Efficiency Comparison of Jarlsberg- and Norvegia Cheese on Bone Markers, Resting Metabolic Rate, Bone Mineral Density, Muscle Strength and Peak VO2 in Cross-Country Skiers of Both Sexes
Phase: NA
Conditions: Bone Health, Performance Enhancing Product Use
Sponsor: Meddoc

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
 
 
RESEARCH PROTOCOL 
 
Final Version 1.6 2nd. October 2023 
Final Version 1.7 8th. November 2023 
Final Version 1.8 5th. February 2024 
Final Version 1.9 29th. August 2024 
 
Title 
  
Efficiency Comparison of Jarlsberg- and Norvegia cheese on 
Osteocalcin and other Bone Markers; Estimation of the Jarlsberg 
cheese Effect on Resting Metabolic Rate, Bone Mineral Density, 
Muscle Strength and Peak VO2 in Cross-Country Skiers of both 
Sexes 
  
 
 
Protocol number: XCS-Jarlsberg/IIA 
EudraCT number: 2022-003264-24 
ClinicalTrial.gov: NCT05447936 
 
Sponsors:  
  
• 
TINE SA, Bedriftsvegen 7, 0950 Oslo, Norway 
• 
Norwegian Research Council 
 
Participating institutions: 
 
• Norwegian School of Sport Sciences. (NIH)Oslo Norway 
• Norwegian University of Life Sciences (NMBU) Ås Norway 
• Skjetten Medical Centre, (SMC) 2013 Skjetten, Norway 
• Østfold University College, (ØUC) Fredrikstad, Norway 
• Meddoc Research A/S. (MR) Hvamstubben 14, 2013 Skjetten, Norway 
• Drammen Hospital (DH), Vestre Viken 
• Clinic of Osteoporosis (CO), Oslo 
 
Project administration: 
Project Manager: Dr Helge E Lundberg, SMC/NIH 
Project Coordinator: Dr Med Vet Anne Cathrine Wist, TINE ASA 
Sport Medicine: Prof. Jorunn Sundgot Borgen, NIH  
Nutrition: Postdoc Dr Therese Fostervold Mathisen, ØUC 
Statistics and Data management: Prof. Emeritus Stig Larsen; Meddoc  
Laboratory Medicine: Prof. Emeritus Helge Holo, NMBU/Meddoc 
Osteoporosis & Rheumatology: Dr. Tove Tveitan Borgen, DH 
Endocrinology: Prof. Emeritus: Erik Fink Eriksen, CO 
 
CONFIDENTIAL  
The information in this document is confidential and will not be disclosed to others without written authorization from Meddoc A/S 
except to the extent necessary to obtain informed consent or for discussions with regulatory authorities, Independent Ethics 
Committees (IEXCS) or persons participating in the conduct of the study. 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
 
Preface 
 
Protocol Authorized:  Helge E Lundberg1, Jorunn Sundgot Borgen2 and  Stig Larsen3. 
Qualifications:  
1 General Practitioner & Sport Medicine  
2 Professor: Physical activity and health  
3 Professor Emeritus: Controlled Clinical Research Methodology and  
  Statistics 
 
 
Signature 1 …............................................................... 
 
Signature 2…………………………………………… 
 
Signature 3…………………………………………… 
 
 
 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
Contact names and addresses. 
Dr. Helge Lundberg 
General Practitioner (GP) and principal investigator  
Skjetten Legesenter, 2013 Skjetten Norway 
Phone: +47 648 31 880/ +47 996 99 619 
E-mail: hl@meddoc.no 
 
Dr. Anne Cathrine Whist 
Research Director TINE SA  
Phone: +47 415 77 778 
Email: Anne.Cathrine.Whist@tine.no 
 
Prof. Jorunn Sundgot Borgen  
Department of Sports Medicine  
Norwegian School of Sport Science   
Phone: +47 232 62 335 / +47 922 41 745 
E-mail: jorunn.sundgot-borgen@nih.no 
 
Dr. Therese Fostervold Mathisen 
Faculty of health welfare and organisation 
Østfold University College 
Phone: +47 957 52 818 
E-mail: theresfm@hiof.no  
 
Prof. Emeritus Stig Larsen 
Meddoc AS 
Phone:  +47 413 26 325 
E-mail: stig.larsen@nmbu.no 
 
Ingvild Lunde, MSc 
Clinical Monitor 
Meddoc Research AS, Hvamstubben 14, 2013 Skjetten Norway 
Tel. +47 468 41 367 
E-mail: IL@meddoc.no 
 
Prof. Emeritus: Erik Fink Eriksen 
Clinic of Osteoporosis 
Spesialistsenteret i Pilestredet, Pilestredet park 12 A, 0176 Oslo 
Tel. +47 229 92 700 
E-mail: efinkeriksen@gmail.com 
 
Hans E Fagertun, MSc  
Statistician 
Meddoc Research AS, Hvamstubben 14, 2013 Skjetten Norway 
Tel. +47 926 42 970 
E-mail: hf@meddoc.no 
 
Vivy Liang Larsen, MSc. 
Data Manager 
Meddoc Research AS, Hvamstubben 14, 2013 Skjetten, Norway 
Tel. +47 412 93 161 
E-mail: vl@meddoc.no 
 
Dr. Tove Tveitan Borgen 
Rheumatologist  
Drammen hospital  
Tel.: + 47 959 33 386 
E-mail: Tove.tveitan.borgen@vestreviken.no 
 
 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
List of Abbreviations 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
BALP 
Bone specific alkaline phosphatase 
BMD 
Bone mineral density 
CRF 
Case Report Form 
cOC 
Carboxylated Osteocalcin 
CTCAE 
Common Toxicity Criteria 
CTX-1 
Collagen 
DEXA 
 Bone Densitometry by X Ray 
DH 
Drammen Hospital 
DHNA 
1,4- Dihydroxy naphthoic Acid 
DM 
Data Management 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
ID 
Identification 
IEC 
Independent Ethical XCS Committee 
LH 
Luteinizing hormone 
MS 
Muscle Strength 
NMBU 
Norges Miljø- og Biovitenskaplige Universitet 
OED 
Optimal Efficacy Dose 
OR 
Osteocalcin ratio 
PI 
Principal Investigator 
PINP 
Procollagen 
PTH 
Parathyroid hormone 
RSP 
Response Surface Pathway design 
ucOC 
Undercarboxylated osteocalcin 
SAE 
Serious Adverse Event 
SAS 
Statistical Analyses System 
SD 
Standard Deviation 
SMC 
Skjetten Medical Centre 
SOP 
Standard Operating Procedure 
VO2 
Peak Oxygen uptake 
XCS 
Cross-country skiers 
 
 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
Distribution of Clinical trial Protocol  
 
Complete Version 
Date 
Writer 
Receivers 
Internal 
review 
Date 
released 
Version 01 
07.01.22 
HEL 
SL  
No 
No 
Version 02 
14.01.22 
HEL 
SL  
No 
No 
Version 03 
21.01.22 
HEL 
SL  
No 
No 
Version 04 
28.01.22 
HEL 
SL  
No 
No 
Version 05 
04.02.22 
HEL 
SL  
No 
No 
Version 06 
01.09.22 
HEL 
SL, JSB, TFM 
No 
No 
Version 07 
08.09.22 
HEL 
SL 
No 
No 
Version 08 
23.09.22 
HEL 
SL 
No 
No 
Final Version 1.0 
27.09.22 
HEL 
SL, JSB, TFM, HH, HF, VL, NT, ACW 
Yes 
No 
Final Version 1.1 
11.10.22 
HEL 
SL, JSB, TFM, HH, HF, VL, NT, ACW, TTB 
Yes 
No 
Final Version 1.2 
25.01.23 
HEL 
SL, JSB, TFM, HH, HF, VL, NT, ACW, TTB, EFE 
Yes 
N 
Final Version 1.3 
21.03.23 
HEL 
SL, JSB, TFM, HH, HF, VL, NT, ACW, TTB, EFE 
Yes 
Yes 
Final Version 1.4 
23.07.23 
HEL 
SL, JSB, TFM, HH, HF, VL, NT, ACW, TTB, EFE 
Yes 
Yes 
Final Version 1.5 
23.08.23 
HEL 
SL, JSB, TFM, HH, HF, VL, NT, ACW, TTB, EFE 
Yes 
Yes 
Final Version 1.6 
2.11.23 
HEL 
SL, JSB, TFM, HH, HF, VL, NT, ACW, TTB, EFE,IL 
Yes 
Yes 
Final Version 1.7 
8.11.23 
HEL 
SL, JSB, TFM, HH, HF, VL, NT, ACW, TTB, EFE,IL 
Yes 
Yes 
Final Version 1.8 
5.02.24 
HEL 
SL, HF, VL, ACW, TTB, EFE,IL 
Yes 
Yes 
Final Version 1.9 
29.08.24 
HEL 
SL, HF, VL, NT  
Yes 
Yes 
 
SL: 
Stig Larsen 
HEL: Helge Einar Lundberg 
HH: 
Helge Holo 
HF:  
Hans Fagertun 
VL: 
Vivy Larsen 
NT: 
Natharat Thiendilokkul 
JSB: 
Jorunn Sundgot Borgen 
TFM: Therese Fostervold Mathisen 
ACW:  Anne Cathrine Whist 
TTB:   Tove Tveitan Borgen 
EFE:    Erik Fink Eriksen 
 
 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
Contents  
RESEARCH PROTOCOL .......................................................................................................... 1 
Preface  ............................................................................................................................................. 2 
Contact names and addresses. ............................................................................................................. 3 
List of Abbreviations ........................................................................................................................... 4 
Distribution of Clinical trial Protocol .................................................................................................. 5 
Contents  ............................................................................................................................................. 6 
I: Synopsis .............................................................................................................................................. 8 
1.1: Project title ................................................................................................................................... 8 
1.2: Protocol numbers.......................................................................................................................... 8 
1.3: Objectives ..................................................................................................................................... 8 
1.4: Population and sampling .............................................................................................................. 8 
1.5: Design and randomization ............................................................................................................ 8 
1.6: Study procedure............................................................................................................................ 8 
1.6.1 Screening: ....................................................................................................................................... 8 
1.6.2 First comparison part: ..................................................................................................................... 8 
1.6.3 Second comparative part: ............................................................................................................... 9 
1.6.4 Dietary Monitoring: ........................................................................................................................ 9 
1.7: Main variables ............................................................................................................................ 10 
1.8: Sample size ................................................................................................................................. 10 
1.10: Flow Chart ................................................................................................................................ 11 
II: Introduction .................................................................................................................................... 12 
2.1: Background ................................................................................................................................ 12 
2.2: Osteocalcin and Vitamin K ........................................................................................................ 14 
2.3: Jarlsberg versus Norvegia Cheese .............................................................................................. 15 
2.4: Objectives. .................................................................................................................................. 16 
III: Population and sampling ............................................................................................................. 17 
3.0: Study unit ................................................................................................................................... 17 
3.1: Reference population.................................................................................................................. 17 
3.2: Study population ........................................................................................................................ 17 
3.2.1: Inclusion criteria. ......................................................................................................................... 17 
3.2.2: Exclusion criteria......................................................................................................................... 17 
3.3: Recruitment of athletes ............................................................................................................... 17 
IV: Design and randomization ........................................................................................................... 18 
4.1: Study design ............................................................................................................................... 18 
4.2: Randomization ........................................................................................................................... 18 
14.3: Power Analysis ......................................................................................................................... 18 
4.4: Identification of subjects ............................................................................................................ 18 
V: Evaluation ....................................................................................................................................... 19 
5.1: Osteocalcin and vitamin K ......................................................................................................... 19 
5.3: Bone mineral density (BMD) ..................................................................................................... 19 
5.4: Muscle strength .......................................................................................................................... 20 
5.5: Peak VO2 .................................................................................................................................... 20 
5.6. Resting metabolic rate (RMR) ................................................................................................... 20 
5.7: Laboratory variables ................................................................................................................... 21 
5.7.1 Biochemical variables: .................................................................................................... 21 
5.7.2 Lipids: .............................................................................................................................. 21 
5.7.3 Bone Turnover markers ................................................................................................... 21 
5.7.4 Sex hormones: ................................................................................................................. 21 
5.7.5: Haematology .................................................................................................................. 21 
5.8: Diet registration .......................................................................................................................... 21 
5.9: Menstruation status .................................................................................................................... 22 
5.10: Cheese, supplement, and activity registration .......................................................................... 22 
5.11: Compliance .............................................................................................................................. 22 

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5.12: Adverse Events (AE) ................................................................................................................ 22 
5.12.1: Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) .............................. 22 
5.12.2:  Grading and classification ........................................................................................................ 23 
5.12.3: Reporting adverse events. ......................................................................................................... 23 
5.13 Patient factors, Vital signs, and Physical examination. ............................................................. 24 
VI: Study procedure ............................................................................................................... 25 
6.1: Definitions .................................................................................................................................. 25 
6.2 Clinical procedure ....................................................................................................................... 25 
6.2.1 Screening: ..................................................................................................................................... 25 
6.2.2: Start-up Day: ............................................................................................................................... 25 
6.2.3 Comparative phase 1: ................................................................................................................... 26 
6.2.3 Comparative phase 2: ................................................................................................................... 26 
6.2.4 Dietary monitoring: ...................................................................................................................... 26 
6.3: Treatment administration of the study ........................................................................................ 26 
6.3.1 Administration and doses ............................................................................................................. 26 
6.3.2 Cheese supply, packing and storage. ............................................................................................ 27 
6.4: Stopping rule .............................................................................................................................. 27 
6.5: Procedures for Blood sampling and analysis. ............................................................................ 27 
6.6: Report of serious adverse effect (SAE) ...................................................................................... 28 
6.7: Time schedule ............................................................................................................................ 28 
6.8: Flow diagram ............................................................................................................................. 29 
VII: Project management and Monitoring ....................................................................................... 30 
VII. Consideration ............................................................................................................................... 32 
8.1: Consideration of steering committee .......................................................................................... 32 
8.2: Approval of the project .............................................................................................................. 32 
8.3: Informed consent ........................................................................................................................ 32 
8.4: Protection of personal data ......................................................................................................... 33 
IX. Data Management ......................................................................................................................... 34 
9.1: Electronical Case Record Forms (eCRF) ................................................................................... 34 
9.2: Study Database ........................................................................................................................... 34 
9.3: Data handling ............................................................................................................................. 34 
X: Discontinuation of treatment ........................................................................................................ 35 
XI Statistical Model ............................................................................................................................. 36 
11.1 Presentation of results ............................................................................................................... 36 
11.2 Statistical methods ..................................................................................................................... 36 
11.3 Power analysis and sample size determination ......................................................................... 36 
XII: Operational Matter ..................................................................................................................... 37 
12.1: Investigator’s agreement .......................................................................................................... 37 
12.2: Instructions ............................................................................................................................... 37 
12.3: Amendments to the protocol .................................................................................................... 37 
12.4: Protocol deviations ................................................................................................................... 37 
12.5: Compliance monitoring ............................................................................................................ 37 
12.6: Responsibilities ........................................................................................................................ 37 
12.7: Confidentiality .......................................................................................................................... 37 
XIII Amendment ................................................................................................................................. 38 
13.1: Menstruation status ( pkt. 5.9, 1.6 & 1.10) ............................................................................... 38 
13.2: Inclusion criteria ( pkt. 3,1 & 3.2 and 1.4) ............................................................................... 38 
XIV References .................................................................................................................................... 39 
XV Appendix ....................................................................................................................................... 41 
14.1: 
Serious Adverse Event Form ............................................................................................. 41 
14.2: 
The set of CRF’s ................................................................................................................ 41 
14.3: 
Monitoring report form ..................................................................................................... 41 
14.4: 
CV investigators and study coordinators ........................................................................... 41 
14.5: 
Patient information ............................................................................................................ 41 
 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
I: Synopsis 
1.1: Project title 
Comparison of Jarlsberg- and Norvegia cheese efficiency on Osteocalcin (OC) and Bone 
Turnover Markers (BTM); Evaluation of the effect of Jarlsberg cheese on BTM, Resting 
Metabolic Rate (RMR), Bone Mineral Density (BMD), Muscle Strength (MS) and Peak VO2 
in Cross-Country Skiers (XCS) of both sexes 
1.2: Protocol numbers 
Protocol number: XCS-Jarlsberg/IIA 
Regional Ethical Committee number: 537024  
EudraCT number: 2022-003264-24 
ClinicalTrial.gov: NCT05447936 
1.3: Objectives 
The study objective consists of the following two aims: 
1. Compare the effect of daily intake of Jarlsberg and Norvegia cheese in change of the 
OC level and Carboxylated Osteocalcin(cOC), Bone Mineral Density (BMD), 
Trabecular bone score (TBS) and other bone markers in active XCS of both genders. 
2. Compare the effect daily intake of Jarlsberg and Norvegia cheese in change of the 
Resting metabolic rate (RMR), Muscle Strength (MS), LM and Peak VO2 in active 
XCS of both genders. 
1.4: Population and sampling 
The study population consists of active XCS of both genders past 17 years of age for females 
and 18 years for males. 
1.5: Design and randomization 
The study is performed as an open randomized stratified parallel group designed trial with two 
strata. Gender is used as a stratification factor. The two equal sized strata are chosen because 
of different OED of cheese for women and men, and because the dose-response study 
previously performed has shown different response in men and women. 
1.6: Study procedure  
1.6.1 Screening: 
The recruited XCS fulfilled the inclusion and avoiding exclusion criteria for the study, will 
undergo a screening investigation of 1 week. The candidate for participation fulfilling the 
criteria and signed the informed consent form for participation will be included in the study. 
Physical activity and diet registration will be performed. The week before the first investigation, 
the participants will be asked to fill in their diet for four days in a data application created for 
this study. The diet registration will be performed and monitored. 
1.6.2 First comparison part: 
The duration of the first comparative part is eight weeks. The XCS will randomly be allocated 
(1:1) to either daily intake of Jarlsberg cheese or Norvegia cheese for 8 weeks. The daily intake 
of Jarlsberg® cheese will be the sex-related estimated optimal efficacy dose (OED) for XCS 
and the comparative dose of Norvegia. The two cheese doses are nearly equal regarding total 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
energy, protein, carbohydrate, fat, and calcium. The trial cheese can be consumed with other 
food at breakfast, lunch, or other meals during the day. The daily doses of both cheeses will be 
5 slices of cheese (75g/day) for females and 6 slices (90g/day) for males 
The first clinical investigation in the study will take place and is denoted as Day 0. The 
participants will receive a study identification number and be informed not to use other cheese 
than the one received in the study. During this initial clinical examination, all demographic 
data, social factors, history of disease and vital signs will be recorded. Blood samples will be 
drawn fastening for measurements of Osteocalcin and vitamin K2; Haematological and 
biochemical variables like HbA1C and Lipids, magnesium, calcium, phosphate, and urea; 
Collagen (CTX-1) and procollagen (PINP), parathyroid hormone (PTH), and bone specific 
alkaline phosphatase (BALP); Estradiol and testosterone; LH, FSH and SHBG. Additionally, a 
DXA with VAT and Bodyfat (BF) investigation will be performed. In addition to BMD and 
TBS, the body composition variables  Lean body mass (LM) and Fat free mass (FFM),  will be 
measured together with RMR, muscle strength and Peak VO2 before starting the clinical part. 
After four weeks the participants will meet for the second visit. Blood samples for 
measurements Osteocalcin and the specific bone turnover markers (BTM) will be drawn. The 
participants  will be given a new sample of cheese and calcium tablets for the next four weeks 
and new date for the next visit. 
Diet registration for four days will be performed in the data application every 8 weeks in the 
study. The diet registration will be monitored by a professional nutritionist.  
The last investigation in this first comparative part of  will take place at week 8. The participants 
will undergo a common clinical examination like the one performed initially. Blood samples 
for measurements of Osteocalcin, vitamin K2, and BMT will be taken. Haematological and 
biochemical variables except for vitamin D, parathyroid hormone (PTH), Estradiol and 
testosterone; LH, FSH and SHBG will be measured. 
1.6.3 Second comparative part:  
The duration of the second comparative part is 16 weeks and starts at study-week 8. The 
participants will receive new cheese, and calcium tablets every 4 weeks and meet for new 
clinical examination every 8 weeks. 
The first clinical examination the this second comparative part will be performed at study-
week 16. A diet registration will be performed the last week before the visit. A common 
clinical examination will be performed and blood samples for measurements of Osteocalcin, 
vitamin K2, the specific BTMs, sex hormones and biochemical variables will be drawn. The 
participants  will be given new sample of cheese and calcium tablets for four weeks and a date 
for the next visit. 
This visit performed at week 24 is the last in clinical examination in the study and equal to the 
initial study visit. Blood samples will be taken for measurements of Osteocalcin, BTMs, 
vitamin K2 and biochemical and haematological variables. Sex hormones, muscle strength, 
Peak VO2, DXA investigation for BMD, TBS and LM, and RMR will be measured in the 
same way as at day 0. 
The female participants will be interviewed about their menstruation status including 
menarche length, cycles day and use of hormonal contraception.  
 
1.6.4 Dietary Monitoring:  
The participants will fill in their dietary intake in an application at baseline and every 8th 
week of the study. During the last visit an Eating Disorder Examination Questionnaire- Short, 
(Prenjak K, et al BMC Psychiatry 2020;20:1–7) derived from EDE-Q © Fairburn and Beglin, 
2008 will be a part of the interview. 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
The questions will be woven into the anamnestic interview and not as a questionnaire to 
ensure that the participants do not suffer from disordered eating.  
1.7: Main variables 
The main variables in this study will be the Osteocalcin development, BTMs, RMR and BMD. 
Supporting variables are muscle strength, LM and Peak VO2 and gender hormones. The 
vitamin K2 variants MK-7, 8, 9, 9(4H), HbA1C, vitamin D, Ca++, Mg++ and urea, will be 
secondary variables. As safety variables, haematological- and biochemical variables and 
adverse events (AE) will be recorded at each visit. The participants’ activity will be 
continuously recorded. 
1.8: Sample size 
With a significant level of 5%, a power of 90% and a clinically relevant difference in total 
osteocalcin increase of one-time SD between the two groups, at least 24 XCSs in each group 
must be included. By correcting for dropouts during the first part of the study, 30 XCS will be 
included in each group. Totally 60 XCSs will be recruited for participation. 
 
1.9: Study duration 
The duration of the study will be 24 weeks for each participant.  
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment period of XCS  
 
 
 
01.01-31.05.23 
    
Inclusion of the first participant  
 
 
 
17th April 2023           
Inclusion of the last participant 
 
 
 
28th April  2023      
     
Last participant finalized comparative study part 
 
23rd June 2023                
Last patient finalized follow-up part  
 
 
14th Oct 2023      
 
 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
1.10: Flow Chart 
 
 
 
Comparison part I 
 
 
Comparison part II 
 
 
Week 0 
Week 4 
Week 8 
Week 16 
Week 24 
Jarlsberg cheese group 
x 
 
x 
x 
x 
Norvegia cheese group 
x 
 
x 
x 
x 
Inclusion / Exclusion 
criteria. 
x 
 
 
 
 
Patient factors 
history of disease 
x 
 
 
 
 
 
Concomitant treatment 
Diet registration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
- Blood pressure 
- Pulse rate 
- Body weight 
x 
x 
x 
x 
 
 
 
x 
x 
x 
x 
Blood sampling 
Bone specific markers 
Osteocalcin-Vitamin K 
-HbA1C & Lipids 
-Vitamin D 
 
Sex Hormones 
-Haematological 
-Biochemical 
 
DXA; BMD, TBS, RMR 
LM, MS & Peak VO2 
Physical training  
 
x 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
 
x 
x 
 
 
 
x 
 
x 
 
 
 
x 
 
x 
x 
 
 
 
x 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Menstruation status 
 
 
 
 
x 
Adverse Events [CTCAE] 
x 
x 
x 
x 
x  
Cheese compliance 
End-of-study 
 
x 
x 
x 
x 
x 
 
 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
II: Introduction 
2.1: Background  
 
Athletes competing in endurance sports are frequently exposed to episodes of Low Energy 
Availability (LEA) in association with the demands of their sport. It is proposed in the Relative 
Energy Deficiency in Sports (REDs), and the Female Athletic Triade, that LEA compromises 
bone health in both male and female athletes1. LEA is characterized by the perturbation of 
several hormones involved in the regulation of bone (re) modelling. LEA also causes menstrual 
disturbances; the most severe one is functional hypothalamic amenorrhea (FHA). This 
condition is reversible, but is considered a challenge for athletes, because either less training or 
increased energy intake is required. The highest prevalence of menstrual disturbances is seen 
in leanness and endurance sports such as running2. Not until recently the existence of LEA 
associated with bone loss was acknowledged in men, and therefore there are scarce data in male 
WBEA. Studies have shown that high-impact -exercise training can be highly osteogenetic with 
a low energy cost. Low repetition high-impact interventions have been shown to increase bone 
mineral density (BMD), cortical thickness and estimated strength, and preliminary evidence 
suggests that some of these effects may occur despite LEA3. Prolonged moderate impact 
exercise may help mitigate effects of short-term LEA, but it is unclear whether this would be 
of benefit to long-term bone health3. Given that bone health in endurance athletes can be 
compromised due to LEA, investigation of methods which may protect bone health in the face 
of LEA is of clinical importance4. 
The RED-S is a great problem in endurance sports. WBEA like cross country skiers often 
suffers from this condition. In case of muscular loss and bone stress injuries they miss a lot of 
training, and both their performance and their physical and mental well-being will suffer from 
this1,6. Cross Country Skiers (XCS) must train for several years to develop their full potential, 
and few other endurance sports (except for instance bicycling/swimming) have a higher demand 
for training volume to achieve this7. The procedures that have been suggested to treat LEA-
related conditions have not been verified by controlled clinical trials, and further studies to 
clarify and improve our knowledge must be performed. 
It is well established that dietary calcium and vitamin D are beneficial for skeletal health. 
Additionally, it has been documented that vitamin K has beneficial effects on the skeleton7. 
Activated or carboxylated osteocalcin has a key role in bone-formation ,8,9. It is one of the 17 
body’s GLA proteins and activated in a process involving vitamin K2. In Japan, vitamin K has 
been approved as an aid for treating osteoporosis, but the doses recommended are high and the 
efficiency is limited or absent10. 
Many dairy products are good calcium sources and cheese is an important source of vitamin K2. 
This indicates that cheese consumption may strengthen bones, but the effect of eating cheese 
rich in vitamin K2 have not been studied abundantly.  
There are several vitamin K variants, and the long-chained vitamin K2 variants have proven to 
be much more efficient in activating osteocalcin than short chained K2 or K1. In the western 
diet, fermented dairy products such as cheese are the best sources of long-chain vitamin K2, and 
health benefits related to vitamin K in cheese have been reported11,12,13,14. Jarlsberg cheese has 
been shown to be particularly rich in vitamin K2. In a recently published dose-response study, 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
aiming to estimate an optimal daily Jarlsberg dose related to carboxylation of osteocalcin, gave 
some unexpected and interesting results15,16. The carboxylated osteocalcin(cOC) and the 
osteocalcin ratio (R0 = cOC/ucOC) increased significantly with increasing Jarlsberg dose up to 
60 g/day before it flattened out and even declined. The surprise was that the total osteocalcin 
(tOC=cOC + ucOC) increased significantly with 46.1% after a few weeks of daily Jarlsberg 
cheese intake. These results were verified in our next study aiming to estimate a maintenance 
daily dose of Jarlsberg. To the best of our knowledge, no clinical study has previously showed 
that the OCN level can be increased by food. However, laboratory animal study has shown that 
1,4-dihydroxy-2-naphthoic acid (DHNA) increases the tOC level and showed an anti-
osteoporotic effect in ovariectomized mice with increasing of bone density and trabecular 
thickness17. 
In our comparative study the effect of Jarlsberg Cheese was compared with the effect of 
Camembert cheese not containing vitamin K2 and DHNA18. No differences were detected 
between the groups regarding haematological variables, but interesting differences were 
detected in the biochemical variables. Serum Calcium, Magnesium, and HbA1c were 
significantly reduced in the Jarlsberg group, but found unchanged in the comparative group. 
PINP, tOC, cOC, RO and vitamin K2 increased significantly (p<0.01) after 6 weeks in the 
Jarlsberg-group. PINP remained unchanged in the Camembert-group. The other variables 
decreased slightly in the Camembert-group but increased significantly (p≤0.05) after switching 
to Jarlsberg®. No CTX-changes detected in neither of the groups. Serum triglycerides increased 
slightly in both groups. Switching to Jarlsberg, total cholesterol and LDL-cholesterol were 
significantly reduced (p≤0.05). HbA1c, Ca++ and Mg++ were significantly reduced in the 
Jarlsberg-group, but unchanged in the C-group. Switching to Jarlsberg, HbA1c and Ca++ 
decreased significantly. The effect of daily Jarlsberg® intake on increased s-osteocalcin level is 
not a general cheese effect. Jarlsberg® containing vitamin K2 and DHNA which increases PINP, 
tOC, cOC and RO and decreases Ca++ and Mg++. These effects reflect increased bone anabolism.  
 
The dominating vitamin K2 vitamer is MK-9 in most cheeses, but the amount varies 
considerably19. However, some cheeses also contain MK-9(4H). Jarlsberg cheese is rich in 
this compound20. This cheese is made with lactic acid bacteria producing MK-8 and MK-9 
and Propionibacterium freudenreichii (PF) producing MK-9(4H). In the fermentation process 
to obtain the vitamin K2 vitamer MK-9(4H), PF additionally produces DHNA. We have 
shown that Jarlsberg cheese contains both the vitamin K2 vitamers and DHNA. The results 
from our studies make Jarlsberg cheese consumption very promising and we argue that it 
should be investigated whether Jarlsberg Cheese might prevent reduced BMD.  
Our previous studies have been performed on healthy premenopausal women between 25 and 
50 years of age and the estimated daily optimal efficacy dose (OED) of Jarlsberg was 60 
grams. The study population was chosen because most of the osteoporotic patients are 
women16.  
Osteoporosis represents substantial health related- and social challenges. Although bone loss 
is most common among women and elderly persons of both genders, it also affects the 
younger generation. Young athletes are frequently exposed to microfractures, and the 
syndrome of Relative Energy Deficiency in Sport (RED-S) with or without disordered eating, 
is as mentioned a widespread problem among athletes in weight-dependent sports such as 

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running and cross country skiing3,21. The syndrome causes impairment of metabolic rate, 
menstrual function, bone health, immunity, protein synthesis and cardiovascular health. The 
aetiological factor of this syndrome is low energy availability2. Our results, supported by 
other international studies22-26, strongly indicate that the compounds of Jarlsberg cheese may 
have a promising prophylactic effect on reduced BMD and might affect lipid levels and 
glucose metabolism. Osteocalcin is showed to build strong bones by increasing the BMD, 
improve muscular strength, stimulate testosterone production; it has a beneficial effect on 
cardiac health, lipid pattern and adopositas22-26. Daily intake of Jarlsberg cheese may have a 
general positive impact on young athletes by protecting against different diseases due to the 
contents of DHNA and vitamin K2. DHNA is showed to increase trabecular thickness in 
ovariectomized mice17. Cheese has not been regarded as a particularly healthy food because 
of the contents of milk fat. For young athletes, however the extra energy supply by the cheese 
is a positive factor in the face of LEA. We do not yet know if the Jarlsberg® Cheese could be 
used as a food supply to improve bone health, and we do not know if it could help young 
athletes to maintain or improve bone health. 
Since young XCS are at risk for LEA and RED-S, we want to perform studies on XCS 
athletes. 
Recently a dose response study on XCS was performed, and OED for female athletes was 
estimated to 70 grams of Jarlsberg ® Cheese, and 80 grams for male athletes to increase the 
tOC and cOC27. The effect of this OED should be tested. All previous studies show a 
significant decrease in serum magnesium and calcium, and a significant increase of serum 
urea and serum phosphate. The increase in BMD is not significant, but the increase in RMR 
is.  
 
 2.2: Osteocalcin and Vitamin K 
Activated osteocalcin has a key role in bone formation and maintenance. It is one of the 
body’s 17 so called GLA proteins, all of which being activated by carboxylation in a process 
involving vitamin K. While vitamin K dependent coagulation factors are practically fully 
carboxylated under normal conditions, osteocalcin is not. The ratio of fully carboxylated to 
under carboxylated osteocalcin in the blood (OR) reflects a person’s vitamin K status. The 
high levels of under carboxylated osteocalcin in healthy people indicate that suboptimal 
vitamin K status or subclinical vitamin K deficiency is common in Western societies 23. Very 
low ORs have been associated with osteoporotic fractures 26. 
Figure 1 shows the structure of common forms of vitamin K. Vitamin K1 is produced in 
plants and found at high concentrations in leafy vegetables and is the dominating variant in 
the Western diet.  
 

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Figure 1: Structures of some vitamin K vitamers 
 
Vitamin K2 (menaquinone, MK) is found in several variants (Fig 1). The short-chained MK-4 
can be formed from vitamin K1 in humans and is found in animal products like liver. The K2 
vitamers with longer side chains, like MK-7, MK-8, MK-9, and MK-9(4H) are of bacterial 
origin. They can be found in certain fermented foods. In the Western diet fermented dairy 
products like cheese are the main source of vitamin K2. 
The long chained MKs have been found to have greater extra-hepatic activity than K1 and 
MK-4, possibly due to more efficient uptake and much longer serum half-life 11,12. 
Prospective cohort studies have demonstrated health benefits that can be attributed the intake 
of vitamin K2 but not K1, and the main contributor to the vitamin K2 is cheese containing 
MKs with long side chains 13,14.  
2.3: Jarlsberg versus Norvegia Cheese 
The dominating K2 vitamer is MK-9 in most cheeses, but the amount varies considerably19. 
However, some cheeses also contain MK-9(4H). Jarlsberg cheese is rich in this compound20. 
This cheese is made with lactic acid bacteria producing MK-8 and MK-9 and 
Propionibacterium freudenreichii (PF) producing MK-9(4H). 
Although vitamin K2 related health benefits have been associated with cheese, the effects of 
cheese consumption on bone health have never been studied in intervention studies. Because 
of its high vitamin K2 content Jarlsberg cheese is well suited for such a study.  
Recently, a dose-response study in healthy Norwegian women was performed with a 3-level 
between patient Response Surface Pathway design 15,16. The study was performed in 19 
women with daily intake of Jarlsberg cheese during a period of 5 weeks15. This study showed 
a significant increase of OC and cOC. Jarlsberg Cheese has been compared to Camembert 
cheese which does not contain any vitamin K2, and no similar effects on the Osteocalcin level 
was detected after Camembert consumption18. Norvegia Cheese is very similar to Jarlsberg 
Cheese. The only differences are lack of MK-9(4H) and DHNA (Table I). 

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Table I: Vitamin K content of 100g a) Norvegia cheese and b)Jarlsberg cheese  
 
a) Norvegia cheese 
 
 
MK-4 
K1 
MK-7 
MK-8 
MK-9 
MK-
9(4H) 
Σ vitamin 
K 
Mean concentration original 
Norvegia (n=10) 
4,1 
3,7 
1,6 
8,9 
25,7 
n.d. 
44,0 
relSTDEV between samples 
17 % 
14 % 
24 % 
27 % 
27 % 
- 
22 % 
Mean concentration low-fat 
Norvegia (n=10) 
2,5 
2,6 
1,1 
6,1 
18,7 
n.d. 
31,0 
Expanded uncertainty 
-15 / 17 % -12 / 20% -16 / 16 % -12 / 49 % -11 / 20 % -11 / 21 % -12/ 21 % 
 
b) Jarlsberg cheese 
 
MK-4 
K1 
MK-7 
MK-8 
MK-9 
MK-
9(4H) 
Σ vitamin 
K 
Mean concentration original 
Jarlsberg (n=21) 
5,0 
2,9 
1,6 
9,0 
25,6 
40,8 
85,0 
relSTDEV between samples 
original Jarlsberg (n=21) 
31 % 
31 % 
15 % 
17 % 
22 % 
23 % 
12 % 
Mean concentration low-fat 
Jarlsberg 
2,5 
2,4 
1,5 
10,5 
42,0 
26,0 
84,8 
Expanded analytical 
uncertainty 
-15 / 17 % -12 / 20% -16 / 16 % -12 / 49 % -11 / 20 % -11 / 21 % -12/ 21 % 
 
 
The amount of the vitamers MK-4,7,8 and 9 is equal in Jarlsberg and Norvegia Cheese but 
differs regarding MK-9(4 H). We want to study if this is the background for our previous 
results15,16,18. 
 
 2.4: Objectives.  
 
The study objective consists of the following two aims: 
 
1. Compare the effect of daily intake of Jarlsberg and Norvegia cheese in change of the 
OC level and Carboxylated Osteocalcin(cOC) BMD and other bone markers in active 
XCS of both genders. 
2. Compare the effect daily intake of Jarlsberg and Norvegia cheese in change of the 
Resting metabolic rate (RMR), Muscle Strength (MS) and Peak VO2 in active XCS of 
both genders. 
 

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III: Population and sampling 
 
3.0: Study unit 
The study unit is active athletes.  
3.1: Reference population 
Active athletes of both sexes from 17 years of age for females and 18 years for males 
representing sports with equal loading. 
3.2: Study population 
3.2.1: Inclusion criteria.  
Active XCS from 17 years of age for females and 18 years for males. 
3.2.2: Exclusion criteria.  
Active XCS fulfils at least one of the following criteria will be excluded from participation in 
the study: 
• Eating disorder 
• Pregnancy  
• Known gastrointestinal disorder. 
• Abnormal liver or kidney function. 
• Diabetes  
• Suffering from verified cancer. 
• Under systemic treatment with corticosteroids or other immunosuppressive drugs the 
last 3 weeks before start of the trial treatment. 
• Participating in another clinical trial with pharmaceuticals the last six weeks before 
start of this trial treatment. 
• Known milk product allergy.  
• Suffering from diseases or injuries that disable them to perform VO2 or muscular 
strength tests.            
• Not able to understand information. 
• Do not want or not able to give written consent to participate in the study. 
 
3.3: Recruitment of athletes 
The active XCS will be recruited by the primary investigators team and by advertising in 
social media. They will be recruited from high schools of sports, and cross-country teams and 
clubs in the area around Oslo. Active XCS fulfils the inclusion and avoid the exclusion 
criteria will be asked to participate and to give written consent for participation. 
 
 
 
 

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IV: Design and randomization 
 
4.1: Study design 
The study is performed as an open randomized stratified parallel group design with two 
strata28. Sex is used as a stratification factor. The two equal sized strata are chosen because of 
different Optimal Effective Dose (OED) of cheese for women and men, and because the dose- 
response study previously performed has shown different response in men and women29.  
 
Within each stratum the participants will be allocated into two treatment groups by block 
randomisation. 
 
 
 
4.2: Randomization  
The athletes will be randomized (1:1) to either daily intake of Jarlsberg cheese or Norvegia 
cheese by using block randomization with random block size between 2 and 629. The daily 
amount of cheese will be equal in the two cheese-groups with 5 slices (75g) for females and 6 
slices (90g) for males.  
 
14.3: Power Analysis 
With a significant level of 5%, a power of 90% and a clinically relevant difference in total 
osteocalcin increase of one-time SD between the two groups, at least 24 XCSs in each group 
must be included. By correcting for dropouts during the first part of the study, 30 XCS will be 
included in each group. Totally 60 XCSs will be recruited for participation29. 
 
 4.4: Identification of subjects 
All the XCS will be given one study identification number of four digits constructed as 
follows: 
Digit 1: 
Indicate the gender study arm (1=female, 2=male)  
Digit 2&3: 
Indicate the athlete number consecutively within each sex arm 
(01,02,03 etc.)  
 
 
 

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V: Evaluation  
5.1: Osteocalcin and vitamin K 
The main response variable in both the first part of the two sex arms in the study will be tOC, 
the bone specific markers procollagen (PINP), Collagen (CTX1), Bone specific Alkaline 
Phosphatase (BALP) and parathyroid hormone (PTH). In the second part of the study, Bone 
mineral density (BMD) will be the most central variable in addition to Resting metabolic rate 
(RMR), Muscle strength and peak VO2. The Osteocalcin ratio R0, vitamin K2 including the 
different vitamers MK 7, 8, 9 and 9/4H and vitamin K1 will be used as secondary variables in 
both study parts.  
 
5.2: Bone specific markers 
 
The bone specific markers investigated in the study are Procollagen (PINP), Collagen 
(CTX1), Bone specific Alkaline Phosphatase (BALP), Parathyroid hormone (PTH). 
 
5.3: Bone mineral density (BMD) 
Participants will be weighed in their underwear, and height will be measured with a fixed 
stadiometer (Seca scale, Mod: 8777021094, S/N: 587728124885, Seca Deutschland, 
Hamburg, Germany). A dual energy X-ray absorptiometry (Lunar iDXA, E’CORE Software, 
version 14.10.022; GE Healthcare, Madison, WI) performing a three-site scan (lumbar area 
[L2-L4]; femoral neck, trochanter, and shaft [proximal femur]; and whole body compares the 
bone density with the bone density expected for a healthy adult of the same age, sex and 
ethnicity as the patient. Total body composition for different necessary measures will be 
performed. The difference is calculated as a standard deviation (SD) score. The difference 
between the patient measurement and that of a young healthy adult is known as a T score. The 
T scores classify as follows: 
- 
above -1 SD is normal. 
- 
between -1 and -2.5 SD is defined as mildly reduced bone mineral density (BMD) 
compared with peak bone mass (PBM) 
- 
below -2.5 SD is defined as osteoporosis30. 
The difference between the participants measurement and that of someone of the same age 
and gender is known as a Z score. A Z-score below -2 indicate a bone density lower than it 
should be for someone of the participant’s age. A Z-score is supposed to be 0, above 0 is very 
good, below -1 is poor. Z-Score < −1 is recommended further follow-up and clinical 
examination of secondary risk factors31.  
Trabecular Bone Score (TBS) will be calculated from the lumbar spine images using TBS 
iNsight software (Medimaps, Geneva, Switzerland) version 3.0.1. As there is no reference 
population for TBS in individuals < 40 years, only the absolute values will be used. 
Evaluation of the microarchitecture of either tibia or femur neck would give even better 
information about the bone health of the athletes, and we are looking for possibilities32. 
 Bodyfat (BF) investigation will be performed. In addition to BMD and TBS, the body 
composition variables  Lean body mass (LM), Bodyfat (BF) and Fat free mass (FFM),  will be 
measured together with RMR, muscle strength and Peak VO2 before starting the clinical part 
and at the end of the study.  

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5.4: Muscle strength 
Maximal (1 repetition maximum, 1RM) upper body muscle strength will be evaluated by 
seated pull-down by use of a Technogym Radiant (Technogym, Gambettola, Italy) apparatus 
and by half-squat performed in a Smith machine (Technogym 2SC multipower, Gambettola, 
Italy). Test procedure will be initiated by three sets of exercise-specific warm-up with 
gradually increasing load (ten repetitions at 40%, six repetitions at 60%, and three repetitions 
at 80% of expected 1RM). The first attempt will be performed with a load approximately 5% 
below the expected 1RM. After each successful attempt, the load will be increased by 2–5% 
until the athlete fails to lift the load after 2–3 consecutive attempts. The rest period between 
each attempt will be 3–4 min. The movement for seated pull-down will start with the 
handlebar positioned at the same height as the forehead. The athletes must pull the handlebar 
down to the hip bone. Elbows must be held slightly lateral to simulate a double-poling pull, 
and the wire must be parallel to the back support on the bench. For the 1RM to be accepted, 
the handlebar must be pulled completely down in one continuous motion with hands 
parallel33. 
For half-squat, at the familiarization session, the correct depth (90° knee angle) will be noted 
for reproduction. The position of the feet will be marked, and the correct depth controlled 
with an elastic band33,34. 
For additional information about changes in muscle mass during the study, lean body mass 
(LM) will be extracted from the body composition outcomes obtained from the DXA 
measurement. 
5.5: Peak VO2 
Peak VO2 will be measured by performing a cardiopulmonary exercise test on a treadmill 
(ELG 90/200 Sports; Woodway, Weil am Rhein, Germany) with an incremental protocol until 
exhaustion. Gas exchange will be measured using a breath-by-breath gas analysis system 
(Oxycon Pro analyzer; Jaeger, Würzburg, Germany) with a Hans Rudolph two-way breathing 
mask (2700 series; Hans Rudolph, Kansas City, KS). Each test is initiated by an individual 
adjusted warm-up of 15 minutes at 70% of HRmax. The incremental test protocol involves an 
incline of 10% with individual adjustment of load each minute until reaching exhaustion, 
resulting in a total duration of about 4-6 minutes with constant load the last minute. Measures 
of respiratory exchange ratio (RER) ≥ 1.10, and lactate concentration ≥ 7.0 mmol/L measured 
1 min after test termination and analysed immediately in a 1500-Sport-lactate analyser (YSI, 
Yellow Springs Instruments, Yellow Springs, OH), were required to ensure a valid measure of 
maximal oxygen uptake (VO2max). A Borg scale rating ≥ 17 may additionally be used to 
confirm the test result 35. 
5.6. Resting metabolic rate (RMR) 
RMR will be measured by IC using a respiratory gas analyser (Oxycon Pro, Jaeger, 
Germany). Ambient conditions are registered, and the analyser is gas and volume calibrated 
each morning prior to the measurements, according to the recommendations stated in the user 
manual from the manufacturer user manual for Oxygen Pro, Jaeger, Germany. Gas exchange 
and ventilator variables will be measured continuously using the breath-by-breath method. 
Participants will be instructed to rest for 10 min, wearing a two-way breathing mask covering 
their nose and mouth (2700 series: Hans Rudolph, Inc). Thereafter, the measurement period is 
started by connecting the mask to the gas analyser, and data collection continues for a total of 

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20 minutes. To get reliable results a steady state of 5 minutes of no more than 10% variation 
of gas exchange is required. The results from the RMR measurements will be related to the 
estimated RMR. The most reliable formula for estimating the RMR is the Cunningham 
formula; 22 x Fat free mass + 500. We will obtain the fat-free mass from the DXA scan. 
Ratio: measured/estimated RMR should be above 0,9.36 
5.7: Laboratory variables  
The haematological and clinical biochemical variables to be measured are listed below.  
 
5.7.1 Biochemical variables: 
Creatinine  
Albumin 
Urea  
ALAT 
Calcium 
Magnesium  
Phosphate 
Ferritin 
Vitamin D  
 
5.7.2 Lipids:  
 
Total Cholesterol 
HDL cholesterol  
LDL cholesterol 
Triglycerides 
5.7.3 Bone Turnover markers 
Collagen 1 (CTX-1) 
Procollagen 1 (PINP) 
Parathyroid hormone (PTH) 
Bone specific alkaline phosphatase (BALP) 
5.7.4 Sex hormones: 
Estradiol 
Progesterone 
Testosterone 
LH 
FSH 
5.7.5: Haematology 
Haemoglobin (Hgb)                
HbA1C              
                     
5.8: Diet registration 

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Diet registration will be performed by the participants. The daily intake of all food will be 
recorded daily for four days consecutively at screening and every eight weeks during the 
study. A pre-evaluated questionnaire based “diet.no” will be used and recorded on an 
electronical diet APP by the participants. The diet registration will be supervised by a 
qualified monitor. The results will be evaluated by the investigating team.  
 
5.9: Menstruation status 
To control the hormone blood sample results to female XCS, this group will be interviewed 
about their menstruation status. This includes menarche length, cycles day and use of 
hormonal contraceptives.   
 
5.10: Cheese, supplement, and activity registration 
The cheese, supplement of vitamin D and activity will med recorded in a form for daily 
registration. The activity will be recorded weekly. The parameters to be recorded are low- and 
high intensity running and roller-ski in hours, and low- and high-load strength exercise. The 
forms are handed out every fourth week of the study and collected by the investigator or the 
research assistant.  
 
5.11: Compliance 
The participants must eat their daily prescribed dose of cheese and vitamin D, register their 
activity weekly, and fill in their diet APP 4 days before their control every 8 weeks. 
5.12: Adverse Events (AE) 
5.12.1: Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) 
The CTCAE is divided in 26 System Organ Class (SOC) in accordance with the MedDRA 
hierarch. Within each SOC, AE are listed and accompanied by descriptions of severity or 
grade:  
• 
Blood and lymphatic system disorders (11 Items) 
• 
Cardiac disorders (36 Items) 
• 
Congenital, familial, and genetic disorders (1 Items) 
• 
Ear and labyrinth disorders (9 Items)  
• 
Endocrine disorders (11 Items) 
• 
Eye disorders (25 Items) 
• 
Gastrointestinal disorders (117 Items) 
• 
General disorders and administration site conditions (24 Items) 
• 
Hepatobiliary disorder (16 Items) 
• 
Immune system disorders (6 Items) 
• 
Infections and infestations (76 Items) 
• 
Injury, poisoning and procedural complications (78 Items) 
• 
Investigations (38 Items) 
• 
Metabolism and nutrition disorders (24 Items) 
• 
Musculoskeletal and connective disorders (41 Items) 
• 
Neoplasms benign, malignant and unspecified incl. cysts and polyps (5 Items) 
• 
Nervous system disorders (63 Items) 
• 
Pregnancy, puerperium and perinatal conditions (5 Items) 

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• 
Psychiatric disorders (20 Items) 
• 
Renal and urinary disorders (20 Items) 
• 
Reproductive system and breast disorders (51 Items) 
• 
Respiratory, thoracic and mediastinal disorders (59 Items) 
• 
Skin and subcutaneous tissue disorders (34 Items) 
• 
Social circumstances (2 Items) 
• 
Surgical and medical procedures (1 Item) 
• 
Vascular disorders (17 Items) 
5.12.2:  Grading and classification  
Grade refers to the severity of the AE.  The CTCAE displays Grade 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
 
Grade 0 =  
None 
Grade 1 =  
Mild: asymptomatic or mild symptoms; clinical or diagnostic. 
Observations only; intervention not indicated. 
Grade 2 =  
moderate: minimal, local, or non-invasive intervention indicated; 
Limiting age-appropriate instrumental Activity of Daily Living (ADL) 
Grade 3 = 
severe or medically significant but not immediately life-threatening: 
Hospitalization or prolongation of hospitalization indicated; disabling; 
Limiting self-care ADL 
Grade 4 =  
Life-threatening consequences; urgent intervention indicated 
Grade 5 = 
Death related to AE. 
 
Relation to trial medication as: Definitely, Probably, Possibly or Unrelated 
Action taken as: 
 
None, Interruption, Modified or Discontinued 
AE treatment as:                    None, Continue Medication, Procedure or Hospitalization. 
Outcome at last visit as:  
Resolved, Ongoing or Fatal. 
 
Definitions of relationship to study treatment are as follows: 
 
Unrelated: 
bears no relation to timing of medication, like symptoms or signs 
expected in the disease process, does not recur on re-challenge. 
Possibly: 
bears relation to timing of medication, like symptoms or signs expected 
in the disease process, does not recur on re-challenge. 
Probably: 
bears clear relation to timing of medication, distinct from symptoms or 
signs expected in the disease process, does not recur on re-challenge. 
Definitely: 
bears clear relation to timing of medication, distinct from symptoms or 
signs expected in the disease process, recurs on re-challenge. 
 
5.12.3: Reporting adverse events. 
An adverse event (AE) is any untoward symptom or sign befalling a patient in a clinical trial 
regardless of its relationship to the study medications. All AEs must be described in detail and 
their severity and putative relationship to the study medication noted. 
AEs may be considered serious. The definition of this is as follows: 
 
• 
Death 
• 
Life threatening 
• 
Leads to or prolongs hospitalization 

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• 
Results in persistent of significant disability 
• 
Any new important medical information. 
 
5.13 Patient factors, Vital signs, and Physical examination.  
The patient factors to be recorded in the study will be age in years from birth to the screening 
visit, height in cm and body weight in kg. Previous medical history, duration of any disease in 
months from the final diagnosis to the screening visit, previous and on-going treatment of the 
disease will be observed. During each physical examination, body weight, concomitant 
disease and treatment will be recorded. Additionally, vital signs defined as Systolic and 
Diastolic blood pressure in mmHg and Heart rate in beats/min will be recorded in sitting 
position after five-minute rest. To eliminate any vitamin D disturbances the participants are 
provided supplement of 40µg Vitamin D from the start till the end of the study. 

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VI: Study procedure 
6.1: Definitions 
Important definitions are:  
1) Osteocalcin Ratio (R0): cOC (carboxylated Osteocalcin)/ uOC (undercarboxylated 
osteocalcin). 
2) Bone Mineral Density (BMD) and Trabecular Bone Score (TBS). 
3) Lean Body Mass (LM) extracted from the body composition outcomes obtained from 
DXA. 
4) RMR ratio (resting metabolic rate ratio). Observed RMR/ 22x FFM+ 500 (The 
Cunningham formula) 
5)  Peak VO2 which is maximal oxygen uptake. 
6.2 Clinical procedure 
6.2.1 Screening: 
The recruited XCS fulfilling the inclusion and avoided the exclusion criteria will be registered 
and asked to participate in the study. The athletes who are willing to sign the informed 
consent form will be enrolled in the study. During this one week the participants will undergo 
a clinical screening and an appointment for the starting visit in the study one week later. 
Before the first investigation, the participants will be asked to fill in their diet for four days in 
a data application created for this study. The diet registration will be performed and 
monitored by a nutritionist. All the athletes will be instructed not to change their usual intake 
of food during the study but change the usual used cheese with the study cheese. During this 
initial clinical examination, all demographic data, social factors, history of disease and vital 
signs will be recorded.  
6.2.2: Start-up Day: 
A clinical investigation with blood sampling will be performed at the start-up denoted as Day 
0, and they are all asked to meet fastening, and without hard training two days in front. Blood 
samples will be collected for measurements of Osteocalcin, vitamin K2; Biochemical 
variables like; Ca, Mg, Na, potassium, urea, phosphate, creatinine, ferritin, haemoglobin, 
HbA1C, Lipids, CTX-1, PINP, BALP, PTH, Estradiol, Testosterone, LH, FSH and vitamin D. 
Additionally, DXA investigation of BMD and TBS, FFM and LM and RMR will be recorded, 
and muscle strength, and Peak VO2  will be tested before starting the clinical part. 
A time schedule for the inclusion visit day will be followed. The participants will meet to 
their appointment at NIH fasting from midnight. The two first examinations will be RMR and 
DXA measurements, and both lasts for 30 minutes. The two procedures are performed by 
qualified personnel at NIH. The next station fasting is blood sampling in the laboratory by a 
qualified bioengineer. After the blood sampling they will meet for medical interview by the 
primary investigator, recording ongoing and previous diseases, concomitant and former 
treatment, inclusion, and exclusion criteria, and signing the informed conscient form. The 
next step is examination of blood pressure, pulse rate and weight, and the medical session will 
be finished with handling and the cheese registration form, and their allocated sample of 
cheese type. 
Blood samples will be handled in accordance with the laboratory centre procedures, and the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 registered. 
The next step in the program is then lunch and rest for approximately 2 hours. 

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After lunch they will start with the VO2 tests on treadmill and be sent for the muscular 
strength tests. Both VO2 test and muscular strength tests will be supervised by qualified 
master students. 
6.2.3 Comparative phase 1: 
The XCS will randomly be allocated (1:1) to either daily intake of Jarlsberg cheese or 
Norvegia cheese. The daily intake of Jarlsberg cheese will be the OED for XCS and the 
comparative dose of Norvegia. The two cheese doses are nearly equal regarding total energy, 
protein carbohydrate and fat magnesium and calcium. The trial cheese can be consumed with 
other food at breakfast, lunch, or other meals during the day. The cheese may also be 
consumed heated/melted. All participants will be provided vitamin D supplement of 
40µg/day. The activity level is continuously recorded in the cheese-supplement – and activity 
record- form. 
The participants meet for blood sampling in week 4 and 8 for measurements of Osteocalcin 
and Bone Turnover Markers (BTM). At  week 8 week a clinical examination with 
measurement of vital signs and body weight will be performed. Additionally, blood samples 
will be taken for measurements of biochemical variables and vitamin K2. The participants will 
be asked to fill in their diet for four days in the data application created for this study every 8 
weeks. The diet registration will be performed and monitored. 
6.2.3 Comparative phase 2: 
All participants in both groups meet for the new investigation in week 16 and week 24, which 
is the last visit in the study. In both visits new clinical investigations will be performed with 
measurement of vital signs and body weight. During the last visit week 24, blood samples will 
be taken for measurements of Bone specific markers, vitamin K2 and biochemical variables. 
Sex hormones, muscle strength, Peak VO2 and DXA investigation of BMD,TBS, FFM and LM 
will be measured at in the same way as at day 0. 
CTCAE version 4.0 will be used for registration of AE. In case of AE of grade 3 or 4 
according to CTCAE occur for more than three days, the responsible investigator will act. The 
intake of cheese will be stopped and the XCS will be followed up until the symptoms 
disappear. The total duration from the last intake of the cheese to the disappearance of the 
symptoms will be recorded in days together with the treatment procedure. They will be 
reminded to fill in their dietary record. 
 
6.2.4 Dietary monitoring: 
The participants will fill in their dietary intake in an application at baseline and every 8th 
week of the study. During the last visit an Eating Disorder Examination Questionnaire- Short, 
derived from EDE-Q © Fairburn and Beglin40, will be a part of the interview. The questions 
will be woven into the anamnestic interview and not as a questionnaire to ensure that the 
participants do not suffer from disordered eating.  
 
6.3: Treatment administration of the study 
6.3.1 Administration and doses  
At baseline (week 0) the female and male strata will be provided a cheese sample for 4 weeks 
consumption of the type of cheese group they are allocated into. The female participants will 
be provided a sample resembling 75 grams cheese (5 slices) a day, and the male participants 

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will be provided 90 grams (6 slices) per day. The dose of Jarlsberg and Norvegia cheese is 
equal, and the dose is fixed due to OED from the former dose-finding study. After 4 weeks all 
participants will be provided new cheese samples of their study cheese. This will be repeated 
every 4 weeks till the end of the study at 24 as described previously. The dose of Jarlsberg 
and Norvegia cheese is equal. 
 
 
Tabell II: Cheese Energy Contents per 100 grams 
    
Energy Sources 
Jarlsberg Cheese 
Norvegia Cheese 
Total Energy 
1458 kJ (351 kcal) 
1458 kJ(351kcal) 
fat 
27g 
27 g 
carbohydrates 
0 g 
0 g 
protein 
27g 
27g 
calcium  
770mg 
820mg 
phosphate 
550mg 
590mg 
6.3.2 Cheese supply, packing and storage. 
The cheese will be delivered in 250-gram packages. The participants will receive the cheese by the 
investigator every 4 weeks. Both the Jarlsberg- and the Norvegia cheese used in the study will be 
given free of charge to the participating athletes.    
Each package is labelled in accordance with the procedure for clinical trials. Additionally, the 
participants will be informed on how to perform the intake of the cheese and to store the cheese in a 
refrigerator at a temperature from 4 to10C. Expiry date will be printed on the label. 
 
 
Table III: Label on each package 
 
Description 
For use only in clinical trial 
Trial substance 
Type of cheese 
Expire date 
 
Administration 
Oral intake  
Investigator 
 
Name of exporter 
TINE A/S:   
Phone number 
+47 908 67088   
Study 
Comparative study in Active XCS 
EudraCT number 
2022-003264-24 
Protocol id  
XCS-Jarlsberg/IIA  
Storage 
Refrigerator between 4 to10C 
  
 
6.4: Stopping rule  
In case of life-threatening AE or Serious Adverse Events (SAE) occurs, the cheese intake 
must stop, and the participant treated and followed up in accordance with GP-centre routines.  
6.5: Procedures for Blood sampling and analysis.  
Blood will be drawn via a cubital vein and separated into serum by centrifugation. Two ml 
serum will be sent Vitas for Osteocalcin analysis and 2 ml send for K2 analysis at the 

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biochemical laboratory of NMBU. 4 ml will be sent to the Hormone Laboratory of Aker 
University Hospital. The blood samples for measurements of the haematological and 
biochemical variables will be handled in accordance with the standard procedures at the 
laboratory of Norwegian School of Sports Sciences and sent to Fürst laboratory in Oslo for 
analysis.  
6.6: Report of serious adverse effect (SAE) 
The participant will be advised to contact the investigator if she/he suffers from severe AE or 
any other annoying conditions.  
In the case of SAE, the investigator must complete the SAE form and send it to the health 
authorities with copy to TINE and the project manager Prof. Stig Larsen within 24 hours.   
  
Dr. Helge Lundberg  
Skjetten Medical Centre 
PB 24, N-2026 Skjetten 
Norwegian School of Sports Science 
         Department of Sports Medicine  
         Office: +47 64831880 
         Cell phone: +47 99 69 96 19 
         E-mail: hl@meddoc.no 
 
6.7: Time schedule 
The duration of the study will be 24 weeks for each participant.  
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment period of XCS  
 
 
 
01.01-31.05.23 
    
Inclusion of the first participant  
 
 
 
17th April 2023           
Inclusion of the last participant 
 
 
 
28th April  2023      
     
Last participant finalized comparative study part 
 
23rd June 2023                
Last patient finalized follow-up part  
 
 
14th Oct 2023      
    
 
 

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6.8: Flow diagram 
 
 
 
 
 

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VII: Project management and Monitoring 
7.1: Project management 
The study will be administered by a Steering committee headed by Dr Anne Cathrine Wist 
and consist of Dr Helge E Lundberg, Prof Jorunn Sundgot- Borgen, Associate Prof Therese 
Fostervold Mathisen, Prof. Emeritus Stig Larsen, Prof. Emeritus Helge Holo, Prof Emeritus 
Erik Fink Eriksen and Dr Tove Tveitan Borgen. The study will be monitored by a CRA from 
Meddoc. The data manager for this study will be Vivy Liang Larsen Meddoc Biometric 
Group, Norway and coordinated by Dr Anne Catherine Wist and Prof Stig Larsen. Dr 
Fagertun will be responsible of the Data Management and the Statistical Analysis and Prof 
Helge Holo for the laboratory analysis.  The steering committee will have a joint responsible 
for publication of the results in international journals.  
7.2. Quality assurance demands. 
The validated data management (DM) system InCRF will be used for electronically collecting 
the data. The system selected is compliance with GCP guidelines and subject to 21 CFR 
(Code of federal regulations) FDA part 11 requirements. All the data created in this study will 
be entered at site, stored, and monitored electronically. The study case record forms (CRF) 
will be available at the DM-system and the data entered directly into the system at the site. 
Monitoring will be performed electronically and copies of the laboratory results and printed 
eCRF with Investigator’s signature will be the source-documents. 
In conducting the trial, TINE as the Sponsor accepts that the Ethics Committee or regulatory 
body may, at any time by appointment, conduct an audit of the study site, the laboratories 
conducting any clinical testing or the GMP manufacturing facilities. 
7.3: Start-up and closing visit  
The project manager and the clinical monitor will perform the start-up visit at the 
participating site. The visit will consist of a site inspection, information, instruction and 
handing the CRFs. 
The project manager and the clinical monitor will perform the closing visit within one month 
after the last participant has finalized the study. All the trial material will be removed from the 
site. 
7.4: Monitoring procedure 
Essential demographic data will be documented with the participants’ record notes as the 
source data and send to the monitor by e-mail after entering the InCRF-system. Source data 
will also include the date of written consent, times and dates of blood sampling and physical 
examinations.  
It is the responsibility of the investigator to maintain accurate and up to date records of all 
clinical trial related activities, which should be legibly entered onto the CRFs provided. The 
CRFs should be made available in the event of a formal investigator site audit. 
The site will be monitored seven times during the study. This includes both the start-up and 
the closing visits. Monitoring report will be sent to the project manager for every site 
inspection.  
7.5. Curriculum vitae 
All involved researchers participating in the study must show an updated CV documenting 
their expertise in the relevant clinical field. The CV must be signed and dated by the 

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physician and a copy must be attached to the protocol if required according to international 
rules. Another copy should be kept in The Trial Master File and a third copy in the Site File.  
 
7.6. Site File 
Meddoc will supply the investigator with a Site File. The Site File should contain all 
documents relevant for the study. The investigator is responsible to keep the Site File updated 
and secure that all required documents are present in the File. The Site File will be inspected 
during the monitor visits. 
  
 
 

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VII. Consideration 
8.1: Consideration of steering committee 
The study will be carried out according to the Helsinki declaration with latest amendments, 
Good Clinical Practice (GCP) and International Ethical Guidelines for Health-related 
Research Involving Humans (CIOMS guidelines). The participants are active cross-country 
skiers and will only be included in this clinical trial after approval of the trial by the regional 
Ethical Committee (REK) and after the XCS have received oral and written information and 
signed informed consent.  
The product to be used in this trial is Jarlsberg cheese commercially available in Norway. To 
the best of our knowledge, no AE is reported except from person with intolerance of milk and 
milk product. It is known that vitamin K2 passing a certain daily dose may increase and 
strengthen the bone tightness and may therefore have a prophylactic effect on bone fracture. 
This occurs frequently among active cross-country skiers. Jarlsberg cheese is shown to be one 
of the Norwegian produced cheeses with the highest level of vitamin K2. 
In a previously conducted dose-response study on cross country skiers we found the optimal 
efficacy dose (OED) to increase the osteocalcin levels. Our hypothesis is that this effect is 
caused by the fermentation of lactic acid to propionic acid by the Propionibacterium 
freudenreichii in the Jarlsberg Cheese, producing MK 9-4H K2 vitamer and DHNA. The first 
aim of this study is to compare the effects with the effect of Norvegia Cheese that does not 
contain MK 9-4H and DHNA to verify the hypothesis. Our second aim is to study the 
development of BTM, BMD, muscular strength and peak VO2 by the OED of Jarlsberg 
Cheese, to verify if the cheese could be recommended as prophylactical to prohibit LEA-
related conditions. 
All participants invited to this clinical trial are entitled to make their decision based on the 
fullest amount of information available at that time. In order to make the choice, they will be 
given a written document expressed in a clear concise language of their native tongue to 
consider. The document will tell potential participants about the aim of the study. 
Additionally, that blood sampling will be performed between five and eight times in 
connection with clinical examinations during the two study parts.   
Summary: All the included volunteers will receive the daily intake of cheese and clinical 
examinations free of charge and receive a modest compensation for participation. All 
participants will be given oral and written information and have to give their written consent 
to participate in the study. To the best of our knowledge, this study fulfils the entire 
international requirement to an ethical controlled clinical trial.  
8.2: Approval of the project 
This study will be performed in Norway and the study protocol together and other requested 
information will be sent for approval by Regional Ethical Committee (REK). Inclusion of 
participants will not be started before the approval is received. 
The database and storage will be in Norway and must be approved by the Data Register in 
Norway. 
 
8.3: Informed consent 
Before the start of the trial, the investigator will explain the confidentiality of participation in 
this research project, the objectives of the trial, the specific requirements for the participating 

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XCS, the trial design and the consequences of participation. Additionally, the investigator has 
to obtain written informed consent from the participants before inclusion in the study.  
8.4: Protection of personal data 
The monitor may know the identity of the participants during verification of the source data.  
However, the monitor has unconditional professional secrecy. 
All participant-related material leaving the trial site will be anonymous so that the volunteer 
only can be identified by date of birth, initials and XCS study identification number. The 
investigator is responsible for keeping a list with the full names, their citizens’ number, and 
corresponding study numbers according to the demands in GCP. 
The participants will receive all the Jarlsberg cheese in the study for free. Additionally, they 
will get the clinical examination for free and receive a moderate economical compensation. In 
case they get extra transportation costs for the participation, this will be covered by the study.  
 
 
 
 

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IX. Data Management  
9.1: Electronical Case Record Forms (eCRF) 
The validated electronical data management system InCRF will be used for collecting the 
data. Mainly the data will be entered on eCRFs by the responsible investigator at stage. Prior 
to study start; a data entry instruction document will be made. In this study a copy of source 
data will be collected on a paper. Source data consist of both printouts from the laboratory. In 
case of printing CRF data from InCRF instead of using paper CRF, it is important that also 
these are stored. The printed CRF data need investigator’s signature and date. 
9.2: Study Database 
The validated data management system InCRF will be used for collecting the CRF data. The 
system selected is compliant with GCP guidelines and subject to 21 CFR (Code of federal 
regulations) FDA part 11 requirements. The final database will be stored in the Statistical 
Analysis system (SAS ver. 9.4 or later). 
9.3: Data handling 
The DM will perform the data checks. Once all the errors or issues are corrected or resolved, 
the investigator shall sign all the eCRFs to acknowledge all the data in the database has 
reviewed and corrected. After all the eCRFs has electronically signed by the investigator, the 
Study Statistician will perform final SAS checks and proof reading of safety listing. 
Thereafter, the database can perform final database hard lock.  
The database will be transformed to a labelled SAS database, which also will be locked to 
prevent all possible changes or additions. In this copy, the responsible statistician can make 
derivations but no corrections of the data. If corrections are needed, the main basic study 
database must be re-opened and corrected. The international procedure for such changes will 
be followed. 
 
 
 

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X: Discontinuation of treatment 
 
A XCS may discontinue from the study at any time if in the view of the Investigator it is in 
the participant best interests. Alternatively, the XCS has the right to discontinue the consent 
and exit the study without prejudice regarding his/her future treatment or care. 
If a XCS doesn’t show up to an agreed visit the investigator should try to motivate the XCS to 
continue.  
10.1: Discontinuation not related to the study question 
XCS discontinues the study of administrative reasons or reasons documented not related to 
the trial treatment will be classified as “Drop out” and replaced by new XCS. The dropouts 
will be described specially in the statistical analysis.  
10.2: Discontinuation related to the study question 
XCS discontinues the study of reasons related or might be related to the trial treatment will be 
classified as “Withdrawal”. These will not be replaced by new XCS but included in both the 
Per-Protocol (PP) and the ITT analysis using the procedure “Last observations carried 
forward” (LOCF).   

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XI Statistical Model 
11.1 Presentation of results 
Assumed continuously distributed variables expresses by mean values with 95% confidence 
intervals 37. As an index of dispersion Standard Deviation (SD) will be used. 
Categorized variables will be expressed in Contingency Tables 38. 
11.2 Statistical methods 
The differences between the groups will be considered significant if the p-value is less or 
equal to 5 %. Comparison between groups regarding assumed continuously distributed 
variables will be performed by using analyses of covariance (ANCOVA) with a basic 
observation as covariance and repeated measurements 39. Contingency table analyses will be 
used for comparison of discrete distributed variables.38. Correlation and regression analysis 
will be performed to estimate the connection in the development between variables.  
11.3 Power analysis and sample size determination 
With a significant level of 5%, a power of 90% and a clinically relevant difference in total 
osteocalcin increase of one-time SD between the two groups, at least 24 XCSs in each group 
must be included. By correcting for dropouts during the first part of the study, 30 XCS will be 
included in each group. Totally 60 XCSs will be recruited for participation29.  
 

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XII: Operational Matter 
12.1: Investigator’s agreement 
Before the start of the trial the investigator will confirm the agreement to participate in the 
trial by signing the Investigator's Agreement Form (Appendix IX). 
12.2: Instructions 
The investigators will give instructions by the data manager group and the clinical monitor 
supported by the project manager at the start-up visit and during the study.  
12.3: Amendments to the protocol 
 
Changes in the protocol can be required by the Ethical Committee, project manager or TINE. 
Changes must be written in amendments approved by the steering committee, investigator, 
Tina SA, and Ethical Committee. Amendments must be numbered and be together with the 
original protocol. 
It is forbidden to add new parameters consisting of measurements on the patients in the study 
unless they are covered as amendments in the protocol or taken due to the health and safety of 
the patient.  
12.4: Protocol deviations 
Deviations from the protocol should be restricted as much as possible and will be fully 
recorded and justified. The Project manager will be informed as soon as possible of all 
protocol deviations.  
12.5: Compliance monitoring 
The Project manager and the Investigator will ensure that the site is suitable for the trial and 
that the participating XCS is well informed of the particulars of the trial. The Project manager 
and Investigators should check, protocol compliance, handling of the test articles and 
recording of data during the critical stages of the trial. A report is prepared of each visit and 
kept in the trial master file (TMF). 
12.6: Responsibilities 
The investigator will acknowledge the responsibilities and the agreement to participate in the 
trial by dating and signing the agreement form. The Project manager will verify that adequate 
arrangements have been made for the observations, measurements and recording of the data. 
12.7: Confidentiality  
The obtained data and results will be used by TINE for marketing purpose. The main study 
database will be stored in the product database of TINE.   
The steering committee has the demand and the right to try the results published in an 
international medical journal. The draft of the manuscript must be presented for the sponsor 
for comments, discussion and final approve. The sponsor cannot stop the publication unless it 
is proved that publication of the results may destroy for marketing of the product. 
The results from the study cannot be presented in any meeting or congresses without approval 
by the sponsor. The data obtained in this study must be handled confidentially by the member 
of the steering committee until the first registration of the product is performed. 
 
 
 

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XIII Amendment 
 
13.1: Menstruation status ( pkt. 5.9, 1.6 & 1.10) 
To control the hormone blood sample results to female XCS, this group will be interviewed 
about their menstruation status. This includes menarche length, cycles day and use of 
hormonal contraceptives. 
 
13.2: Inclusion criteria ( pkt. 3,1 & 3.2 and 1.4) 
3.1: Reference population. Active athletes of both sexes from 16 years of age representing 
sports with equal loading. 
3.2: Study population. Active XCS from 16 years of age. 
1.4: Population and sampling. The study population consists of active XCS of both genders 
past 16 years of age. 
 
13.3: Cheese dose( pkt.1.6, 4.2 & 6.3.1) 
4.2: The daily amount of cheese will be equal in the two cheese-groups with 5 slices (75g) for 
females and 6 slices (90g) for males.  
 
13.4: Study procedure ( pkt.1.6 & 5.2, 5.3 & 6.1, 6.2). 
6.2: DXA investigation of BMD and TBS will be performed, and RMR measured together 
with muscle strength, LM and Peak VO2 before starting the clinical part. 
 
 
 
 
 
 
 
 
 
 

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Comparison Jarlsberg vs Norvegia in XCS                        Final Version 1.9; August 2024  
 
      
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XV Appendix 
14.1: Serious Adverse Event Form 
14.2: The set of CRF’s 
14.3: Monitoring report form  
14.4: CV investigators and study coordinators 
14.5: Patient information