Bicycle Exercise and Lifestyle Intervention in Newly Diagnosed Diabetes
Phase: NA
Conditions: Life Style
Sponsor: University Hospital, Basel, Switzerland

BELIFE-Study, Study Protocol, Version 
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Page 1 of 37 
 
 
 
Bicycle Exercise and Lifestyle Intervention in 
Newly Diagnosed Diabetes  
–  
BELIFE Study 
Clinical Study Protocol 
 
 
 
 
 
 
Study Type: 
Randomized, multi-center, proof-of-concept study  
Study Categorisation: 
Risk category A 
Study Registration: 
EKNZ 2018-01920 
ClinicalTrials.gov: NCT03827382 
Swiss 
National 
Clinical 
Trials 
Portal 
(SNCTP) 
SNCTP000003087  
 
Study Identifier: 
BELIFE-Study  
Sponsor, Sponsor-Investigator or 
Principal Investigator: 
Prof. Dr. med. Marc Y. Donath, University Hospital Basel, 
Endocrinology, Diabetes and Metabolism 
Petersgraben 4, CH-4031 Basel,  
 
Investigational Product: 
n/a 
Protocol Version and Date: 
Version 1.10 of 30.10.2023 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of the sponsor. The 
information may not - in full or in part - be transmitted, reproduced, published, or disclosed to others 
than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies) without prior written 
authorization from the sponsor except to the extent necessary to obtain informed consent from those 
who will participate in the study. 
 
 
Schweizerische Ethikkommissionen für die Forschung am Menschen 
Commissions d’éthique suisses relative à la recherche sur l'être humain 
Commissioni etiche svizzere per la ricerca sull'essere umano 
Swiss Ethics Committees on research involving humans 
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Signature Page  
 
Study number 
EKNZ 2018-01920 
Study title 
Bicycle Exercise and Lifestyle Intervention in Newly Diagnosed 
Diabetes– BELIFE Study 
 
The sponsor-investigator and trial statistician have approved the protocol version 1.10 of 30.10.2023 
and confirm hereby to conduct the study according to the protocol, current version of the World Medical 
Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable and the local 
legally applicable requirements. 
 
Sponsor-investigator: 
Prof. Dr. med. Marc Y. Donath, University Hospital Basel, Endocrinology, Diabetes and Metabolism, 
Petersgraben 4, CH-4031 Basel  
 
 
 
Place/Date 
 
Signature 
 
 
 
Basel
21.11.2023 | 16:42 CET
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Local principal investigator at study site: 
 
 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
Site 
Cantonal Hospital Solothurn, Clinic Olten, Baslerstrasse 150, 
CH-4600 Olten, +41 62 311 44 94 
Principal investigator 
Dr. med. Matthias Hepprich, Leitender Arzt  
 
 
 
Place/Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
Basel
21.11.2023 | 14:28 MEZ
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Table of Contents 
STUDY SYNOPSIS ................................................................................................................................. 7 
ABBREVIATIONS ................................................................................................................................. 11 
STUDY SCHEDULE .............................................................................................................................. 12 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 14 
Sponsor, Sponsor-Investigator .............................................................................................................. 14 
Principal Investigator(s) ......................................................................................................................... 14 
Statistician ............................................................................................................................................. 14 
Laboratory.............................................................................................................................................. 14 
Monitoring Institution ............................................................................................................................. 14 
Data Safety Monitoring Committee ....................................................................................................... 14 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................. 15 
Study Registration ................................................................................................................................. 15 
Categorisation of Study ......................................................................................................................... 15 
Competent Ethics Committee (CEC) ..................................................................................................... 15 
Ethical Conduct of the Study ................................................................................................................. 15 
Declaration of Interest ........................................................................................................................... 15 
Patient Information and Informed Consent............................................................................................ 15 
Participant Privacy and Confidentiality .................................................................................................. 16 
Early Termination of the Study .............................................................................................................. 16 
Protocol Amendments ........................................................................................................................... 16 
3. 
BACKGROUND AND RATIONALE .............................................................................................. 17 
Background and Rationale .................................................................................................................... 17 
Investigational Product (Treatment, Device) and Indication .................................................................. 17 
Preclinical Evidence .............................................................................................................................. 17 
Clinical Evidence to Date ....................................................................................................................... 17 
Explanation for Choice of Comparator (or Placebo) ............................................................................. 18 
Risks/Benefits ........................................................................................................................................ 18 
Justification of Choice of Study Population ........................................................................................... 18 
4. 
STUDY OBJECTIVES ................................................................................................................... 19 
4.1 Overall Objective ............................................................................................................................. 19 
4.2 Primary Objective ............................................................................................................................ 19 
4.3 Secondary Objectives...................................................................................................................... 19 
4.4 Safety Objectives ............................................................................................................................. 19 
5. 
STUDY OUTCOMES ..................................................................................................................... 20 
5.1 Primary Outcome ............................................................................................................................. 20 
5.2 Secondary Outcomes ...................................................................................................................... 20 
6. 
STUDY DESIGN ............................................................................................................................ 20 
General Study Design and Justification of Design ................................................................................ 20 
Methods of Minimizing Bias ................................................................................................................... 21 
6.1.1 Randomization .................................................................................................................... 21 
6.1.2 Blinding Procedures ............................................................................................................ 21 
7. 
STUDY POPULATION .................................................................................................................. 22 
Eligibility Criteria .................................................................................................................................... 22 
Recruitment and Screening ................................................................................................................... 22 
Assignment to Study Groups ................................................................................................................. 22 
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Criteria for Withdrawal/Discontinuation of Participants ......................................................................... 22 
8. 
STUDY INTERVENTION ............................................................................................................... 23 
Identity of Investigational Products (Treatment/Medical Device) .......................................................... 23 
8.1.1 Experimental Intervention ................................................................................................... 23 
8.1.2 Control Intervention (Standard Treatment) ......................................................................... 23 
Administration of Experimental and Control Interventions .................................................................... 23 
8.1.3 Experimental Intervention ................................................................................................... 23 
8.1.4 Control Intervention ............................................................................................................. 23 
Dose/Device Modifications .................................................................................................................... 23 
Compliance with Study Intervention ...................................................................................................... 23 
Data Collection and Follow-up for Withdrawn Participants ................................................................... 24 
Trial-specific Preventive Measures ....................................................................................................... 24 
Concomitant Interventions (Treatments) ............................................................................................... 24 
9. 
STUDY ASSESSMENTS ............................................................................................................... 25 
Study Flow Chart and Table of Study Procedures and Assessments .................................................. 25 
Assessments of Outcomes .................................................................................................................... 25 
9.1.1 Assessment of Primary Outcome ....................................................................................... 25 
9.1.2 Assessment of Secondary Outcomes ................................................................................. 25 
9.1.3 Assessment of Safety Outcomes ........................................................................................ 25 
9.1.4 Assessments in Participants who Prematurely Stop the Study .......................................... 25 
Procedures at Each Visit ....................................................................................................................... 25 
9.1.5 Visit 1: Day 0 – Initial Consultation ..................................................................................... 25 
9.1.6 Visit 2-6: Day 2/7/30/60/90 – Study Visits ........................................................................... 26 
9.1.7 Visit 7: Day 180 – Follow Up ............................................................................................... 26 
9.1.8 Visit 8: 1 Year – Telephone Follow Up................................................................................ 27 
10. SAFETY ......................................................................................................................................... 28 
10.1.1 Definition and Assessment of (Serious) Adverse Events and Other Safety Related 
Events 28 
10.1.2 Reporting of SAEs and Other Safety Related Events ......................................................... 29 
10.1.3 Follow Up of (S)AEs ............................................................................................................ 29 
11. STATISTICAL METHODS ............................................................................................................. 30 
Hypothesis ............................................................................................................................................. 30 
Determination of Sample Size ............................................................................................................... 30 
Statistical Criteria of Termination of Trial .............................................................................................. 30 
Planned Analyses .................................................................................................................................. 30 
11.1.1 Datasets to be Analyzed, Analysis Populations .................................................................. 30 
11.1.2 Primary Analysis ................................................................................................................. 30 
11.1.3 Secondary Analyses ........................................................................................................... 31 
11.1.4 Interim Analyses .................................................................................................................. 31 
11.1.5 Safety Analysis .................................................................................................................... 31 
11.1.6 Deviation(s) from the Original Statistical Plan .................................................................... 31 
Handling of Missing Data and Drop-outs ............................................................................................... 31 
12. QUALITY ASSURANCE AND CONTROL .................................................................................... 32 
Data Handling and Record Keeping/Archiving ...................................................................................... 32 
12.1.1 Case Report Forms ............................................................................................................. 32 
12.1.2 Specification of Source Documents .................................................................................... 32 
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12.1.3 Record Keeping/Archiving .................................................................................................. 32 
Data Management ................................................................................................................................. 32 
12.1.4 Data Management System ................................................................................................. 32 
12.1.5 Data Security, Access and Back-up.................................................................................... 32 
12.1.6 Analysis and Archiving ........................................................................................................ 32 
12.1.7 Electronic and Central Data Validation ............................................................................... 33 
Monitoring .............................................................................................................................................. 33 
Audits and Inspections .......................................................................................................................... 33 
Confidentiality and Data Protection ....................................................................................................... 33 
Storage of Biological Material and Related Health Data ....................................................................... 33 
13. PUBLICATION AND DISSEMINATION POLICY.......................................................................... 34 
14. FUNDING AND SUPPORT ............................................................................................................ 34 
15. INSURANCE .................................................................................................................................. 34 
16. REFERENCES ............................................................................................................................... 35 
17. APPENDICES ................................................................................................................................ 37 
17.1 SF-36 Questionnaire ................................................................................................................... 37 
17.2 SIMPAQ Questionnaire ............................................................................................................... 37 
 
 
 
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STUDY SYNOPSIS  
 
Sponsor / Sponsor-
investigator 
Prof. Marc Donath, MD 
 
Co-Investigators 
Prof. Roland Bingisser, MD 
Prof. Philipp Schuetz, MD 
Prof. Gottfried Rudofsky, MD 
Dr. Matthias Hepprich, MD 
Study Title: 
Bicycle Exercise and Lifestyle Intervention in Newly Diagnosed Diabetes 
Short Title / Study ID: 
BELIFE 
Protocol Version and 
Date: 
Version 1.10 of 30.10.2023 
Trial Registration: 
ClinicalTrials.gov, Swiss National Clinical Trials Portal (SNCTP) EKNZ 
2018-01920 
Study Category 
A  
Clinical Phase: 
N/A 
Background and 
Rationale: 
Lifestyle intervention is a fundamental aspect in the treatment of type 2 
diabetes. Implementation of lifestyle changes early after diagnosis often 
suffices to control metabolic dysregulation and may even have a durable 
impact. However, implementation of these changes is often difficult for 
multiple reasons including noncompliance as well as doubt on efficacy of 
sport and diet changes compared to drugs. Furthermore, most patients 
with type 2 diabetes remain asymptomatic for a prolonged period of time. 
Thus, they lack an immediate relief of symptoms and do not feel the 
benefit of changes in lifestyle. Often, untreated type 2 diabetes first 
manifests itself with symptoms of polyuria and polydipsia. This offers a 
unique opportunity to demonstrate the potential of lifestyle changes. 
However, in daily practice, symptomatic patients with polyuria and 
polydipsia or with HbA1c levels >10% at diagnosis are typically referred 
to an emergency room, hospitalized and treated with drugs as a first line 
treatment.  
In the present study, we aim to implement a lifestyle intervention as a first-
line treatment in recent onset type 2 diabetes. In the emergency room, the 
bed will symbolically be removed and the patient requested to perform a 
bicycle exercise. Non-ER patients will be invited to perform the bicycle 
exercise as soon as possible. We expect from this educational trigger that 
patients will realize the therapeutic power of sport. Preliminary 
interventions using this approach at our emergency room demonstrated 
the potential of such an intervention. However, internal and external 
validation, efficacy and safety of a lifestyle intervention in an emergency 
room remain to be shown in a multi-center controlled study. 
Objective(s): 
The aim of the study is to test the efficacy, feasibility, and safety of a 
bicycle exercise followed by an intensive lifestyle intervention for 3 months 
in patients with recent onset and medically untreated type 2 diabetes. 
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Outcome(s): 
Primary:  
The primary endpoint of this study is achievement of metabolic control 
without anti-diabetic medication 3 months after study enrollment. For the 
purpose of this study, metabolic control is defined as an HbA1c below a 
target stratified for three groups according to HbA1c at baseline: HbA1c 
>14%  target < 10%; HbA1c < 14% and > 10% target < 8%; HbA1c < 
10% target < 7.5%  
 
Secondary:  
- 
Absolute HbA1c reduction per stratification group (groups 
consist of HbA1c > 14 %, HbA1c < 14 % and > 10 % and HbA1c 
< 10 %) 
- 
Change of HbA1c at 6 and 12 months after enrollment 
compared to control group 
- 
Proportion of patients achieving target per stratified group after 3 
and 6 months without anti-diabetic medication other than 
Metformin 
- 
Changes in pH, base excess and bicarbonate 90 minutes after 
bicycle exercise compared to baseline 
- 
Change of weight at 3, 6 and 12 months after enrollment 
compared to baseline and to standard of care 
- 
Changes in blood glucose at the end of, as well as 30 and 90 
minutes after bicycle exercise compared to baseline 
- 
Feasibility of bicycle exercise at study enrollment in the ER, 
defined as absence of problem reports through the study team 
(e.g. patient cooperation) 
- 
Safety of bicycle exercise, defined as:  
o 
Absence of SAEs during the exercise 
o 
No signs of acute cardiopulmonary decompensation in 
patients during bicycle exercise 
o 
No necessity to prematurely terminate the bicycle 
intervention because of other health or safety concerns 
- 
Safety of intensive lifestyle intervention within 3 months following 
study enrollment, with the following endpoints: 
o 
Number of SAEs in the intervention group compared to 
the control group 
o 
Number of rescue medication administered in the 
intervention group compared to the control group 
- 
Length of initial hospitalization, as well as number and length of 
re-hospitalizations and unplanned re-consultations within 3 
months after initial consultation 
- 
Changes in physical activity at 6 months compared to baseline 
assessed by SIMPAQ questionnaire (Endpoint: hours of physical 
activity) 
- 
Changes in physical activity at 3 and 6 months compared to 
baseline assessed by actigraph (Endpoint: Stepgoal reached) 
- 
Number of anti-diabetic medication at 30, 60, 90 days, as well as 
6 months and one year compared to baseline in both arms 
- 
Proportion of patients receiving insulin therapy after 6 months 
and one year in the intervention group compared to the control 
group 
- 
Absolute health-care related costs at 3, 6 and 12 months in both 
arms 
- 
Quality of life at 6 months in the intervention group compared to 
standard of care as assessed by SF-36 questionnaire. 
Study Design: 
Randomized, multicenter, proof-of-concept study. 
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Inclusion / Exclusion 
Criteria: 
Inclusion criteria: 
- 
Informed consent as documented by signature  
- 
Type 2 diabetes diagnosed within the last two years according to 
the American Diabetes Association (ADA) criteria  
- 
Age ≥ 18 years 
- 
HbA1c ≥ 7.5 % 
 
Exclusion criteria: 
 
Clinically instable patient as defined by the physicians on duty 
including signs of new cardiac ischemia in the ECG, systolic 
blood pressure ≥ 200 mmHg, fever ≥ 38.5 °C, symptoms of 
SIRS or reduced vigilance. 
 
Anti-diabetic medication for ≥ 24 hours 
 
Inability to perform a bicycle exercise during 30 minutes 
 
Previous lifestyle-intervention by an endocrinologist 
 
Engagement in physical activity more than five times per week 
 
Enrollment in other interventional study 
 
Measurements and 
Procedures: 
Measurement of clinical parameters (heart rate, blood pressure), venous 
blood gas analysis (pH, pCO2, base excess, bicarbonate) at baseline and 
120 min after beginning of bicycle exercise. Blood glucose levels at 
baseline and 30, 60 and 120 min after beginning of bicycle exercise. Blood 
glucose levels, vital parameters, concomitant medication after 2, 7, 30, 60 
and 90 days; HbA1c at baseline, 2 (only intervention group), 3 and 6 
months and one year; physical activity at baseline, 3 and 6 months. In the 
intervention group additional self-measurements of blood glucose levels 
during the first week and within the week before visit at day 30 and 90 
after randomization. 
Study 
Product/Intervention:  
Patients will be randomized either to standard care or to a bicycle exercise 
followed by an intensive lifestyle intervention on top of non-
pharmacological standard care. 
After rehydration, patients allocated to the intensified lifestyle intervention 
group will be instructed to perform 30 minutes of bicycle exercise at 60 % 
of the calculated maximum heart rate (according to Franckowiak et al.)20 
followed by an intensive lifestyle intervention. Patients will be discharged 
if the clinical status is stable and no comorbidities require further 
hospitalization. Follow-up visits at the Clinic of Endocrinology for further 
instructions and consultation will be carried out after 2, 7, 30, 60 and 90 
days, half a year and a year. 
In order to monitor blood glucose levels, patients will be instructed on visit 
2 to take measurements at home and will be asked to send their fasting 
glucose levels of the first week to the study team for monitoring of the 
metabolic situation. This will also be done in the week before visits of day 
30 and 90. 
The schedule for the intervention arm consists of 3 to 5 aerobic training 
sessions (duration 15-40 minutes each) and 2 resistance trainings per 
week, as well as weekly motivational coaching via telephone by the study 
psychologist. Everyday activity will be objectively monitored using the 
patient’s mobile phone and a blinded actigraph (activity tracker). Exercise 
sessions will be monitored by weekly phone calls and documented. To 
assess baseline physical activity all patients will fill in the SIMPAQ 
questionnaire at baseline and at 6 months. 
Control Intervention 
(if applicable): 
The control arm will consist of the standard care delivered by the involved 
centers. 
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Number of 
Participants with 
Rationale: 
The aim of this study is to assess whether bicycle exercise followed by an 
intensive lifestyle intervention can sufficiently restore metabolic control 
without anti-diabetic drugs at 3 months after study enrollment as 
compared to a standard of care control group. 
Based on our clinical experience we expect that 80 % in the intervention 
group will reach the primary endpoint of metabolic control with no anti-
diabetic drugs compared to only 40% in the usual care control group. The 
inclusion of 28 patients per group (n total 62 patients including 10 % lost 
to follow-up) will provide 80 % power at an alpha level of 0.05.  
Study Duration: 
The primary endpoint will be assessed at 3 months. The overall study 
duration is 1 year.  
Study Schedule: 
11/2018 of First-Participant-In (planned) 
12/2025 of Last-Participant-Out (planned) 
Investigator(s): 
Investigators: 
Beckey Trinh, MD, Jonathan Mudry, MD-PhD, and Matthias Hepprich, MD 
Division of Endocrinology, Diabetes and Metabolism 
Department of Internal Medicine 
University Hospital Basel, Switzerland 
+41 61 265 25 25 
beckey.trinh@usb.ch 
jonathan.mudry@usb.ch 
matthias.hepprich@usb.ch 
 
Study Centers: 
Department of Medicine, University Hospital Basel 
Department of Medicine, Cantonal Hospital Olten  
Hôpital du Jura - site de Delémont 
Statistical 
Considerations: 
All subjects will be considered on a per-protocol basis. For our primary 
analysis, we will compare the two arms with a Fisher’s exact test and we 
will also estimate effect size with a logistic regression model reporting 
odds ratios (OR) and corresponding 95% confidence intervals. All tests 
will be two-tailed; p<0.05 will be defined as significant. Data will be 
analyzed using Graph Pad Prism, STATA and IBM SPSS. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as 
far as applicable) as well as all national legal and regulatory requirements. 
 
 
 
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ABBREVIATIONS 
ADA 
American Diabetes Association 
AE 
Adverse event 
ASR 
Annual safety report 
BASEC 
Business Administration System for Ethical Committees, 
(https://submissions.swissethics.ch/en/) 
BGA 
Blood gas analysis 
CA 
Competent authority (e.g. Swissmedic) 
CEC 
Competent ethics committee 
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin, in Italian: OSRUm) 
CRF 
Case report form  
CTCAE 
Common terminology criteria for adverse events 
CTU 
Clinical Trial Unit 
DSBG 
Departement für Sport, Bewegung und Gesundheit 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EKNZ 
Ethikkommission Nordwest- und Zentralschweiz 
ER 
Emergency room 
GCP 
Good clinical practice  
H0 
Null hypothesis 
H1 
Alternative hypothesis 
HbA1c 
Glycated hemoglobin A 
ICF 
Informed consent form 
ICH 
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements 
for 
Pharmaceuticals for Human Use  
ISF 
Investigator site file 
ISO 
International Organisation for Standardisation 
MHR 
Maximum heart rate 
SAE 
Serious adverse event 
s.c. 
Subcutaneous 
SIMPAQ 
Simple physical activity questionnaire 
SIRS 
Systemic inflammatory response syndrome 
SNCTP 
Swiss National Clinical Trials Portal 
SUSAR 
Suspected unexpected serious adverse reaction  
TMF 
Trial master file  
 
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STUDY SCHEDULE  
 
Study Periods 
 
ER 
Intervention Period 
Follow-up 
Telephone FU 
Visit 
1 
2 
3 
 
4 
 
5 
 
6 
7 
8 
Time (day) 
0 
2 +/- 1 
7 +/- 3 
weekly 
30 +/- 7 
weekly 
60 +/- 14 
weekly 
90 +/- 14 
180+/-14 
1 year +/-45 
Patient information and 
informed consent 
x 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
Medication 
x 
 
 
 
x 
 
x 
 
x 
x 
x 
ECG (electrocardiograph) 
(x) 
 
 
 
 
 
 
 
 
 
 
In- /exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
 
 
 
 
 
 
 
 
 
 
Vital signs  
x 
x 
x 
 
x 
 
x 
 
x 
x 
only weight 
Fasting blood samples 
(including glucose, insulin 
and c-peptide) 
 
x 
 
 
 
 
 
 
x 
x 
 
Glycated hemoglobin A1c  
x 
 
 
 
 
 
x 
 
x 
x 
x 
Randomization 
x 
 
 
 
 
 
 
 
 
 
 
Bicycle intervention 
x 
 
 
 
 
 
 
 
 
 
 
Diabetes counselling (i. e. 
general information, self 
glucose measurements) 
 
x 
(x) 
 
 
 
 
 
 
 
 
Nutrition counselling 
 
 
x 
 
 
 
 
 
 
 
 
Telephone (coaching) 
interview  
 
 
 
x 
 
x 
 
x 
 
 
 
Report about physical 
activity (SIMPAQ) 
 
x 
 
 
 
 
 
 
 
x 
 
Adverse events 
x 
x 
x 
 
x 
 
x 
 
x 
x 
 
Actigraph readout 
 
 
x 
 
 
 
 
 
x 
x 
 
Quality of life questionnaire 
SF-36 
 
x 
 
 
 
 
 
 
 
x 
 
Start of Metformin therapy 
 
 
 
 
 
 
 
 
(x) 
 
 
 
Table 1 Study schedule of the intervention group. (x) optional  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Periods 
 
ER 
standard care period 
Follow-up 
Telephone FU 
Visit 
1 
6 
7 
8 
Time (day) 
0 
90 +/- 14 
180+/-14 
1 year +/-45 
Patient information and 
informed consent 
x 
 
 
 
Demographics 
x 
 
 
 
Medical history 
x 
 
 
 
Medication 
x 
x 
x 
x 
ECG (electrocardiography) 
(x) 
 
 
 
In- /exclusion criteria 
x 
 
 
 
Physical examination 
x 
 
 
 
Vital signs  
x 
x 
x 
only weight 
Fasting blood samples 
(including glucose, insulin 
and c-peptide) 
x 
x 
x 
 
Glycated hemoglobin A1c  
x 
x 
x 
x 
Randomization 
x 
 
 
 
Diabetes counselling (i. e. 
general information, self 
glucose measurements) 
(x) 
x 
 
 
Nutrition counselling 
(x) 
x 
 
 
Report about physical 
activity (SIMPAQ) 
x 
 
x 
 
Adverse events 
x 
x 
x 
 
Quality of life questionnaire 
SF-36 
x 
 
x 
 
Start of Metformin therapy 
(x) 
(x) 
 
 
 
Table 2 Study schedule of the control group. (x) optional  
 
 
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1. STUDY ADMINISTRATIVE STRUCTURE  
Sponsor, Sponsor-Investigator  
Prof. Dr. med. Marc Y. Donath, University Hospital Basel, Endocrinology, Diabetes and Metabolism 
Petersgraben 4, CH-4031 Basel 
 
Principal Investigator(s)  
Prof. Dr. med. Marc Y. Donath, University Hospital Basel, Endocrinology, Diabetes and Metabolism 
Petersgraben 4, CH-4031 Basel, +41 61 265 50 78 
 
Dr. med. Matthias Hepprich, Endocrinology, Department of Medicine Cantonal Hospital Olten  
Baslerstrasse 150, CH-4600 Olten, +41 62 311 44 94 
 
Statistician  
Prof. Dr. med. Philipp Schütz, Endocrinology, University Department of Internal Medicine Cantonal 
Hospital Aarau 
Tellstrasse 25, CH-5001 Aarau, +41 62 838 41 41 
 
Laboratory 
Laboratory analysis will be done by the associated laboratories of the study centers. For the University 
Hospital Basel: Labormedizin, University Hospital Basel, Petersgraben 4, CH-4031 Basel. 
 
Cantonal Hospital Olten, Central Laboratory, Baslerstrasse 150, CH-4600 Olten, +41 62 311 51 01 
 
Hôpital du Jura - site de Delémont, Laboratoire, Fbg des Capucins 30, 2800 Delémont. 
 
Monitoring Institution 
Monitoring will be performed by an independent, professional and certified monitor within the University 
Hospital Basel. 
There will be a total of two visits from the monitor at each study site containing an initiation and a final 
monitoring visit. 
 
Data Safety Monitoring Committee  
Not applicable. 
 
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2. ETHICAL AND REGULATORY ASPECTS  
The decision of the competent ethics committee (CEC) concerning the conduct of the study will be made 
in writing to the sponsor-investigator before commencement of this study. The clinical study can only 
begin once approval from all required authorities has been received. Any additional requirements 
imposed by the authorities shall be implemented. 
 
Study Registration  
The study will be registered on clinicaltrials.gov and the Swiss National Clinical Trials Portal (SNCTP) 
on www.kofam.ch 
 
Categorisation of Study  
This is a randomized, multicenter, proof-of-concept study with the risk category A. 
 
Competent Ethics Committee (CEC)  
The clinical study will be reviewed and approved by the CEC “Ethikkommission Nordwest- und 
Zentralschweiz” (EKNZ). Approval by the EKNZ will cover the planned centers Basel and Olten. 
 
Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in the 
current version of the Declaration of Helsinki, the guidelines of good clinical practice (GCP) issued by 
the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH), in case of medical device: the European directive on medical devices 93/42/EEC and the 
ISO Norm 14155 and ISO 14971, the Swiss law and Swiss regulatory authority’s requirements. The 
CEC and regulatory authorities will receive annual safety and interim reports and be informed about 
study stop/end in agreement with local requirements.  
 
Declaration of Interest  
This is an investigator driven study without conflicts of interest. 
 
Patient Information and Informed Consent 
The investigators will explain to each participant the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits and any discomfort it may entail. Each 
participant will be informed that the participation in the study is voluntary and that he/she may withdraw 
from the study at any time and that withdrawal of consent will not affect his/her subsequent medical 
assistance and treatment.  
The participant must be informed that his/her medical records may be examined by authorized 
individuals other than their treating physician. 
All participants for the study will be provided a participant information sheet and an informed consent 
form (ICF) describing the study and providing sufficient information for participant to make an informed 
decision about their participation in the study.  
The formal consent of a participant, using the approved ICF, must be obtained before the participant is 
submitted to any study procedure.   
The participant should read and consider the statement before signing and dating the ICF, and should 
be given a copy of the signed document. The ICF must also be signed and dated by the investigator (or 
his designee) at the same time as the participant sign, and it will be retained as part of the study records. 
 
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Participant Privacy and Confidentiality  
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilizing subject 
identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorized representatives of an ethics committee (EC) may require 
direct access to parts of the medical records relevant to the study, including participants’ medical history. 
 
Early Termination of the Study  
The sponsor-investigator may terminate the study prematurely according to certain circumstances, for 
example: 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
when the safety of the participants is doubtful or at risk, respectively, 
 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise,  
 
early evidence of benefit or harm of the experimental intervention  
 
Protocol Amendments 
Substantial amendments are only implemented after approval of the CEC and CA respectively. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-
being of human subjects may proceed without prior approval of the sponsor and the CEC/CA. Such 
deviations shall be documented and reported to the sponsor and the CEC/CA as soon as possible. 
All non-substantial amendments are communicated to the CA as soon as possible if applicable and to 
the CEC within the annual safety report (ASR).  
 
 
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3. BACKGROUND AND RATIONALE  
Background and Rationale  
 
Current standards for diabetes care recommend the initiation of pharmacological therapy16 as well as 
lifestyle interventions at new onset of type 2 diabetes mellitus12. The implementation of regular physical 
activity and dietary measures are effective in the treatment of type 2 diabetes, resulting in stabilization 
of plasma glucose in the acute phase, increase in lean body mass and reduction of insulin resistance 
and glycated hemoglobin A1c. While physical activity is broadly promoted19 in the medical community 
as an effective prevention and treatment of glucose intolerance, many patients fail to include lifestyle 
changes into their daily routines. A study by Morrato et al. discovered that only 38 % of type 2 diabetes 
patients in the United States engage in regular physical activity, leaving the majority of patients inactive, 
thus, putting strong emphasis on the need for further efforts to promote physical activity in the diabetes 
population13. 
The beneficial effects of physical activity on glucose tolerance and blood sugar levels have been shown 
by several studies. Ried-Larsen et al. did not find equivalence of lifestyle intervention compared to 
standard diabetes care in respect to glycemic control at 12-months follow-up. However, in the lifestyle 
intervention group, a reduction of oral anti-diabetic medication was reached in significantly more patients 
compared to the standard care group14. Physical activity has not only been shown to be effective in 
long-term improvement of metabolic parameters17, but also has a direct effect on blood glucose levels 
shortly after by increasing insulin sensitivity of peripheral tissues18. 
In addition to overall health benefits to diabetes patients, lifestyle interventions such as physical activity 
and dietary measures show the potential to have a cost-reducing impact on the health care system. The 
“Look AHEAD” trial by Espanlad et al. assessed the impact of lifestyle interventions in diabetic patients 
on the development of their healthcare costs. They found that applied lifestyle interventions led to a 
reduction of healthcare costs mainly on the ground of reduced and shorter hospitalizations and fewer 
needed medications15. 
We believe it is crucial to stress the importance of lasting lifestyle changes for metabolic control from 
the very point of diagnosis. Intervention early in the course of the disease often suffices to control 
metabolic dysregulation and may even have a durable impact. However, as mentioned above, multiple 
reasons including non-compliance as well as doubt about the efficacy of sport and diet changes 
compared to drugs make a lasting change in lifestyle difficult. Furthermore, most patients with type 2 
diabetes remain asymptomatic for a prolonged period of time, leaving patients in doubt about the 
immediate benefit of lifestyle changes. Often, untreated type 2 diabetes manifests itself for the first time 
with symptoms of polyuria and polydipsia. This offers a unique opportunity to demonstrate the potential 
of lifestyle changes. However, in daily practice, symptomatic patients with polyuria and polydipsia are 
typically referred to an emergency room and are treated with drugs and hospitalized. With this study, 
we therefore aim to implement lifestyle intervention as first line treatment in new onset type 2 diabetes 
patients. We expect to achieve a durable educational impact with this approach and to increase the 
patients’ motivation for glycemic control through healthy lifestyle while keeping pharmacological aids at 
a minimum. 
 
Investigational Product (Treatment, Device) and Indication  
No investigational products are used in this trial. 
 
Preclinical Evidence  
Not applicable. 
 
Clinical Evidence to Date  
Refer background and rationale.  
 
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Explanation for Choice of Comparator (or Placebo)  
The control treatment used in this trial is based on the current standard of care for diabetes according 
to national and international guidelines (American Diabetes 2012). There is no medical disadvantage 
for the participants of the control group. 
 
Risks/Benefits  
Subjects will only be performing the bicycle exercise when they are found to be eligible by the 
responsible medical doctor with concern to their clinical status. During the remaining study period 
patients are encouraged to be physically active. This may increase the risk for physical activity 
associated accidents (i.e. adverse events) but does not represent a greater risk within the study 
compared to general physical activity in the normal population. 
It is expected that intensified lifestyle intervention will generally be beneficial to the subjects and 
especially with respect to the medical treatment of diabetes and associated co-morbidities. Patients in 
the intervention group will be monitored closely by the study physicians and psychologist. With the 
results of this study, bicycle exercise may become an important educational intervention in the 
emergency setting and thereby of outstanding importance for the further course of diabetes 
management. 
There are no specific risks or benefits for the standard care group receiving routine treatment. 
 
Justification of Choice of Study Population  
A total of 62 patients with new onset of type 2 diabetes mellitus will be included in this study.  
 
 
 
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4. STUDY OBJECTIVES  
4.1 Overall Objective 
This is a proof-of-concept study to test the efficacy, feasibility, and safety of a bicycle exercise followed 
by an intensive lifestyle intervention for the following three months in patients with newly diagnosed or 
medically untreated type 2 diabetes. 
 
4.2 Primary Objective 
The primary objective is to investigate whether an intensive lifestyle intervention in untreated type 2 
diabetes can adequately lower blood glucose and HbA1c levels compared to conventional standard of 
care anti-diabetic treatment.  
 
4.3 Secondary Objectives 
Secondary objectives are 
- 
To implement methods to monitor patients’ activity levels and support motivation for the 
following training sessions 
- 
To test the impact of an intensive lifestyle intervention on HbA1c-levels and its dependency on 
the level at baseline 
- 
To assess change of weight at 3, 6 and 12 months after enrollment compared to baseline and 
to standard of care 
- 
To evaluate changes in heart rate, blood pressure, blood glucose, pH, base excess and 
bicarbonate after a 30-minute bicycle exercise 
- 
To evaluate re-hospitalization and unplanned re-consultation rate during the study in both 
arms 
- 
To evaluate changes in physical activity during and after the study intervention compared to 
baseline 
- 
To evaluate number of anti-diabetic medication at 30, 60, 90 days, as well as 6 months and 
one year compared to baseline in both arms 
- 
Cost-effectiveness  
- 
To compare changes in quality of life in the intervention group to the standard-of-care group. 
 
4.4 Safety Objectives 
- 
To test the safety and feasibility of a 30-minute bicycle exercise in hyperglycemic patients 
- 
To test the safety of an intensive lifestyle intervention within 3 months following study 
enrollment 
 
 
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5. STUDY OUTCOMES 
5.1 Primary Outcome 
The primary endpoint of this study is achievement of metabolic control with intensive lifestyle 
intervention 3 months after study enrollment. For the purpose of this study, metabolic control is defined 
as a fasting glucose < 7.6 mmol/l and an HbA1c below a target stratified for three groups according to 
HbA1c at baseline: HbA1c > 14 %  target < 10 %; HbA1c < 14 % and > 10 %  target < 8 %; HbA1c 
< 10 %  target < 7.5 %.  
 
5.2 Secondary Outcomes 
Secondary outcomes are as follows: 
- 
Absolute HbA1c reduction per stratification group (groups consist of HbA1c > 14 %, HbA1c < 
14 % and > 10 % and HbA1c < 10 %) 
- 
Change of HbA1c at 6 and 12 months after enrollment compared to control group 
- 
Proportion of patients achieving target per stratified group after 3 and 6 months without anti-
diabetic medication other than Metformin 
- 
Changes in pH, base excess and bicarbonate 90 minutes after bicycle exercise compared to 
baseline 
- 
Change of weight at 3, 6 and 12 months after enrollment compared to baseline and to 
standard of care 
- 
Changes in blood glucose at the end of, as well as 30 and 90 minutes after bicycle exercise 
compared to baseline 
- 
Feasibility of bicycle exercise at study enrollment in the ER, defined as absence of problem 
reports through the study team (e.g. patient cooperation) 
- 
Safety of bicycle exercise, defined as:  
o 
Absence of SAEs during the exercise 
o 
No signs of acute cardiopulmonary decompensation in the patient during bicycle 
exercise 
o 
No necessity to prematurely terminate the bicycle intervention because of other health 
or safety concerns 
- 
Safety of intensive lifestyle intervention within 3 months following study enrollment, with the 
following endpoints: 
o 
Number of SAEs in the intervention group compared to the control group 
o 
Number of rescue medication administered in the intervention group compared to the 
control group 
- 
Length of initial hospitalization, as well as number and length of re-hospitalizations and 
unplanned re-consultations within 3 months after initial consultation 
- 
Changes in physical activity at 6 months compared to baseline assessed by SIMPAQ 
questionnaire (Endpoint: hours of physical activity) 
- 
Changes in physical activity at 3 and 6 months compared to baseline assessed by actigraph 
(Endpoint: Stepgoal reached) 
- 
Number of anti-diabetic medication at 30, 60, 90 days, as well as 6 months and one year 
compared to baseline in both arms 
- 
Proportion of patients receiving insulin therapy after 6 months and one year in the intervention 
group compared to the control group 
- 
Absolute health-care related costs at 3, 6 and 12 months in both arms 
- 
Quality of life at 6 months in the intervention group compared to standard of care as assessed 
by SF-36 questionnaire. 
 
6. STUDY DESIGN  
General Study Design and Justification of Design  
This is an investigator-initiated, randomized, parallel design trial with one intervention arm (bicycle 
exercise followed by intensive lifestyle modification) and one standard-of-care arm in patients with newly 
diagnosed or medically untreated type 2 diabetes mellitus. The bicycle intervention at enrollment 
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comprises approximately two hours with pre- and post-preparations and 30 minutes of moderate 
physical activity on a bicycle. The whole study period takes one year for both arms. Subjects in the 
intervention arm will be contacted by the study psychologist by telephone on a weekly basis for coaching 
and follow-up. Actigraph data readout will occur at baseline, 3 and 6 months. Additionally, everyday 
physical activity will be assessed by the SIMPAQ questionnaire at baseline and 6 months. Regular 
routine follow-up visits will be done for both groups in the respective hospitals, outpatient clinics or by 
the subjects’ responsible general practitioner to acquire data on vital signs, glucose values and 
medication as well as adverse events. See Table 1 for further details.  
 
 
 
Figure 1 Schematic overview of study enrollment and initial intervention.  
 
 
Methods of Minimizing Bias  
 
6.1.1 
Randomization  
Participants will be randomized into the “lifestyle intervention” or “conventional anti-diabetic treatment” 
arm using a computer-generated random number in the electronic data managing application secuTrial®. 
Participants will be randomized 1:1 to the study groups. 
 
6.1.2 
Blinding Procedures  
Blinding of patients and study personal is not possible for this study.  
 
 
 
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7. STUDY POPULATION  
Eligibility Criteria  
Participants fulfilling all of the following inclusion criteria are eligible for the study 
- 
Able to give informed consent as documented by signature (Appendix ICF) 
- 
Type 2 diabetes diagnosed within the last two years according to the ADA-criteria 
- 
Age ≥ 18 years 
- 
HbA1c ≥ 7.5 % 
 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant: 
- 
Clinically instable patient as defined by the physicians on duty e. g. signs of new ischemia in 
the ECG, systolic blood pressure ≥ 200 mmHg, fever ≥ 38.5 °C, symptoms of SIRS or reduced 
vigilance. 
- 
Anti-diabetic medication for ≥ 24 hours 
- 
Inability to perform a bicycle exercise during 30 minutes 
- 
Previous lifestyle intervention by an endocrinologist 
- 
Engagement in physical activity more than five times per week 
- 
Enrollment in other interventional study 
 
Recruitment and Screening  
Patients are recruited after seeking medical consultation at the emergency room, medical outpatient 
clinic of the respective study centers or their general practitioners. Patients will be assessed and enrolled 
in the study by the study team. 
 
Assignment to Study Groups  
Patients are randomized to the intervention or the control arm using a computer-generated number after 
agreeing to participate in the study. 
 
Criteria for Withdrawal/Discontinuation of Participants  
Participants may withdraw or be withdrawn at any time. Subjects who discontinue participation may be 
replaced. Reasons for discontinuation are: 
- 
Participant withdraws informed consent 
- 
Participant does not comply with study treatment or the concomitant procedures. Non-
compliance for this study is defined as completion of less than 50% of the training program 
during two weeks 
- 
Pregnancy 
- 
Participant is no longer willing to continue the study because of any reason 
- 
The incidence or severity of adverse events (AEs) indicate a potential health hazard to the 
participant 
Withdrawal will be documented in the database with all other study data. 
 
 
 
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8. STUDY INTERVENTION  
Identity of Investigational Products (Treatment/Medical Device)  
There is no investigational product nor medical device used. 
 
8.1.1 
Experimental Intervention  
In this study’s interventional group no drugs except for the patient’s original medication and Metformin 
starting after 3 months are used. The 30 minutes bicycle exercise will be performed on a standard bike 
home trainer. 
 
8.1.2 
Control Intervention (Standard Treatment)  
Standard therapy for type 2 diabetes usually consists of a variation of oral anti-diabetic medication 
and/or s. c. insulin therapy as well as a limited lifestyle intervention according to national and 
international guidelines (American Diabetes 2018)12.  
 
Administration of Experimental and Control Interventions  
8.1.3 
Experimental Intervention  
Patients allocated to the intervention arm will be instructed to perform 30 minutes of bicycle exercise at 
60 % of the calculated maximum heart rate (MHR: 208 x (0.7 – age))20. During the following 3 months 
they will take part in an intensive lifestyle intervention. Patients in the intervention group may also start 
Metformin therapy (titrated to 1000 mg 1-0-1 unless there is medical contraindication) 3 months after 
study enrollment. The schedule for the intervention arm consists of 3 to 5 aerobic training sessions 
(duration 15-40 minutes each) and 2 resistance trainings per week, as well as weekly motivational 
coaching via telephone by the study psychologist. The training sessions will be put together by a team 
from the department of physical education of the University of Basel (DSBG, Departement für Sport, 
Bewegung und Gesundheit). All Patients in the intervention group will receive a training adapted to their 
capabilities by trainers from the DSBG. The overall physical activity level during the course of the study 
will be monitored by an actigraph provided by the DSBG and read out at baseline, 3 and 6 months. The 
weekly step count goal is 70’000 steps per week. Additionally, overall physical activity will be monitored 
by weekly telephone interviews as not all physical activity (i.e. bike hometrainer) is recorded by the 
actigraph. 
 
8.1.4 
Control Intervention 
The control arm for this study will receive standard type 2 diabetes treatment after study enrollment. 
This treatment usually consists of a limited lifestyle intervention and oral anti-diabetic medication (i.e. 
Metformin, SGLT2-inhibitors, DPP-Inhibitors, GLP-1-receptor agonists etc.) or insulin therapy. 
 
Dose/Device Modifications  
Therapy for the participants of the intervention group has to be reassessed if: 
- 
glucose values remain elevated above 15 mmol/l for more than 7 consecutive days 
- 
in case of symptomatic hyperglycemia or re-hospitalization 
In these cases, standard of care according to national and international guidelines will be implemented. 
 
Compliance with Study Intervention  
Patients in the intervention arm will be motivated by a specially trained psychologist and provided with 
an actigraph to monitor daily step count, overall physical activity and the scheduled training sessions. 
Personal motivation for the training sessions will be supported through telephone interviews, during 
study visits and with continuous self-evaluation. If the bicycle exercise is not completed or completed 
partly, this will be documented in the CRF. 
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Data Collection and Follow-up for Withdrawn Participants  
Participants may withdraw or be withdrawn at any time. Subjects who discontinue participation will not 
be replaced. Withdrawal will be documented in the database with all other study data. All gathered data 
and samples until withdrawal of informed consent will be used anonymously for analysis. Follow-up will 
not take place if the patient has withdrawn informed consent, in all other cases follow-up will take place 
as planned. 
 
Trial-specific Preventive Measures 
Participants of the bicycle and intensive lifestyle modification group will, in addition to the general clinical 
visits, be closely monitored and coached with weekly telephone calls, thereby ensuring appropriate 
glucose management. If needed, standard of care medical treatment will be initiated also in the 
interventional group. All patient specific data will be recorded in an electronic case report form (eCRF).  
Patients who were randomized into the intervention group will be instructed in correct self-measurement 
of blood glucose by a member of the study team at study enrollment or on visit 2. They will receive a 
blood glucose monitor to document fasting glucose every morning during the first week of the study. 
This way the study team is able to supervise the metabolic situation and may start rescue medication if 
needed. 
 
Concomitant Interventions (Treatments)  
Permitted concomitant treatments are all medication the patient has taken prior to the initial visit. We 
expect no influence on the study by treatment of other diseases. Not permitted are any oral anti-diabetic 
drugs (except for Metformin) or Insulin for the intervention group, except in case it needs to be 
administered as rescue medication. 
 
 
 
 
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9. STUDY ASSESSMENTS  
 
Study Flow Chart and Table of Study Procedures and Assessments 
Please refer to Table 1 and Figure 1. 
 
Assessments of Outcomes  
 
9.1.1 
Assessment of Primary Outcome 
Glycated hemoglobin A1c will be measured by the same means (POCT or venous blood sampling) as 
done at baseline, and 3 months after enrollment. 
 
9.1.2 
Assessment of Secondary Outcomes 
Please refer to chapters 5.2. 
 
9.1.3 
Assessment of Safety Outcomes 
9.1.3.1 
Adverse Events  
We consider the risks of this study to be very low. Possible risks may occur if glycemic control cannot 
be achieved and maintained with lifestyle intervention. Consequently, the patient may experience 
symptoms of hyperglycemia requiring further medical attention. Patients will be systematically 
questioned about the occurrence of AEs at each study visit. The patients’ safety will be monitored by 
assessment of blood sample parameters and the recording and evaluation of all study related AEs. 
9.1.3.2 
Laboratory Parameters 
Laboratory parameters to be monitored for patient safety will be blood glucose, glycated hemoglobin 
A1c, pH, bicarbonate and base excess.  
9.1.3.3 
Electrocardiography 
Patients will receive electrocardiographic diagnostics before enrollment into the study if deemed 
necessary by the treating physician. 
9.1.3.4 
Vital Signs 
Blood pressure, heart rate and body weight will be measured at each study visit. Additionally, blood 
pressure will be measured during bicycle intervention in 15-minute intervals. The intervention will be 
stopped if systolic pressure exceeds 240 mmHg. A member of the study team will be present at all times 
during the bicycle exercise. 
Please refer also to chapter 5.2. 
9.1.4 
Assessments in Participants who Prematurely Stop the Study 
Patients who prematurely withdraw from the study will be substituted. Withdrawal will be documented in 
the database with all other study data. Follow-up will not take place if the patient has withdrawn informed 
consent, in all other cases follow-up will take place as planned. 
 
Procedures at Each Visit 
9.1.5 
Visit 1: Day 0 – Initial Consultation 
All Patients will be recruited at the ER department or outpatient clinic of a participating study center or 
by their personal practitioner after presenting with a newly diagnosed or untreated type 2 diabetes 
mellitus. The treating physician will assess whether the patient is clinically fit to participate in the study 
and will order an ECG if necessary. 
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If the patient meets all of the inclusion and none of the exclusion criteria, he or she is required to sign 
the ICF. The patient will then be randomized 1:1 to the intervention or the control group. 
Medical history is taken followed by a physical examination and drawing of blood samples for a venous 
blood gas analysis (pH, pCO2, base excess, bicarbonate, glucose) and a baseline HbA1c (may be up 
to 14 days old).  
Patients allocated to the intervention group will then perform a 30-minute bicycle exercise at 60 % of 
the age-adjusted maximal heart rate. Blood samples will again be drawn at the end of the exercise as 
well as 30 and 90 minutes after its completion to determine blood glucose levels and to do a venous 
BGA at 90 minutes after the bicycle exercise. 
All participants of the intervention group will receive a structured plan for an intensive lifestyle 
intervention for the following 3 months as well as an actigraph provided by the DSBG to monitor daily 
physical activity between study visits. 
Patients allocated to the control group will receive the standard diabetes care practiced at the study 
center according to national and international guidelines. 
Patients will be discharged when clinically stable and no comorbidities require further hospitalization. 
 
9.1.6 
Visit 2-6: Day 2/7/30/60/90 – Study Visits 
At each study site the study visits will take place at the respective endocrine or medical policlinic. Study 
visit 2 will be combined with specific diabetes consultation where patients learn how to measure their 
blood glucose.  
Further study visits will be combined with regular check-ups for newly diagnosed diabetes patients. 
 
1. Vital signs (heart rate, blood pressure and body weight) will be measured at any study visit 
2. Patients will be questioned about the occurrence of AEs or other difficulties with the conduct 
of the study at any study visit 
3. HbA1c will be measured at visits 5 and 6 
4. Intervention group participants will be instructed in correct self-measurement of blood glucose 
by a member of the study team at study enrollment or on visit 2 and will receive a blood 
glucose monitor to document fasting glucose every morning during the first week of the study 
5. Patients will be instructed on when and how to measure their blood glucose at home by the 
diabetes counseling. For the study they will be asked to write down a diurnal profile of their 
blood glucose measurements three days before each study visit in addition to their regular 
measurements. For the diurnal profile fasting glucose in the morning as well as before each 
principal meal should be measured. To increase adherence they will receive reminders from 
the study team by telephone 
6. The self-evaluation of the lifestyle intervention will be discussed with the patient at visit 2 
7. Home measured blood glucose values will be discussed with the patients of the intervention 
group at any study visit 
8. SIMPAQ and SF-36 questionnaires will be filled out at visit 2 
9. In between visits 2-6 weekly coaching by phone will be held to improve the adherence to the 
lifestyle interventionActigraph readout will be conducted at visit 6 
10. Re-hospitalizations and unplanned physician consultations will be assessed through 
questioning at visit 6 in both arms 
11. Participants allocated to the control group will be monitored at 3 and 6 months after study 
entry. This means they do not participate in visits 2-5 and will only be seen by the study team 
for visit 6 and 7 after enrollment. They will therefore not be as closely monitored as the 
intervention group and will not receive weekly phone calls by the study psychologist 
 
9.1.7 
Visit 7: Day 180 – Follow Up 
1. Vital signs (heart rate, blood pressure, temperature) and weight will be measured 
2. Blood glucose and current HbA1c will be measured 
3. A blood sample will be drawn for asservation 
4. Patients of both study groups will fill out the SIMPAQ- and SF-36 questionnaire to evaluate 
quality of life and daily physical activity compared to baseline 
5. Anti-diabetic medication of the patient will be assessed through questioning 
6. Re-hospitalizations and unplanned physician consultations will be assessed through 
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questioning 
7. Patients who participated in the intervention group will be questioned about current physical 
activity levels and if they maintained the intense lifestyle intervention during the 3 months 
without weekly phone calls and further support by the study team 
8. Actigraph readout will be done 
 
9.1.8 
Visit 8: 1 Year – Telephone Follow Up 
Telephone follow-up visit with the general practitioner, treating endocrinologist or participant to inquire 
about HbA1c, weight and medication one year after study enrollment. This visit will be held for both 
groups. 
 
 
 
 
 
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10. SAFETY  
During the entire duration of the study, all serious adverse events (SAEs) are collected, fully investigated 
and documented in source documents and case report forms (CRF). Study duration encompasses the 
time from when the participant signs the informed consent until the last protocol-specific procedure has 
been completed, including a safety follow-up period.  
 
10.1.1 Definition and Assessment of (Serious) Adverse Events and Other Safety Related Events 
An adverse event (AE) is any untoward medical occurrence in a patient or a clinical investigation 
participant administered a pharmaceutical product and which does not necessarily have a causal 
relationship with the study procedure. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. 
ICH E6 1.2 
A serious adverse event (SAE) is classified as any untoward medical occurrence that: 
 
results in death, 
 
is life-threatening, 
 
requires in-patient hospitalization or prolongation of existing hospitalization, 
 
results in persistent or significant disability/incapacity, or 
 
is a congenital anomaly/birth defect. 
In addition, important medical events that may not be immediately life-threatening or result in death, or 
require hospitalization, but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed above should also usually be considered serious. ICH E2A 
SAEs should be followed until resolution or stabilization. Participants with ongoing SAEs at study 
termination (including safety visit) will be further followed up until recovery or until stabilization of the 
disease after termination.  
 
Assessment of Causality 
Both investigator and sponsor-investigator make a causality assessment of the event to the study drug, 
based on the criteria listed in the ICH E2A guidelines: 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The sponsor-investigator evaluates any SAE that has been reported regarding seriousness, causality 
and expectedness. If the event is related to the investigational product and is both serious and 
unexpected, it is classified as a SUSAR.  
 
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Assessment of Severity 
The grades for severity described in the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 5.0) are used.  
 
10.1.2 Reporting of SAEs and Other Safety Related Events  
 
Reporting of SAEs 
All SAEs must be reported immediately and within a maximum of 24 hours to the sponsor-investigator 
of the study. The sponsor-investigator will re-evaluate the SAE and return the form to the site. 
If it cannot be excluded that the SAE is attributable to the intervention under investigation, the 
Investigator reports it to the EC via BASEC within 15 days. lf the SAE occurs at one of the study sites, 
the coordinating investigator reports the events to the CEC within 15 days. The other ECs involved in 
the trial receive SAEs resulting in death in Switzerland via sponsor-investigator via BASEC within 7 days. 
Exemptions from expedited reporting may be possible if the SAE is either a clear result of the underlying 
disease or well-known and described in the currently approved product information (mainly for phase IV 
studies). Please define those SAEs that are exempted from expedited reporting. 
 
Reporting of SUSARs 
A SUSAR needs to be reported to the EC (local event via local investigator) via BASEC and to 
Swissmedic for category B and C studies (via sponsor-investigator) within 7 days, if the event is fatal, 
or within 15 days (all other events). 
The sponsor-investigator must inform all investigators participating in the clinical study of the occurrence 
of a SUSAR. All ECs involved in the trial will be informed about SUSARs in Switzerland via sponsor-
investigator via BASEC according to the same timelines. 
 
Reporting of Safety Signals 
All suspected new risks and relevant new aspects of known AEs that require safety-related measures, 
i.e. so called safety signals, must be reported to the sponsor-investigator within 24 hours. The sponsor-
investigator must report the safety signals within 7 days to the EC (local event via local investigator) via 
BASEC and to Swissmedic in case of a category B or C study. 
The sponsor-investigator must immediately inform all participating investigators about all safety signals. 
The other ECs involved in the trial will be informed about safety signals in Switzerland via the sponsor-
investigator. 
 
Reporting and Handling of Pregnancies 
Pregnant participants must immediately be withdrawn from the clinical study and substituted as 
gestational diabetes patients require a stricter blood glucose management and more likely an insulin 
therapy and therefore meet our exclusion criteria. Any pregnancy during the treatment phase of the 
study and within 30 days after discontinuation of the intervention will be reported to the sponsor-
investigator within 24 hours. The course and outcome of the pregnancy should be followed up carefully, 
and any abnormal outcome regarding the mother or the child should be documented and reported. 
 
Periodic reporting of safety 
An ASR is submitted once a year to the local EC via local investigator from all sites. The sponsor-
investigator prepares it, and then submits it to the participating investigators. The participating 
investigators submit it to the local committees. 
 
10.1.3 Follow Up of (S)AEs 
All subjects who experience AEs will be followed until the event resolves or until the subject’s 
participation in the study ends. For those AEs judged to be unrelated to the study intervention, the 
outcome at last observation will be recorded on the appropriate pages of the CRF. 
Subjects experiencing AEs that were judged to be possibly, probably, or definitely related to a study 
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intervention will be followed until the events resolve or until the event is judged to be chronic or stable. 
Resolution of such events will be documented on the appropriate pages of the CRF. 
 
11. STATISTICAL METHODS  
 
Hypothesis 
We hypothesize that lifestyle intervention lowers HbA1c effectively without antidiabetic drugs. The null-
hypothesis (H0) is that there will be no significant difference between the proportions of patients 
achieving metabolic control in the intervention group and the control group. The alternative hypothesis 
(H1) is that there will be significantly more patients achieving metabolic control in the intervention group. 
For the purpose of this study, metabolic control is defined as a fasting glucose < 7.6 mmol/l and an 
HbA1c below a target stratified for three groups according to HbA1c at baseline: HbA1c > 14 %  target 
< 10 %; HbA1c < 14 % and > 10 %  target < 8 %; HbA1c < 10 %  target < 7.5 %.  
 
Determination of Sample Size  
The aim of this study is to assess whether bicycle exercise followed by an intensive life style intervention 
can sufficiently restore metabolic control without anti-diabetic drugs as compared to a standard care 
control group. 
Based on our clinical experience we assume that 80 % in the intervention group will reach the primary 
endpoint of metabolic control with no anti-diabetic drugs compared to only 40 % in the standard care 
control group.  
A publication by Martinus et al.21 on adherence to a study sport program for newly diagnosed type 2 
diabetes mellitus patients, shows up to 80 % adherence for the group that was additionally supported 
by a psychologist for increased motivation. The adherence to the program was significantly better in the 
group with support by the psychologist, as were the results regarding improvement of physiological 
parameters such as body mass, fat mass or strength. 
A review on the effect of physical exercise on glycemic control found an average decrease of HbA1c by 
0.6 mmol/l through exercise22 in diabetes patients at least one year after diagnosis and with a moderate 
hemoglobin elevation. Based on this data, our target ranges were extrapolated for patients with new-
onset diabetes and higher HbA1c. 
The inclusion of 28 patients per group (n total 62 patients including 10 % lost to follow-up) will provide 
80 % power at an alpha level of 0.05. A number of 15 to 25 patients per center is envisaged. 
 
Statistical Criteria of Termination of Trial  
There will be no statistical criteria to terminate the trial early. 
 
Planned Analyses  
 
11.1.1 Datasets to be Analyzed, Analysis Populations 
Data will be analyzed as intention to treat after all participants have finished the study. 
 
11.1.2 Primary Analysis 
Analysis will be done by the investigators. For our primary analysis, we will compare the two arms with 
a Fisher’s exact test and we will also estimate effect size with a logistic regression model reporting odds 
ratios (OR) and corresponding 95% confidence intervals using STATA. All tests will be two tailed; p < 
0.05 will be defined as significant.  
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11.1.3 Secondary Analyses 
We will use the Wilcoxon Rank Sum test for not normally distributed data and Fisher’s exact test for 
categorical data to compare changes between the two groups. All tests will be two tailed; p < 0.05 will 
be defined as significant. Data will be analyzed using STATA, Graph Pad Prism and IBM SPSS. 
The parameters assessed via blood sampling during and after the bicycle exercise will be analyzed 
using descriptive statistics and appropriate graphical representation.  
Values of pH, base excess and bicarbonate at 120 minutes after beginning of the bicycle exercise will 
be compared to the baseline values using medians and interquartile range as well as appropriate 
graphical representation. The statistical significance of the difference between the two medians will be 
tested using the Wilcoxon signed-rank test for paired data. 
The same statistical procedure will be applied to the values of blood glucose at the end of, as well as 
60 and 120 minutes after beginning of the bicycle intervention. 
Safety outcomes (please refer to chapter 5.2) will be illustrated using descriptive statistics. 
Re-hospitalization and uplanned re-consultation rate 3 months after study enrollment will be quantified 
by number of hospitalizations and/or physician re-consultations as well as total length of 
hospitalization(s) in days. Data will be tested using the Mann-Whitney U-test. 
SIMPAQ questionnaire results will be depicted using descriptive statistics and medians of the two 
groups evaluated using the Mann-Whitney U-test. 
Results of the actigraph readouts at baseline, 3 months and 6 months will be compared inter-individually 
to assess if the endpoint has been fulfilled or not.  
Number of anti-diabetic medication at 1, 2, 3 and 6 months as well as one year compared to baseline 
will be depicted using Graph Pad Prism. Average number of medication in both groups will be compared 
at 3 and 6 months after baseline. 
Health-care related costs will be calculated for each study arm based on actual costs in respective 
cantons for medication as well as according to Tarmed (outpatient-clinic tariff system). 
SF-36 questionnaire will be evaluated using IBM SPSS and compared between the two groups using 
the Mann-Whitney U-test at baseline and after 6 months. 
 
11.1.4 Interim Analyses 
There are no interim analyses planned. 
 
11.1.5 Safety Analysis 
Descriptive analysis will be used. Please refer also to chapter 5.2 
 
11.1.6 Deviation(s) from the Original Statistical Plan  
Any deviation(s) from the original statistical plan will be described and justified in the protocol and 
reported to the EC. 
 
Handling of Missing Data and Drop-outs  
Results will be summarized using all available data. Multiple attempts will be made to obtain missing 
data. Missing data will not be imputed. Drop-outs will not be replaced. 
 
 
 
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12. QUALITY ASSURANCE AND CONTROL  
 
Data Handling and Record Keeping/Archiving  
 
12.1.1 Case Report Forms  
A subject screening and enrollment log will be completed for all eligible or non-eligible subjects with the 
reasons for exclusion. For each subject enrolled a CRF must be completed and signed by the principal 
investigator or co-investigator. Data will be transferred from the source documents directly to the e-CRF. 
All source documents, enrollment logs, p-CRFs, ICFs and other documents pertaining to the conduct of 
the study must be kept on file by the investigator for a minimum of 10 years after study termination. If a 
subject withdraws from the study, the reason must be noted in the enrollment log or p-CRF.  
All participants receive an identification number (ID) and no person identifying data such as name or 
initials are collected in the p-CRF. 
 
12.1.2 Specification of Source Documents  
Source data (visit dates, ICFs, SAEs, AEs, concomitant medication, results of relevant examinations, 
laboratory values, glucose readings) will be available at the site to document the existence of the study 
participants. Source data will include the original documents relating to the study, as well as the medical 
treatment and medical history of the participant. 
 
12.1.3 Record Keeping/Archiving  
All study data must be archived for a minimum of 10 years after study termination or premature 
termination of the clinical trial. 
 
Data Management  
 
12.1.4 Data Management System  
The study data collected in the p-CRF will be transferred to a web-based electronic data capture (EDC) 
system, named secuTrial® (version 5.3.4.6, 2018). Each EDC system of the participating centers runs 
on a server maintained by the appropriate IT-department of each hospital. The e-CRF is implemented 
by the research group in collaboration with the clinical trial unit (CTU) of the medical faculty at the 
University of Basel, Basel, Switzerland. 
Authorized persons at the study sites are responsible for data entry into the EDC system. 
 
12.1.5 Data Security, Access and Back-up  
The EDC system is accessible via a standard browser on an web-connected device. Password 
protection ensures that only authorized persons can enter the system to view, add or modify data 
according to their permissions.  
User administration and training is performed by the IT-department and CTU Basel according to 
predefined processes. 
A regular backup of the EDC study data is performed according to the processes of the IT-department 
of the University Hospital Basel. 
 
12.1.6 Analysis and Archiving 
The EDC system will be locked after all data is monitored and all raised queries have been resolved. 
Data is exported and transferred to the investigator by the CTU Basel according to internally defined 
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processes. The exported data will be archived by the investigator. 
Data for analysis will be extracted from the database export and analysis will be conducted with Graph 
Pad Prism. Source data/documents and p-CRFs will be stored at study site for at least 10 years and be 
destroyed thereafter. 
 
12.1.7 Electronic and Central Data Validation  
Data is entered into the eCRF (version 5.3.4.6, 2018) and can be validated for completeness and 
discrepancies automatically. 
An audit trail system maintains a record of initial entries and changes (reasons for changes, time and 
date of changes, user identification of entry and changes). 
Data entered into the eCRF will be reviewed by the responsible investigator and an independent monitor 
will raise queries using the query management system implemented. Designated investigators have to 
respond to the query and confirm or correct the corresponding data. Thereafter the monitor can close 
the query. 
 
 
Monitoring  
There will be a monitoring of the study by an independent, professional, qualified study monitor from the 
University Hospital Basel. There will be one initiation visit and one close-out visit. The source 
data/documents are accessible to monitors and questions are answered during monitoring. 
 
 
Audits and Inspections  
Authorized representatives of the national or local health authorities and ECs will be permitted to inspect 
or audit the facilities, records and original data relevant to this study. 
 
 
Confidentiality and Data Protection 
All personal and medical information obtained for this study is confidential and disclosure to third parties 
other than those noted below is prohibited. Participant’s data will be identified by study and subject ID 
number. 
Upon the participant’s permission, medical information will be given to his or her personal physician or 
other appropriate medical personnel responsible for her or his welfare. 
Data generated by this study must be available for inspection upon request by representatives of the 
appropriate national and local health authorities, and the EC for each study site, if appropriate. 
Source documents will be permitted to the study team and for purposes of monitoring, audits and 
inspections by local authorities and appropriate monitoring staff during and after the study. No third party 
will be given access to the source data. Data stored in the eCRF (secuTrial®, version 5.3.4.6, 2018) is 
anonymized. 
 
 
Storage of Biological Material and Related Health Data  
Health related data will be stored in an anonymized eCRF (secuTrial®, version 5.3.4.6, 2018).  
Additional samples will be taken and stored for 10 years, they will be destroyed thereafter. 
 
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13. PUBLICATION AND DISSEMINATION POLICY  
The study will be published in an international peer-reviewed journal irrespective of whether its results 
were positive or negative. 
 
 
14. FUNDING AND SUPPORT   
Funding (third-party) will be applied for after approval from EC and are secured in house. 
 
 
15. INSURANCE  
All assessments and information material mentioned and the smart watch device in this protocol are 
free of charge for the subject.  
The study procedures will be covered by the general liability insurance Helvetia of the University 
Hospital Basel, as will be certified by Legal Service, University Hospital Basel. A copy of the certificate 
will be filed in the investigator site file (ISF) and the trial master file (TMF). 
 
 
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16. REFERENCES  
1. Declaration of Helsinki, Version October 2013, 
(http://www.wma.net/en/30publications/10policies/b3/index.html )  
2. International Conference on Harmonization (ICH, 1996) E6 Guideline for Good Clinical 
Practice. 
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf) 
3. International Conference on Harmonization (ICH, 1997) E8 Guideline: General Considerations 
for Clinical Trials 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8
_Guideline.pdf) 
4. Humanforschungsgesetz, HFG Bundesgesetz über die Forschung am Menschen 
(Bundesgesetz über die Forschung am Menschen, HFG) vom 30. September 2011/ Loi 
fédérale relative à la recherche sur l’être humain (loi relative à la recherche sur l’être humain, 
LRH) du 30 septembre 2011 / Legge federale concernente la ricerca sull'essere umano 
(Legge sulla ricerca umana, LRUm) del 30 settembre 2011  
5. Verordnung über klinische Versuche in der Humanforschung (Verordnung über klinische 
Versuche, KlinV) vom 20. September 2013 / Ordonnance sur les essais cliniques dans le 
cadre de la recherche sur l’être humain (Ordonnance sur les essais cliniques, OClin) du 20 
septembre 2013. Ordinanza sulle sperimentazioni cliniche nella ricerca umana 
(Ordinanza sulle sperimentazioni cliniche, OSRUm) del 20 settembre 2013  
6. Heilmittelgesetz, HMG Bundesgesetz über Arzneimittel und Medizinprodukte 
(Heilmittelgesetz, HMG) vom 15. Dezember 2000 / Loi fédérale sur les médicaments et les 
dispositifs médicaux (Loi sur les produits thérapeutiques, LPT) du 15 décembre 2000 / Legge 
federale sui medicamenti e i dispositivi medici (Legge sugli agenti terapeutici, LATer)   
7. ISO 14155:2011 Clinical investigation of medical devices for human subjects -- Good clinical 
practice (www.iso.org) 
8. ISO 10993 Biological evaluation of medical devices (www.iso.org) 
9. MEDDEV 2.7/3 revision 3, May 2015 
10. Medizinprodukteverordnung (MepV) vom 17. Oktober 2001 / Ordonnance sur les dispositifs 
médicaux (ODim) du 17 octobre 2001 / Ordinanza relativa ai dispositivi medici (ODmed) del 
17 ottobre 2001. 
11. WHO, International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/)  
12. Standards of Medical Care in Diabetes—2018. Diabetes Care Jan 2018, 41 (Supplement 
1) S1-S2; DOI: 10.2337/dc18-Sint01 
13. Morrato  EH, Hill  JO, Wyatt  HR, Ghushchyan  V, Sullivan  PW: Physical activity in U.S. 
adults with diabetes and at risk for developing diabetes, 2003. Diabetes Care 2007;30(2):203–
9 
14. Johansen MY, MacDonald CS, Hansen KB, Karstoft K, Christensen R, Pedersen M, Hansen 
LS, Zacho M, Wedell-Neergaard A, Nielsen ST, Iepsen UW, Langberg H, Vaag AA, Pedersen 
BK, Ried-Larsen M. Effect of an Intensive Lifestyle Intervention on Glycemic Control in 
Patients With Type 2 DiabetesA Randomized Clinical Trial. JAMA. 2017;318(7):637–646. 
doi:10.1001/jama.2017.10169 
15. Espeland MA, Glick HA, Bertoni A, et al; Look AHEAD Research Group. Impact of an 
intensive lifestyle intervention on use and cost of medical services among overweight and 
obese adults with type 2 diabetes: the action for health in diabetes. Diabetes Care. 
2014;37(9):2548-2556. 
16. Gorter  KJ, van de Laar  FA, Janssen  PG, Houweling  ST, Rutten  GE.  Diabetes: glycaemic 
control in type 2 (drug treatments). http://clinicalevidence.bmj.com/x/systematic-
review/0609/overview.html. Accessed July 4, 2017. 
17. Balkau B, Mhamdi L, Oppert JM, et al. Physical activity and insulin sensitivity: the RISC 
study. Diabetes. 2008; 57 (10): 2613–8. 
18. Krotkiewski M, Lönnroth P, Mandroukas K, Wroblewski Z, Rebuffé-Scrive M: The effects of 
physical training on insulin secretion and effectiveness and on glucose metabolism in obesity 
and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia28 :881 –890,1985 
19. Smith, A. D., A. Crippa, J. Woodcock and S. Brage (2016). "Physical activity and incident type 
2 diabetes mellitus: a systematic review and dose-response meta-analysis of prospective cohort 
studies." Diabetologia 59(12): 2527-2545. 
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20. Franckowiak, Shawn C. et al. “Maximal Heart Rate Prediction in Adults That Are Overweight 
or Obese.” Journal of strength and conditioning research / National Strength & Conditioning 
Association 25.5 (2011): 1407–1412. PMC. Web. 4 June 2018. 
21. MARTINUS, R. , CORBAN, R. , WACKERHAGE, H. , ATKINS, S. and SINGH, J. (2006), 
Effect of Psychological Intervention on Exercise Adherence in Type 2 Diabetic Subjects. 
Annals of the New York Academy of Sciences, 1084: 350-360.  
22. Yang, Z., Scott, C.A., Mao, C. et al. Sports Med (2014) 44: 487. 
https://doi.org/10.1007/s40279-013-0128-8 
 
 
 
 
 
 
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17. APPENDICES 
17.1 SF-36 Questionnaire  
17.2 SIMPAQ Questionnaire 
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