PROJECT OBJECTIVES AND DESIGN  
2.1 Hypothesis and primary objective 
The primary objective is to investigate the association between physical activity, malnutrition 
and sarcopenia and the occurrence of AECOPD / the evolution of the COPD assessment test 
(CAT) over 1 year in a cohort of COPD patients. We hypothesize that being malnourished 
and/or sarcopenic at baseline and a decline of FFMI over time is associated with an increased 
rate of AECOPD and an increased (or increasing) CAT score. 
2.2 Primary and secondary endpoints 
The primary endpoint is the rate of exacerbation depending on the explanatory variables FFMI, 
hand grip strength (HGS) and C-reactive protein (CRP), measured at baseline, after 6 and after 
12 months. We will examine the correlation between the evolution of FFMI/HGS/CRP and the 
occurrence of AECOPD / the evolution of the CAT. 
Secondary endpoints include further parameters from our COPD cohort, such as physical 
activity and further biochemical markers (e.g., protein, albumin, 25-OH vitamin D3), which will 
be analyzed by descriptive statistics (including cross-sectional and longitudinal analyses). 
 
2.3 Project design 
A national, monocentric, prospective, observational, exploratory cohort study. 

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3 
PROJECT POPULATION AND STUDY PROCEDURES 
3.1 Project population, inclusion and exclusion criteria  
Inclusion: any patient with COPD GOLD stage B or higher giving written informed consent to 
participate. The study population will consist of our current telehealth care (THC) cohort of 
COPD patients as well as newly recruited COPD patients. 
Exclusion: any patient who is unable to provide informed consent or to follow the trial 
procedures. Insufficient knowledge of the trial language is therefore a reason of exclusion. 
3.2 Recruitment, screening and informed consent procedure 
Patients will be mainly recruited from our established THC cohort of COPD patients 11 by 
dedicated study nurses of the Lungenzentrum St. Gallen at the Kantonsspital St. Gallen (phone 
calls and, if necessary, other channels of communication). New participating patients will also 
be acquired, namely through ongoing recruitment by the referring physicians in daily practice. 
All referred COPD patients will be screened systematically by our study nurses on a daily basis. 
Screening procedures for study inclusion involve routine daily practices. Eligible patients will be 
informed about the study through personal communication and, if willing to participate, provided 
with the dedicated informed consent sheet sent along with this proposal. Written informed 
consent is a prerequisite for study inclusion. No compensation payments will be distributed. 
3.3 Study procedures 
All patients will be followed using the THC procedure as previously described 11, 12. Specifically, 
the CAT score is measured once per week and patients answer questions on a daily basis that 
aim at the early detection of AECOPD. The study duration is one year per patient. 
In addition, we will measure body composition (e.g., FFMI and fat share) by direct segmental 
multi-frequency bioelectrical impedance analysis (BIA) and/or dual-energy X-ray absorptiometry 
(DXA), HGS (with a dynamometer) and biochemical parameters (e.g., CRP, protein, albumin, 
25-OH vitamin D3). These measurements will take place at baseline and after 6 and 12 months. 
Furthermore, patients are provided with a pedometer to record step count and/or an 
accelerometer to record overall movement/distance traveled. This might be complemented by a 
standardized sit-to-stand physical test at each visit (baseline, 6 and 12 months). We will assess 
the nutritional status by standardized questionnaires (Nutritional Risk Screening [NRS] 2002; in 
case of PDOQXWULWLRQ ³1XWULWLRQDO $VVHVVPHQW´ DFFRUGLQJ WR ORFDO JXLGHOLQHV DQG SURYLGH
nutritional support/therapy by professional personnel. In the final analysis, receipt of nutritional 
support/therapy will be one parameter stratified for. Nutritional parameters will be assessed at 
baseline and after 6 and 12 months. Schedule of assessment in appendix 1. 
3.4 Withdrawal and discontinuation 
Patients are withdrawn from the study by virtue of their own will at any time. 
4 
STATISTICS AND METHODOLOGY 
4.1. Statistical analysis plan 
A sample size of 85 patients is envisaged to be able to detect a significant association 
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exacerbation rate with 80% power at a 5% significance level (two-sided). 
The evolution of the FFMI will be analyzed using linear regression. The association between the 
FFMI and the occurrence of AECOPD will be evaluated using the Andersen-Gill formulation of 
the Cox proportional hazard model as well as joint modeling useful for the analysis of recurrent 
time-to-event data (exacerbation) with time-varying predictors (FFMI). The association between 

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FFMI and CAT will be estimated using linear mixed models or alternately generalized estimating 
equations. 
4.2. Handling of missing data 
The patients expected to be enrolled in the current study consist of patients from our previous 
THC cohort willing to participate in this extension study (approx. 100 patients). Assuming a 
dropout rate of 15% (including patients not willing to participate to the extension study as well as 
patients dropping out in the course of the study), we are expecting to enroll 85 patients in the 
study. Potential dropouts beyond 15% will not be replaced. If a patient withdraws her/his 
consent during the course of the study, no further data will be collected. However, data that 
have been collected before withdrawal will be used for the final analysis. 
5 
REGULATORY ASPECTS AND SAFETY 
5.1 Local regulations / Declaration of Helsinki 
This research project will be conducted in accordance with the protocol, the Declaration of 
Helsinki [3], the principles of Good Clinical Practice, the Human Research Act (HRA) and the 
Human Research Ordinance (HRO) [1] as well as other locally relevant regulations. The Project 
Leader acknowledges his responsibilities as the Project Leader. 
5.2 Notification of safety and protective measures (HRO Art. 20) 
The Project Leader and/or the sponsor are promptly notified (within 24 hours) if immediate 
safety and protective measures have to be taken during the conduct of the research project. 
The Ethics Committee will be notified via Business Administration System for Ethical 
Committees (BASEC) of these measures and of the circumstances necessitating them within 7 
days. 
5.3 Serious events (HRO Art. 21) 
If a serious event occurs, the research project will be interrupted and the Ethics Committee 
notified on the circumstances via BASEC within 7 days according to HRO Art. 211. 
5.4 Radiation 
Not applicable. 
5.5 Amendments 
Substantial changes to the project set-up, the protocol and relevant project documents will be 
submitted to the Ethics Committee for approval according to HRO Art. 18 before 
implementation. Exceptions are measures that have to be taken immediately in order to protect 
the participants. 
5.6 End of project 
Upon project termination, the Ethics Committee is notified within 90 days. In the unlikely event 
that the trial is terminated prematurely, the Ethics Committee is notified within 15 days 
                                                        
1 A serious event is defined as any adverse event where it cannot be excluded, that the event is attributable to the 
sampling of biological material or the collection of health-related personal data, and which: 
a. requires inpatient treatment not envisaged in the protocol or extends a current hospital stay; 
b. results in permanent or significant incapacity or disability; or 
c. is life-threatening or results in death. 

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(including a statement of the reasons for premature termination). Health-related data are 
anonymized upon trial termination. 
5.7 Insurance 
In the event of project-related damage or injuries, the liability of the Kantonsspital St. Gallen 
provides compensation, except for claims that arise from misconduct or gross negligence. 
6 
FURTHER ASPECTS 
6.1 Overall ethical considerations 
Refined prediction of AECOPD leading to timely intervention will positively influence the QoL of 
the individual study participant. Results from the study are thought to be generalizable among 
COPD patients. No incidental findings with immediate relevance to the study participant are 
expected to be made, and genetic findings are anyway precluded in this observational cohort 
study. The study design is perfectly suited to longitudinally track different clinical parameters 
and to assess the evolution of the CAT. The time effort that the participants have to take is 
absolutely reasonable. 
6.2 Risk-Benefit Assessment  
The study poses no additional risks to the patients compared to routine care. The patients can 
benefit from the study through earlier recognition of clinical deterioration, thus allowing for 
earlier therapeutic intervention and attenuation (or even prevention) of disease exacerbation. 
6.3 Rationale for the inclusion of vulnerable participants  
Not applicable. 
7 
QUALITY CONTROL AND DATA PROTECTION 
7.1 Quality measures  
The trial personnel are trained for all important trial aspects. For the purpose of quality 
assurance, audits or site visits may be performed by the Ethics Committee. Direct access to the 
source data and all project-related files and documents is granted on such occasions. 
7.2 Data recording and source data 
Trial data is recorded with paper Case Report Forms (CRF). At the end of the trial, all data is 
transferred to an electronic database for analysis. Source data according to section 2. 
7.3 Confidentiality and coding 
Project data will be handled with uttermost discretion and is only accessible to authorized 
personnel who require the data to fulfil their duties within the scope of the research project. On 
the CRFs and other project specific documents, participants are only identified by a unique 
participant number. The study nurse stores the subject identification list under closure. Data 
protection is warranted respecting the Swiss data protection legislation. 
 
 

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7.4 Retention and destruction of study data and biological material 
All trial data, including documents necessary for patient identification and post-trial care, must 
be archived for a minimum of 10 years upon trial termination. All data are stored on a secure 
and regularly backed-up server provided by KSSG. 
8  FUNDING / PUBLICATION / DECLARATION OF INTEREST 
This project is funded by the Lungenliga St. Gallen and internal funds from the KSSG. It is 
planned that results from the study are published in a peer-reviewed journal, possibly in an 
open access format. The planned authorship (first/last author) for the main publication (in case 
of different emerging publications) will be: Frank Rassouli and Maximilian Bösch as co-first 
authors, and Martin Brutsche as last author. There are no conflicts of interest to declare. 
9 
REFERENCES 
1. 
Ordinance on Human Research with the Exception of Clinical trials (HRO)  
http://www.admin.ch/opc/en/classified-compilation/20121177/201401010000/810.301.pdf  
2. 
Human Research Act (HRA) 
http://www.admin.ch/opc/en/classified-compilation/20121176/201401010000/810.305.pdf  
3. 
Declaration of Helsinki (http://www.wma.net/en/30publications/10policies/b3/index.html) 
4. 
STROBE statement (http://www.jclinepi.com/article/S0895-4356(07)00436-2/pdf) 
10 LITERATURE CITED 
1. 
Landbo C, Prescott E, Lange P, et al. Prognostic value of nutritional status in chronic obstructive 
pulmonary disease. Am J Respir Crit Care Med 1999;160:1856-61. 
2. 
Prescott E, Almdal T, Mikkelsen KL, et al. Prognostic value of weight change in chronic 
obstructive pulmonary disease: results from the Copenhagen City Heart Study. Eur Respir J 
2002;20:539-44. 
3. 
Vestbo J, Prescott E, Almdal T, et al. Body mass, fat-free body mass, and prognosis in patients 
with chronic obstructive pulmonary disease from a random population sample: findings from the 
Copenhagen City Heart Study. Am J Respir Crit Care Med 2006;173:79-83. 
4. 
Ischaki E, Papatheodorou G, Gaki E, et al. Body mass and fat-free mass indices in COPD: 
relation with variables expressing disease severity. Chest 2007;132:164-9. 
5. 
Beijers R, van de Bool C, van den Borst B, et al. Normal Weight but Low Muscle Mass and 
Abdominally Obese: Implications for the Cardiometabolic Risk Profile in Chronic Obstructive 
Pulmonary Disease. J Am Med Dir Assoc 2017;18:533-538. 
6. 
Pothirat C, Chaiwong W, Phetsuk N, et al. The Relationship between Body Composition and 
Clinical Parameters in Chronic Obstructive Pulmonary Disease. J Med Assoc Thai 2016;99:386-
93. 
7. 
Joppa P, Tkacova R, Franssen FM, et al. Sarcopenic Obesity, Functional Outcomes, and 
Systemic Inflammation in Patients With Chronic Obstructive Pulmonary Disease. J Am Med Dir 
Assoc 2016;17:712-8. 
8. 
Jones SE, Maddocks M, Kon SS, et al. Sarcopenia in COPD: prevalence, clinical correlates and 
response to pulmonary rehabilitation. Thorax 2015;70:213-8. 
9. 
Gologanu D, Ionita D, Gartonea T, et al. Body composition in patients with chronic obstructive 
pulmonary disease. Maedica (Buchar) 2014;9:25-32. 
10. 
Schols AM, Ferreira IM, Franssen FM, et al. Nutritional assessment and therapy in COPD: a 
European Respiratory Society statement. Eur Respir J 2014;44:1504-20. 
11. 
Rassouli F, Pfister M, Widmer S, et al. Telehealthcare for Chronic Obstructive Pulmonary 
Disease in Switzerland Is Feasible and Appreciated by Patients. Respiration 2016;92:107-13. 
12. 
Rassouli F, Baty F, Stolz D, et al. Longitudinal change of COPD assessment test (CAT) in a 
telehealthcare cohort is associated with exacerbation risk. Int J Chron Obstruct Pulmon Dis 
2017;12:3103-3109. 
 
 

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Appendix 1: Schedule of assessments 
 
Time (months) 
>-1 day 
0 
+6 
+12 
 
Information Screening  
1st visit 
2nd visit 
Oral 
and 
written 
information 
+ 
 
 
 
Written consent 
 
+ 
 
 
Check inclusion-/ 
exclusion criteria 
 
+ 
 
 
Medical history 
 
+ 
 
 
Participant 
characteristics  
 
+ 
 
 
CAT score 
 
+ 
+ 
+ 
Procedures 
(FFMI, 
BIA, DXA, HGS, etc.) 
 
+ 
+ 
+ 
Questionnaire (NRS) 
 
+ 
+ 
+ 
Sampling 
 
+ 
+ 
+ 
Data analysis 
 
 
+ 
+