Dose Estimation of Jarlsberg Cheese in Young, Active Norwegian Cross-country Skiers (XCS)
Condition: Healthy Nutrition
Study type: Interventional

Summary: 
      The main aim was to estimate the daily OED of Jarlsberg cheese related to increased total
      serum Osteocalcin (tOC) level in young, active female and male Cross-country skiers (XCS).

      The study population consists of active Cross-country Skiers (XCS) of both genders above 18
      years of age.

      The optimal daily intake of Jarlsberg cheese is assumed to have a dose window of [20 - 100]
      gram/day and a starting dose of 47 gram/day for both female and male.

      The study was performed equally as an open, two-armed within-patient Response Surface Pathway
      (RSP) trial with three design level and skewed starting dose.

      The main response variable will be the change in the tOC level after four weeks from baseline
      of the given design level.

      Participants, who fulfil the inclusion criteria, do not meet any of the exclusion criteria
      and willing to give informed consent to participate will receive an appointment for starting
      the study. All demographic data, social factors, history of disease and vital signs will be
      recorded at screening.

      Blood samples was taken at screening and every four weeks. Muscle strength, Peak VO2 and BMD
      recorded at screening and at the end of the clinical part week12.

      Ten female and 10 male XCS divided was be included, perform and completed the study.
    

Detailed description: 
      Aim

        -  To estimate the daily OED of Jarlsberg cheese related to increased total serum
           Osteocalcin (tOC) level in young, active female and male Cross-country skiers (XCS).

        -  To estimate the effect of daily Jarlsberg cheese intake on increased, muscle strength,
           peak VO2 and bone mineral density.

      Study population: The study population consists of active Cross-country Skiers (XCS) of both
      genders above 18 years of age. The study is separated in one female and one male XCS study
      arm.

      Trial treatment:The optimal daily intake of Jarlsberg cheese is assumed to have a dose window
      of [20 - 100] gram/day and a starting dose of 47 gram/day for both female and male. The
      cheese is received in package of 250 gram divided in 16 slices of 15.625 gram. 47 gram
      represents 3 slices of cheese.

      Design and randomization: The female and the male arms of the study will be performed equally
      as an open, two-armed within-patient Response Surface Pathway (RSP) study with three design
      level and skewed starting dose. The two parts will be performed separately in parallel with
      identical RSP-design.

      The main outcome variable will be categorized in the following four categories:

        1. Low to moderate increase in the tOC level: [0- 10%> the last 4 weeks

        2. High increase in the tOC level: ≥10% the last 4 weeks

        3. Low to moderate decrease in the tOC level: <0 - 10% > the last 4 weeks

        4. High decrease in the tOC level: ≥ 10% the last 4 weeks

      Ten XCS in both arms will be included in the first design level and all receiving the
      starting dose of Jarlsberg cheese every day in four weeks. The individual increase in tOC
      from baseline to four weeks will be used to calculate the doses for the XCS in the second
      design level. The individual increase tOC in the second design will decide the daily doses of
      cheese to be used in the third design level.

      The OED for healthy women in pre-menopausal age was previously estimated to 57-gram Jarlsberg
      cheese per day. It is unknown if this OED will be different from active XCS and dependent of
      gender and age.1 The initial dose window in this study was set to [20 - 100] gram based on
      the previous dose-response study in healthy pre-menopausal women.

      Based on prior knowledge, the tOC follows a quadratic function in Jarlsberg cheese dose.1 The
      Osteocalcin seem to increase with increasing dose until a maximum (OED) and reduces for
      higher intake of the cheese. OED might be below the midpoint of the initial dose window of 60
      gr/day. In order to optimize the estimation procedure with the skewed starting dose of
      47g/day or 3 slices of Jarlsberg cheese will be chosen.

      This gives an adjusted starting dose window of [20 - 74] gr/day. In case the results from all
      the five XCS of equal gender in the first design level reports an increase < 10% in the tOC
      level, the RSP-procedure recommend a maximum escalation in the daily intake of Jarlsberg
      cheese in the second design level. The new starting dose-window will then be change with the
      previously used starting dose as lower boundary.2 In the present study the adjusted
      dose-window for the second design level will then be [47 - 85] g/day with the new starting
      dose of 66 g/day. In case the results obtained at the design level recommend different doses
      to be used for the next level, the common RSP procedure will be followed.

      Main variables: The main response variable will be the change in the tOC level after four
      weeks from baseline of the given design level. The osteocalcin ratio R0 defined as the ratio
      between carboxylated osteocalcin (uOC) and under-carboxylated osteocalcin (ucOC) = [cOC /
      ucOC], together with vitamin K2 and the different variants MK-7, MK-8,MK- 9 and MK-9(4H) will
      be used as secondary variables. Diet registration will be performed at screening and every 4
      weeks. Additionally, increase in Muscle strength, Peak VO2 and Bone mineral density (BMD)
      will be measurement at screening and at the end of the study (week 12). Blood samples for
      measurements of HbA1C and Lipids; Collagen (CTX-1) and Procollagen (PINP); Estradiol and
      Testosterone; Progesterone and FSH will be taken at screening and at the last visit week 12
      in the study. The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) will be
      used for registration of Adverse Events (AE) and toxicity score at every investigation visit.

      Study procedure: Participants, who fulfil the inclusion criteria, do not meet any of the
      exclusion criteria and willing to give informed consent to participate will receive an
      appointment for starting the study. All demographic data, social factors, history of disease
      and vital signs will be recorded at screening.

      Blood samples for measurements of Haematological and biochemical variables, HbA1C and Lipids;
      Collagen (CTX-1) and Procollagen (PINP); Estradiol and Testosterone; LH, FSH and SHBG will be
      taken at screening. Additionally, muscle strength, Peak VO2 and BMD will be recorded before
      starting the clinical part.

      The design consists of three design levels within each study arm. Measurement will be taken
      at screening and every four weeks after daily intake of the decided dose of Jarlsberg cheese.
      All the participants will be asked not to change anything in their common intake of food
      during the study except for replacing other cheese with the received daily dose of Jarlsberg.
      Clinical examination, blood sampling for osteocalcin measurement and diet registration will
      be performed every fourth week during the study including follow-up. The physical examination
      includes registration of vital signs, CTCAE and change in concomitant medication. Blood
      sampling will be taken for measurements of tOC, cOC and ucOC and vitamin K. Blood sampling
      for measurements of HbA1C and Lipids; Collagen (CTX-1) and Procollagen (PINP); Estradiol and
      Testosterone; LH and FSH; haematological and bio-chemical variables will be taken at the last
      visit in the study (week 12). Additionally, muscle strength, Peak VO2 and BMD will be
      recorded at week 12.

      Sample size: Ten female and 10 male XCS divided will be included, perform and complete the
      study. The minimum number of participants recommended in each arm in a within-patient RSP
      model is 8
    

Intervention name(s): Jarlsberg cheese
Intervention type(s): Dietary Supplement
Intervention description(s): Jarlsberg cheese is a regular cheese for free sale in grocery stores. The allotted amount of cheese was taken orally each day
Other intervention name(s): Vitamin D
Intervention MeSH terms: Vitamin D
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: The participants were divided into men and women. Within each of these two arms, a three-step dose escalation was performed according to a Respons Surface Pathway procedure.
Masking: None (Open Label)
Primary purpose: Health Services Research
Keywords: Jarlsberg cheese