Mitigating the Health Effects of Desert Dust Storms Using Exposure-Reduction Approaches: Assessment of Health Outcomes in Children With Asthma and in Adults With Atrial Fibrillation During Desert Dust Storms (With vs Without Interventions)
Phase: NA
Conditions: Asthma in Children, Atrial Fibrillation
Sponsor: University of Cyprus

Life+ MEDEA Action C8 Protocol, Version 1.0 
                                
April 2018 
Mitigating the Health Effects of Desert Dust 
Storms Using Exposure-Reduction 
Approaches    
(MEDEA) project 
 
 
ACTION C.8: Assessment of health outcomes 
in adults with atrial fibrillation during desert 
dust storm (DDS) events (with vs without 
intervention measures) 
 
Public Health Intervention Study 
Protocol Template 
(April 2018) 
 
 

Life+ MEDEA Action C8 Protocol, Version 1.0 
                                
April 2018 
MITIGATING THE HEALTH EFFECTS OF DESERT DUST STORMS 
USING EXPOSURE-REDUCTION APPROACHES    
(MEDEA) PROJECT 
 
 
ACTION C.8: ASSESSMENT OF HEALTH OUTCOMES IN ADULTS 
WITH ATRIAL FIBRILLATION (AF) DURING 
DESERT DUST STORM (DDS) EVENTS (WITH VS WITHOUT 
INTERVENTION MEASURES) 
Principal Investigator: 
Name: Dr. Panayiotis Yiallouros 
Position: Professor of Paediatrics 
Department: Medical School 
University: University of Cyprus  
 
Action Leader: 
Name: Dr Victor Novack 
Position: Professor of Medicine and Head of the Clinical Research Center, Soroka University 
Medical Center and Ben-Gurion University of the Negev  
Department: Soroka University Medical Center 
University: Ben Gurion University of the Negev 
Supported by: 
LIFE+ 2016 
The MEDEA project is funded by the European LIFE+ 2016 Climate Change Adaptation 
programme 
 (LIFE16 CCA/CY/000041) 

Life+ MEDEA Action C8 Protocol, Version 1.0 
                                
April 2018 
Version 1  
April, 2018 
 
 
 
 
 
TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS ............................................................................................................. ii 
STUDY TEAM ROSTER............................................................................................................ iv 
Local Study Coordinator: Dr. Panayiotis Yiallouros .............................................................. iv 
Summary ........................................................................................................................................ 1 
Study Title ................................................................................................................................... 1 
Objectives ................................................................................................................................... 1 
Design, Interventions and Outcomes .......................................................................................... 1 
Study Population ......................................................................................................................... 3 
1 
WORKING HYPOTHESIS ................................................................................................. 3 
2 
STUDY OBJECTIVES ......................................................................................................... 3 
2.1 
Primary Objective ........................................................................................................... 3 
2.2 
Secondary Objectives...................................................................................................... 4 
3 
BACKGROUND AND RATIONALE ................................................................................ 4 
3.1 
Background on Condition, Disease, or Other Primary Study Focus .............................. 4 
3.2 
Study Rationale ............................................................................................................... 5 
4 
STUDY DESIGN ................................................................................................................... 6 
5 
SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................ 7 
5.1 
Inclusion Criteria ............................................................................................................ 7 
5.2 
Exclusion Criteria ........................................................................................................... 7 
5.3 
Study Enrollment Procedures ......................................................................................... 8 

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STUDY INTERVENTIONS ................................................................................................ 8 
6.1 
Interventions, Administration, and Duration .................................................................. 8 
6.2 
Handling of Study Interventions ................................................................................... 10 
6.3 
Adherence Assessment ................................................................................................. 10 
7 
STUDY PROCEDURES .................................................................................................... 11 
7.1 
Schedule of Evaluations ................................................................................................ 11 
7.2 
Description of Evaluations ............................................................................................ 12 
7.2.1 Screening and Enrollment Evaluation ...................................................................... 12 
7.2.2 Baseline Assessment and Randomization ................................................................. 12 
7.2.3 Follow-up Assessments ............................................................................................ 13 
7.2.4 Completion/Final Evaluation .................................................................................... 13 
8 
STATISTICAL CONSIDERATION AND ANALYSIS PLAN ...................................... 13 
8.1 
Sample size consideration ............................................................................................. 13 
8.2 
Statistical analysis ......................................................................................................... 14 
8.2.1 
Descriptive statistics ................................................................................................. 14 
8.2.2 Univariate analysis .................................................................................................... 14 
8.2.3 Multivariate analysis ................................................................................................. 15 
9 
ASSESSMENTS OF ADVERSE EVENTS ...................................................................... 15 
10 INTERVENTION DISCONTINUATION........................................................................ 16 
11 DATA COLLECTION ....................................................................................................... 16 
11.1 
Data Collection Forms .................................................................................................. 16 
11.2 
Data Management ......................................................................................................... 17 
12 PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................. 17 
12.1 
Informed Consent Forms .............................................................................................. 17 
12.2 
Participant Confidentiality ............................................................................................ 17 
13 ETHICAL CONSIDERATIONS ....................................................................................... 18 
14 COMMITTEES................................................................................................................... 19 
15 REFERENCES .................................................................................................................... 19 
16 SUPPLEMENTS/APPENDICES ...................................................................................... 20 
 I. Informed Consent Form Template 

Life+ MEDEA Action C8 Protocol, Version 1.0 
                                
April 2018 
STUDY TEAM ROSTER  
   
Cyprus 
Local Study Coordinator: Dr. Panayiotis Yiallouros 
Address: Medical School 
University of Cyprus 
215/6 Palaios dromos, Nicosia-Limassol 
2029 Aglantzia 
Nicosia, Cyprus 
Telephone: 22895212 
Fax: 22895396 
e-mail address: yiallouros.panayiotis@ucy.ac.cy 
Cyprus team members: 
Dr Vasilis Yiannikourides 
Dr Panayiotis Avraamides 
Dr Rozalia Nicolaou 
Dr Elias Papasavvas 
Panayiotis Kouis, PhD 
Maria Kakkoura, PhD 
Paraskevi Kinni 
Margarita Kaliva 
 
 
Greece 
Local Study Coordinator: Dr. Emmanouel Simantirakis 
Address: School of Medicine,  
University of Crete, 
Voutes Campus, 
Heraklion, Crete, 
GR-71003, Greece 
Greece team members 
Dr George Kochiadakis 
Dr Michalis Vernardos 
Dr Lena Dimitriou 
 
 
Israel 
Local Study Coordinator: Dr. Victor Novack 
Address: Soroka University Medical Center,  
POB 151, Beer-Sheva, Israel 
Ben Gurion University of the Negev, 
P.O.B. 653 Beer-Sheva 8410501 Israel 
Israel team members 
Michal Kamenetskii 
Shaked Yarza

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SUMMARY 
Study Title  
Mitigating the Health Effects of Desert Dust Storms Using Exposure-Reduction Approaches 
(LIFE+ MEDEA) 
Objectives  
The primary objective of this panel study will be to quantify the vulnerability of adults with atrial 
fibrillation (AF) during desert dust storm (DDS) outbreaks and provide evidence-based estimates 
demonstrating which intervention/ recommendations work best in mitigating adverse health effects 
in this group of patients (primary outcome: reduction of atrial fibrillation burden by 20%) after 
randomization to three parallel intervention groups: 
a) no intervention for DDS 
b) intervention for outdoor exposure reduction, and  
c) interventions for both outdoor and indoor exposure reduction 
 
The secondary objectives of the study are to: 
1. Demonstrate which of the recommendations are effective in reducing outdoor and indoor 
exposures to DDS in a panel of adults with atrial fibrillation (AF) 
2. Secondary health outcomes will be the occurrence of ventricular arrhythmias assessed 
through the pacemaker and heart rate variability. 
Design, Interventions and Outcomes   
Type of study: Public Health Intervention Study  
 
Intervention: Patients with AF will be recruited and will be randomized during the high DDS 
outbreaks season (Spring 2019 and 2020) with 1:1:1 ratio into three parallel groups to receive:  
a)  No intervention for DDS. 
b)  Intervention for outdoor exposure reduction, by reducing the time spend outdoors  
     and by avoiding physical activity. 
c) Interventions for outdoor (as above) and indoor exposure reduction (by minimizing home 
ventilation and filtering indoor air). 
 
Disease-related adverse health outcomes will be assessed in the three parallel arms of the study.  
 
Approaches for delivering the intervention:  
 A bidirectional, patient-centered e-Platform will be developed in order to facilitate prompt 
communication with the participants and provide early warnings regarding forecasted 

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upcoming DDS events through text messaging and smartphone applications. Furthermore, 
the same IT platform and mobile application will be utilised for the dissemination of the 
exposure reduction guidelines that the participants will follow, depending on which arm 
of the study they have been randomised to. 
 
Assessment of adherence to intervention:  
 Monitor compliance to exposure-reduction guidelines using remote sensors. The 
intervention for outdoor exposure reduction, entailing reduction of the time spend 
outdoors and avoidance of physical activity, will be assessed with the use of smart 
wristwatches that will have a global position system (GPS) and an accelerometer. 
 The intervention for indoor exposure reduction, entailing minimization of home 
ventilation and filtering of indoor air, will be assessed with the use of particle samplers 
that will be placed outside and inside of houses and school classrooms. 
 
Assessment of health outcomes: 
 Daily recordings of AF/ventricular arrhythmia episodes from the participants’ 
pacemakers during the 4-month study period will be downloaded with interrogation of 
the pacemaker during a visit to the Arrhythmia Clinic after the end of the monitoring 
period. 
 Phone interviews every 1 month throughout the high DDS period recording symptoms 
of fatigue, change in medication use, and unscheduled visits to health professionals for 
heart arrhythmias/episodes. 
 Continuous recordings of biological parameters (pulse rate, pulse rate variability, 
temperature) will be obtained by wearing smart watch sensors that will be uploaded on 
line to e-platform.  
 
Primary health outcome will be every detected high atrial frequency episode of >330 ms (180 
beats per minute) lasting for longer than 30 s with an atrial sensitivity of 0.5 mV (assumed as an 
episode of AF). AF burden is defined as the overall time percentage with AF during the observed 
period. For the primary analysis, we will compare the combined effect in the two intervention 
groups versus the control group. Secondarily, the effectiveness of each intervention will be 
compared versus the control group and to each other. 
Secondary health outcomes will be the occurrence of ventricular arrhythmias assessed through 
the pacemaker and heart rate variability. 
 
Duration  
 
Duration of the study: A feasibility (pilot) trial and refinement of protocols and tools will be 
performed during the high DDS outbreaks season of 2018. During the fall of 2018 and 2019, 
MEDEA personnel will initiate the recruitment procedure to enrol eligible AF patients for the two 

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main study periods (high DDS outbreaks season of February to May 2019 and 2020). Data 
collection, data cleaning and statistical analysis will take place in 2020. 
Study Population  
Study population, sample size and location: Men and women with prior implantation of a dual lead 
(atrial and ventricular) pacemaker or ICD, will be recruited from cardiac arrhythmia clinics in 
General Hospital in Nicosia-Cyprus (n=156) in project years 2018-2019 and 2019-2020. 
Recruitment of participants will be facilitated through the network of physicians in Nicosia 
General Hospital. In order to facilitate recruitment, relations will be established with the 
Administrative and Nursing staff of the Clinics and Patients’ Associations and the details of the 
project will be explained to them. During fall 2018 and 2019, MEDEA personnel will start 
recruitment efforts to detect eligible AF patients for participation in the study in the high DDS 
periods of February-May 2019 and 2020.  
The same number of patients will be recruited in each study site (Beer Sheba, Heraklion, Nicosia) 
and we expect that a total of 468 AF patients will be recruited. We estimate a dropout rate of 30%, 
which will eventually give us 324 AF patients to analyse. The feasibility of protocols to assess 
health outcomes in vulnerable patient groups will be tested in the pilot study during the high DDS 
outbreaks season of 2018 with and without implementation of exposure reduction guidelines in all 
study sites in a small number of patients (6 AF patients per study site).  
 
1 
WORKING HYPOTHESIS 
We hypothesize that there will be a reduction of the total AF burden compared to the control 
group in: 
a) The group with intervention aimed to outdoor exposure reduction (b). 
b) The group with intervention aimed to outdoor and indoor exposure reduction (c). 
c) Both (b) and (c) groups combined as compared to the control. 
 
2 
STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this panel study will be to quantify the vulnerability of adults with atrial 
fibrillation (AF) during DDS outbreaks and provide evidence-based estimates demonstrating 
which intervention/ recommendations work best in mitigating adverse health effects in this group 
of patients (primary outcome: reduction of atrial fibrillation burden by 20%) after randomization 
to three parallel intervention groups: 

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a) no intervention for DDS 
b) intervention for outdoor exposure reduction, and  
c) interventions for both outdoor and indoor exposure reduction 
 
The primary health outcome will be defined by using every detected high atrial frequency episode 
of >330 ms (180 beats per minute) lasting for longer than 30 s with an atrial sensitivity of 0.5 mV 
(assumed as an episode of AF). AF burden is defined as the overall time percentage with AF during 
the observed period. For the primary analysis, we will compare the combined effect in the two 
intervention groups versus the control group. Secondarily, the effectiveness of each intervention 
will be compared versus the control group and to each other. 
 
2.2 Secondary Objectives 
The secondary objectives of the study are to: 
1. Demonstrate which of the recommendations are effective in reducing outdoor and indoor 
exposures to DDS in a panel of adults with atrial fibrillation (AF) 
2. Secondary health outcomes will be the occurrence of ventricular arrhythmias assessed 
through the pacemaker and heart rate variability. 
 
3 
BACKGROUND AND RATIONALE  
3.1 Background on Condition, Disease, or Other Primary Study Focus 
 
The MEDEA project is envisioned to provide the field-based evidence for the adoption of a 
strategic plan for mitigating the health effects of desert dust storm (DDS) events in South-
Eastern Europe. Over the past decade, several studies have demonstrated that DDS in 
Mediterranean countries, originating mostly from the Sahara and Arabian Peninsula deserts, 
have been increasing in number and magnitude and linked it to desertification, climatic 
variability and global warming. EU legislation considers DDS impossible to prevent, 
implicitly harmless and discounts their contribution to daily and annual air quality standards 
of particulate matter up to 10 microns (PM10). 
However, there is increasing evidence from epidemiological studies which correlates 
exposure to PM10 during DDS with a significant increase in mortality and hospital 
admissions from cardiovascular and respiratory causes. Therefore, there is a pressing need 
for EU policies to reduce population exposures and increase individual, population and 
institutional resilience to the growing frequency and intensity of DDS. 
MEDEA ultimate goal is to demonstrate the feasibility and effectiveness of an adaptation 
strategy to DDS and better inform EU policy making. 

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3.2 Study Rationale 
Desert dust storm events across Southern Europe 
A dust storm is a phenomenon common to arid and semi-arid regions. In the EU, the term 
“Desert Dust Storms (DDS)” is used in the context of sandstorms originating primarily from 
the Sahara desert but also from the Arabian–Negev desert. The term DDS refers to the 
condition created when finer sand particulate matter (PM) from the desert surface is 
transported over a long distance. DDS pose a major risk to populations residing in affected 
areas, such as in Mediterranean countries belonging to the global dust belt, extending from 
West Africa to the Arabian Peninsula (Querol et al., 2009). During DDS events, which can 
last for several days, PM10 levels are considerably higher than the 2005 EU daily limit value 
of 50 μg/m3 (Achilleos et al, 2014). Dust PM is mostly composed of rock-forming and clay 
minerals and they may carry microbial agents, such as bacteria, fungi and viruses (Griffin et 
al, 2007), and mix with anthropogenic atmospheric pollutants during transport. 
 
Associations of DDS with mortality and hospital admissions 
Historically, DDS were not considered harmful to humans due to their natural origin and 
crustal composition; however, in recent years, a large number of studies worldwide and in 
particular from Cyprus (Middleton et al., 2008; Neophytou et al., 2013), Greece (Samoli et 
al., 2011), Italy (Mallone et al., 2011) and Israel (Vodonos et al., 2014) have reported 
associations of PM10 during DDS outbreaks with increased hospital admissions for asthma, 
chronic obstructive pulmonary disease, cardiovascular disease and increased mortality. The 
pathogenic effect of PM10 inhalation has been attributed to direct physical and toxic action of 
particles on human airway epithelium and systemic inflammatory responses triggering 
endothelial dysfunction or dysfunction of the autonomic nervous system (Leski et al., 2011). 
Increased hospital admissions and mortality are only two of a much larger number of adverse 
outcomes of exposure to DDS PM10. Beyond these serious complications, patients suffer 
symptomatic exacerbations of pre-existing conditions, require unscheduled hospital visits, use 
excessive medications, and lose their sense of well-being, often with days off work or school. 
These relatively less studied consequences are more common, but largely un-quantified and 
un-investigated. Finally, DDS PM10 exposure is associated with sub clinical effects on the 
general population, from mild discomfort, eye and skin irritation to substantial effects on 
biological processes and quality of life. 
 
Framework for designing, implementing and testing an adaptability strategy 
Our knowledge of the health risks associated with exposures to DDS PM in southern Europe 
comes mostly from small-scale local or national studies. Despite their limited scope, these 
investigations have provided sufficient evidence of a real human health risk affecting a large 
proportion of the EU population. Reversing the unfavourable climate trends that are 
exacerbating the effect of DDS in the region is a daunting task, and the benefits of global 
climate change policies will take decades to realize. 

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At the moment, the EU national competent authorities and mass media in the DDS-exposed 
regions, during some of the events, issue not-standardised recommendations to the 
public/vulnerable groups, most commonly advising them to stay indoors, and reduce outdoor 
activities. To date, no scientific evidence exists on the effectiveness of any of these 
recommendations in either reducing the exposure to DDS PM or mitigating related health 
effects. The EU needs to develop evidence-based policies that increase individual, population, 
and institutional resilience to the growing frequency and intensity of DDS. We propose in 
three of the most heavily DDS-affected Mediterranean regions (Cyprus, Crete, and Israel) to 
apply, test and demonstrate the efficacy of patient-specific and population-wide public health 
interventions to reduce personal exposures to DDS as a means of adaptation. 
 
This study will address a significant knowledge gap in the health effects of personal exposures 
to desert dust particles, and establish vulnerability assessments in groups such as adults with 
AF, driven by our findings on the impact of the interventions on exposure, measures of health, 
and morbidity, thus enabling participant countries to build adaptation strategies and evidence-
based policies. During and after the end of the project, this information and knowledge will 
be used to fine-tune tools for informed decision-making and strategic planning both at national 
(individual country stakeholders) and cross national levels and will be disseminated to 
facilitate an exchange of best practices and raise awareness within the population on their 
vulnerability to DDS pollutants as set out in EU policy priorities. 
4 
STUDY DESIGN 
 
Type of study: Randomized clinical trial (Behavioural Intervention) 
 
Patients with AF will be recruited during DDS outbreaks and will be randomized into three 
parallel groups to receive: 
a) No intervention for DDS,  
b) Intervention for outdoor exposure reduction, and  
c) Interventions for both outdoor and indoor exposure reduction. 
 
Disease-related adverse health outcomes will be assessed in all the parallel arms of the study.  
 
Previous publications of the MEDEA partners (Achilleos et al, 2014; Gerasopoulos et al, 
2006; Krasnov et al, 2014), indicated that 2/3 of each year’s DDS events in the Eastern 
Mediterranean region appear during February-May, with 10-15% of the days during this 
period being “DDS days”. Thus we will perform this public health intervention study during 
February–May of 2019 and 2020. 
 

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Study population and location: Men and women with prior implantation of a dual lead (atrial 
and ventricular) pacemaker or ICD, will be recruited from the cardiac arrhythmia clinic at the 
Nicosia General Hospital of Cyprus (n=156) in project years 2018-2019 and 2019-2020. Each 
patient will have assessment of health outcomes during only one high DDS period. 
 
Duration of the study: A feasibility trial and refinement of protocols and tools will be 
performed in the high DDS period of 2018. In the fall of 2018 and 2019, MEDEA personnel 
will start recruitment efforts to detect eligible AF patients for participation in the study during 
the high DDS periods of February-May 2019 and 2020.  
 
Assessment of health outcomes: 
 The occurrence of AF/ventricular arrhythmia episodes will be recorded daily using the 
already implanted participants’ pacemakers or ICD during the 4-month study period. 
The recorded episodes will be downloaded with interrogation of the pacemaker or ICD 
during a visit to the Arrhythmia Clinic after the end of the study period. 
 Phone interviews every 1 month throughout the high DDS outbreaks season will be 
carried out. Data collected will include symptoms of fatigue, change in medication use 
and unscheduled visits to health professionals for heart arrhythmias/episodes. 
 Continuous recordings of biological parameters (pulse rate, pulse rate variability and 
temperature) obtained by wearing smart watch sensors and uploaded on line to the 
secure e-platform.  
 
 
5 
SELECTION AND ENROLLMENT OF PARTICIPANTS  
 
5.1 Inclusion Criteria  
 
The inclusion criteria for this panel study will be patients with permanent dual lead (atrial and 
ventricular) pacemaker or ICD implanted at least two months prior to randomization, with: 
 A history of AF or 
 Detection of AF in pacemaker/ICD monitoring (continuous recording) 
 
5.2 Exclusion Criteria  
 
Exclusion criteria will be:  
 Permanent AF 

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 Patients with reversible causes of AF (eg hyperthyroidism) 
 Inability to understand and use study tools (smartphones, software applications) 
 Terminal illness 
 Active smoking 
 Not living at least 5 days per week in the household 
 
5.3 Study Enrollment Procedures  
 
Men and women with prior implantation of a dual lead (atrial and ventricular) pacemaker or 
ICD, will be recruited from the cardiac arrhythmia clinic at Nicosia General Hospital in 
Cyprus (n=156) in project years 2018-2019 and 2019-2020. Recruitment of participants will 
be facilitated through the network of physicians at Nicosia General Hospital. In order to 
facilitate recruitment, relations will be established with the Administrative and Nursing staff 
of the Clinic and Patients’ Association and the details of the project will be explained to them. 
Patients will be able to ask questions and ask for clarification on all aspects of the program. 
Each patient participating in the program should complete the necessary consent forms 
(EKBK03 consent form, see Appendices).  
 
6 
STUDY INTERVENTIONS  
6.1 Interventions, Administration, and Duration  
 
Following recruitment, we will randomize participants with a 1:1:1 ratio to three parallel 
groups to receive: 
a) no intervention for DDS 
b) intervention for outdoor exposure reduction, by reducing the time spend outdoors and 
by avoiding physical activity 
c) interventions for outdoor (as above) and indoor exposure reduction (by minimizing 
home ventilation and filtering indoor air). 
 
In the indoor intervention arm of the study, exposure reduction measures will be applied in 
the patient’s household/bedroom settings. 
 
After randomization, and prior to the high DDS season, each eligible participant will complete 
a questionnaire, providing socio-demographic characteristics, detailed medical and 
medication history, and will be trained in the tools and procedures to be followed during the 
monitoring sessions while in the community.  

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The study design offers also the opportunity to assess: 
 outdoor exposures to PM,  
 indoor exposures to PM and  
 related health outcomes in three parallel groups during the same DDS events with and 
without intervention measures (Figure C8.1). 
 
 

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6.2 Handling of Study Interventions  
A bidirectional, patient-centered e-Platform will be created to: 
 Communicate promptly forecast alerts to individuals about upcoming DDS events 
through smartphone applications and text messaging 
 Disseminate exposure reduction guidelines 
 
In particular, in the group where there will be intervention for outdoor exposure reduction, the 
intervention will be carried out by: 
 
 Informing the participant for upcoming desert dust storm episodes.  
 Simultaneous transmission of instructions to patient’s smartphone to reduce 
outdoor exposure during the episode (stay indoors, avoid intense physical activity 
outdoors, avoid competitive sports, avoid unnecessary walks). 
 
In the group where there will be interventions for outdoor and indoor exposure reduction, the 
intervention will be carried out by:  
 
 Informing the participant for upcoming desert dust storm episodes.  
 Simultaneous transmission of instructions to patient’s smartphone to reduce a) 
outdoor exposure during the episode (stay indoors, avoid intense physical activity 
outdoors, avoid competitive sports, avoid unnecessary walks), and b) indoor, home 
exposure (closed windows and doors, sealing possible cracks around windows and 
doors in order to minimize home ventilation, and using an air cleaner in order to 
filter indoor air). 
6.3 Adherence Assessment  
The compliance to exposure-reduction guidelines will be monitored with the use of remote 
sensors. The intervention for outdoor exposure reduction, (by reducing the time spend 
outdoors and by avoiding physical activity) will be assessed with the use of smart 
wristwatches that will have global position system (GPS) and accelerometer. The intervention 
for indoor exposure reduction (by minimizing home ventilation and by filtering indoor air) 
will be assessed with the use of particle samplers that will be placed outside and inside houses. 
. 
 
 
 
 
 
 
 
 

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7 
STUDY PROCEDURES 
7.1 
Schedule of Evaluations 
 
Assessment 
Baseline 
Every 1 month  
 3 days. 
4 months  30 
days   
Informed Consent Form   
X 
 
  
Inclusion/Exclusion Criteria  
 X 
 
  
Demographics 
X 
X 
  
Medical History  
X 
X 
  
House assessment 
 
X 
 
Current Medications 
X 
X 
X  
Intervention Discontinuation 
 
X 
X 
Tel Questionnaire 
 
X 
 
Daily recordings of 
AF/ventricular arrhythmia 
episodes 
 
 
X 
Continuous recordings of 
biological parameters (pulse 
rate, pulse rate variability, 
temperature) 
 
X 
X 
Adverse Events  
  
X 
X 

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7.2 Description of Evaluations  
7.2.1 Screening and Enrollment Evaluation 
These evaluations occur to determine if the candidate is eligible for the study. 
 
Consenting Procedure 
Before any screening procedure is performed, informed consent must be obtained. 
There will be one consenting process that describes the study procedure. 
Patients will be asked by the study personnel to read their consent forms, and will be 
given the opportunity to ask any clarification question for the purposes of the study and 
their participation. Following a discussion with the patients, they will be asked to give 
their signed approval. The explanations given to the patients will be in comprehensible 
non-technical terminology. 
 
 
Screening and Enrollment  
In fall 2018 and 2019, screening of patients attending the cardiac arrhythmia clinic will 
be performed with the help of the network of physicians at Nicosia General Hospital. 
During screening, each patient will have at the clinic demographic, medical, medication 
and symptom survey. The enrollment date is the day the participant has met all the 
screening criteria (both inclusion and exclusion criteria) and signs the informed consent 
form. 
 
7.2.2 Baseline Assessment and Randomization 
 
Baseline Assessments 
For participants who have successfully been screened for eligibility and are enrolled into the 
study, baseline assessments will be performed during February of each study year. Prior to the 
high DDS season, each eligible patient will: 
a) Answer a questionnaire regarding socio-demographic characteristics 
b) Provide detailed medical and medication history 
c) Household characteristics assessment 
 
Randomization 
 
Following the eligibility assessment, participants will be randomized using PASS 14 software 
that allows for random number generation. Randomization will be carried out with a 1:1:1 ratio 
to three parallel groups:  

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a) Control group A: No intervention for DDS,  
b) Intervention group B: Intervention for outdoor exposure reduction, and  
c) Intervention group C: Intervention for outdoor and indoor exposure reduction (patient’s  
    household/bedroom settings) 
 
7.2.3 Follow-up Assessments 
 Intervention mid-point assessment April 2019/2020: 
o Current medications 
o Intervention discontinuation 
o Telephone questionnaire 
o Daily recordings of AF/ventricular arrhythmia episodes 
o Continuous recordings of biological parameters (pulse rate, pulse rate 
variability, temperature) 
o Adverse events 
 
7.2.4 Completion/Final Evaluation 
 Intervention end-point assessment May 2019/2020: 
o Current medications 
o Intervention discontinuation 
o Telephone questionnaire 
o Daily recordings of AF/ventricular arrhythmia episodes 
o Continuous recordings of biological parameters (pulse rate, pulse rate 
variability, temperature) 
o Adverse events 
 
8 
STATISTICAL CONSIDERATION AND ANALYSIS PLAN 
We will build a spatial-temporal individual-based database to continuously collect air quality and 
meteorological information along with the patient’s heart rate assessments. This unique database 
will enable a valid analysis of an impact of DDS on heart rate variation. 
8.1 Sample size consideration 
There are no studies that evaluated the reduction in AF burden attributed to reduction in exposure 
to ambient air pollution.  

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We assume that the mean AF burden in the control group will be 15%+/-15%. We conservatively 
estimated the expected intervention effect to be 20% of relative reduction in AF burden. This is 
translated into the reduction of AF burden by mean of 43 minutes per 24 hours.  
Group sample sizes of 108 and 216 achieve 81% power to show a difference in means when there 
is a difference of -3.0 between the null hypothesis mean difference of 0.0 and the actual mean 
difference of 3.0 at the 0.05 significance level (alpha) using a two-sided Mann-Whitney-Wilcoxon 
Test. These results are based on 2000 Monte Carlo samples from the null distributions: 
WeibullMS(15 15) and WeibullMS(15 15), and the alternative distributions: WeibullMS(15 15) 
and WeibullMS(12 15).  
 
8.2 Statistical analysis 
 
8.2.1 
Descriptive statistics 
Summaries of main variables will be presented in form of means and standard deviations for 
normal distributed quantitative variables, medians and ranges for non-normal distributed 
quantitative variables, distribution in percentages for qualitative variables. 
 
8.2.2 
Univariate analysis 
Univariate analysis will be mostly used for analysis initial datasets consisted of personal data 
records. 
The method of analyses for continuous variables will be parametric using Paired and Unpaired t-
test and Repeated Measurements ANOVA.  
Non-parametric procedures will be used if parametric assumptions could not be satisfied, even 
after data transformation attempts. These tests will include Mann-Whitney, Wilcoxon and 
Spearman Correlation tests. 
Categorical variables will be tested using Chi-Square test. 
 

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8.2.3 
Multivariate analysis 
We will apply 2 modelling strategies:  
Case- Crossover design 
The association between DDS events and episodes of cardiac arrhythmia will be assessed in a case-
crossover design (10). This method has been used previously to study triggers of acute 
cardiovascular events (11). We will define case periods by the time of each confirmed episode of 
cardiac arrhythmia, rounded to the nearest hour. We will match control periods on weekday and 
hour of the day within the same calendar month. Conditional logistic regression analysis will be 
performed to analyze the exposure odds ratio with 95% confidence intervals on risk of cardiac 
arrhythmia.  
Hierarchical model 
Generalized Linear Model will be used to fit a Poisson regression of daily AF episodes against 
temporal variables and DDS data based in hierarchical model. Data model with random effect 
include repeated episodes of AF in each patien, the intervention groups and the 3 sites of the 
research. Date model with fixed effect include DDS event during the period of the study.  
Analysis will be performed using R Project for Statistical Computing version 3.0 or higher and 
IBM SPSS software version 23 or higher. 
 
 
 
9 
ASSESSMENTS OF ADVERSE EVENTS  
 
Since, the intervention under study is behavioral/lifestyle intervention, it does not involve 
any specific drug administration nor any change in ongoing medication schedule. 
Furthermore, it does not include any invasive procedure and all the health outcomes are 
assessed using non-invasive methods (smart-watches, phone interviews) and 
questionnaires. Hence, there are no specific safety parameters to quantify adverse health 
events related to interventions.  
 
At any point during the study, patients will have the opportunity to bring any evolving 
information or issue (e.g. health issue) that concerns them to the attention of the primary 
investigator, Dr Panayiotis Yiallouros, whose contact information will be given to all 

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participants during the enrollment phase, and will also be available on the program's 
website. 
 
 
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INTERVENTION DISCONTINUATION  
Subjects may withdraw voluntarily from the study at any time and for any reason. 
 
Patients can make oral complaints to members of the research team as well as to the 
principal investigators of each site. 
 
The criteria for intervention discontinuation will be: 
 Non-adherence to the intervention 
 Moving to a different house than the reported initial one 
 Significant change in health status 
 
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DATA COLLECTION  
11.1 Data Collection Forms 
Health assessment data: 
 The baseline demographic (gender, age, city), medical, medication and symptom 
data will be obtained using surveys/questionnaires. 
 Daily recordings of AF/ventricular arrhythmia episodes will be obtained from the 
participants’ pacemakers. 
 Symptoms of fatigue, change in medication use, and unscheduled visits to health 
professionals for heart arrhythmias/episodes will be recorded via phone interviews. 
 Continuous recordings of biological parameters (pulse rate, pulse rate variability, 
temperature) obtained by wearing smart watch sensors. 
 
Exposure data:  
 Household characteristics will be assessed with the help of a questionnaire at the 
onset of the study. 
 Real time location data will be assessed using personal smartphones application for 
The Global Positioning System (GPS), satellite-based navigation system installed 
in every smartphone.  
 Real time location data from the GPS will be coupled with accelerometer data from 
smart wristwatches.  
 Hourly central data on air pollutants, including; ambient concentrations of PM10, 
PM2.5, as well as meteorological factors (temperature and relative humidity). 

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 Outdoor and indoor PM and chemicals at participants’ households. 
 
11.2 Data Management 
The study will be overseen and managed by the Medical School, University of Cyprus, 
under the supervision of the LIFE+ MEDEA principal investigator, Professor Panayiotis 
Yiallouros.  
All collected data, will be analyzed and discussed between LIFE+ MEDEA partners only 
by using codes to ensure that the anonymity of the participants is fully preserved. 
 
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PARTICIPANT RIGHTS AND CONFIDENTIALITY  
Patients will be informed about the program and the data to be obtained through the 
information material that will provided with the consent form. 
 
During the study, patients will have the opportunity to get any additional information on 
any subject that concerns them from the study personnel and or principal investigator 
(project coordinator) Professor Panayiotis Yiallouros whose contact information will be 
given to all participants during the recruitment process and will also be available on the 
program's website. 
 
Also, any relevant conclusions resulting from the collected data analysis will be 
communicated to patients at the end of the program. This information will concern the 
better monitoring and forecasting of dust storms and the results of the interventions in order 
to reduce exposure of the population to DDS events.  
 
12.1 Informed Consent Forms 
A signed consent form will be obtained from each participant. The consent form will 
describe the purpose of the study, the procedures to be followed, and the risks and benefits 
of participation. A copy will be given to each participant and this fact will be documented 
in the participant’s record.  
 
12.2 Participant Confidentiality  
Administrative safeguards: 
Data will be completely anonymized and encrypted prior to sending to the central 
database. The full record of Cypriot AF patients with names, addresses, and other 
personal information will be kept by the principal investigator, Professor Panayiotis 

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Yiallouros at the Medical School of the University of Cyprus and only authorized 
personnel will have access to this data (LIFE MEDEA+ project scientist Panayiotis 
Kouis). All data to be collected, will be analyzed and discussed between program partners 
only by using codes (a participant identification number (Participant ID, PID) to ensure 
that the anonymity of the participants is fully preserved and to maintain confidentiality. 
 
Technical safeguards: 
Electronic access to Cypriot patient data will require a user name and password that will 
only be held by authorized personnel. All computer entry and networking programs will 
be done using PIDs only. In addition, the Microsoft Azure storage platform that will be 
used for the purpose of data storage and backup, is Health Insurance Portability and 
Accountability Act (HIPAA) compliant, that establishes requirements for the use, 
disclosure, and safeguarding of individually identifiable health information. 
The University of Cyprus has a policy that requires computer users not to leave computers 
unattended and not to exchange entry codes between them. Still, it is worth mentioning 
that after a few hours of non-use, the computer automatically turns off and locks again, 
requiring the use of the input code again. 
In the event that a computer containing personal data is no longer used, the University of 
Cyprus will ensure that the data will either be transferred or destroyed. 
 
Physical safeguards: 
The Medical School of the University of Cyprus is housed at the Shiakolio Educational 
Center, a safe building on Nicosia-Limassol Old Road, in Aglantzia, Nicosia. 
The building is protected internally and with the supervision of the surrounding area, on 
a daily basis with a 24-hour security guard. The guard checks all incoming people in the 
building. 
Data that may be in print will be kept in a closet in the office of the Project Coordinator 
so that no unauthorized person has access to them. 
All records will be kept in a locked file cabinet.   
 
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ETHICAL CONSIDERATIONS 
The study has already obtained clearance from the Cyprus National Bioethics Committee. 
The intervention under study meets the criteria of the Helsinki declaration and follows the 
ICH/GCP and EC rules of good clinical practice. Data from individual countries will be 
completely anonymized and encrypted prior to sending to the central database. 
 
There are no significant ethical considerations, since all necessary safeguards will be taken 
so that all participants do not face any risk and their personal data is protected. Participation 

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will be on a voluntary basis and all participants will be able to withdraw at any point in the 
program. 
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COMMITTEES 
Steering Committee: 
The Steering Committee will scrutinize the quality of the project performance and will act 
as a supervisory body to ensure that the work described in individual actions is carried out. 
The members of the steering committee will include the Project Coordinator, Project 
Manager, and the Leaders of all other project partners (Soroca Clinical Research Center, 
University of Crete, Cyprus University of Technology, E.n.A. Consulting, Department of 
Labor Inspection, Cyprus Broadcasting Corporation, Cyprus Department of Meteorology). 
The Steering Committees will be responsible for the: 
 Decisions on technical roadmaps for the project and monitoring 
implementation; 
 Provision of data for preparation of reports and deliverables to the 
Commission. 
 
External Advisory Committee: 
The external advisory committee will be responsible to counsel the project and to help 
transform our results to policies. The advisory committee will consist of relevant regulatory 
authorities and interested stakeholders. There will be in total 30 members from all 
participating sites (Cyprus, Greece, Israel, i.e. ~10 members from each site). 
 
15 
REFERENCES 
 
 Achilleos S, et al. PM10 concentration levels at an urban and background site in Cyprus: 
the impact of urban sources and dust storms. J Air Waste Manag Assoc 2014; 64:1352-60. 
 Gerasopoulos E, et al. Origin and variability of particulate matter (PM10) mass 
concentrations over the Eastern Mediterranean. Atmos Environ 2006; 40:4679-4690.  
 Griffin D. Atmospheric movement of microorganisms in clouds of desert dust and 
implications for human health. Clin Microbiol Rev. 2007; 20:459-77. 
 Krasnov H, et al. Contribution of dust storms to PM10 levels in an urban arid environment. 
J Air Waste Manag Assoc 2014; 64:89-94. 
 Leski T, et al. Application of a broad-range resequencing array for detection of pathogens 
in desert dust samples from Kuwait and Iraq. Appl Environ Microbiol 2011;77:4285-92. 
 Mallone S, et al. Saharan dust and associations between particulate matter and daily 
mortality in Rome, Italy. Environ Health Persp 2011; 119:1409–1414. 
 Middleton N, et al. A 10-year time-series analysis of respiratory and cardiovascular 
morbidity in Nicosia, Cyprus: the effect of short-term changes in air pollution and dust 

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storms. Environ Health 2008; 22;7:39. 
 Neophytou A, et al. Particulate matter concentrations during desert dust outbreaks and 
daily mortality in Nicosia, Cyprus. J Expo Sci Environ Epidemiol. 2013; 23:275-80. 
 Querol X, et al. African dust contributions to mean ambient PM10 mass-levels across the 
Mediterranean, Basin. Atmos Environ 2009; 43:4266-4277. 
 Samoli E, et al. Acute effects of air pollution on pediatric asthma exacerbation: evidence 
of association and effect modification. Environ Res 2011;111:418-24. 
 
Vodonos A, et al. The impact of desert dust exposures on hospitalizations due to 
exacerbation of chronic obstructive pulmonary disease. Air Qual Atmos Health 2014; 
7:433–439. 
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SUPPLEMENTS/APPENDICES 
I. 
Informed Consent Form Template 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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