<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03821116</url>
  </required_header>
  <id_info>
    <org_study_id>MILK: EPN-Uppsala dnr 2018-328</org_study_id>
    <nct_id>NCT03821116</nct_id>
  </id_info>
  <brief_title>Milk and Soured Milk (filmjölk) Intervention on Oxidative Stress and Inflammation</brief_title>
  <official_title>Milk and Soured Milk (filmjölk) Intervention on Oxidative Stress and Inflammation: A Randomized Crossover Intervention Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Uppsala University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Forte</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Uppsala University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates a high intake of milk compared with a high intake of soured milk&#xD;
      (Swedish filmjölk) on markers of oxidative stress and inflammation in a randomized crossover&#xD;
      intervention study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A diet rich in antioxidants reduces oxidative stress and inflammation and could potentially&#xD;
      improve health and lower the rate of hip fracture. Milk and dairy are also promoted as part&#xD;
      of a healthy diet since they contain 18 of 22 essential nutrients including calcium,&#xD;
      phosphorous, and vitamin D and have been suggested to be associated with lower risk of&#xD;
      cardiovascular disease, especially stroke, type 2 diabetes, and cancer. Meta-analyses of milk&#xD;
      and dairy on fracture and mortality risk in cohort studies are, however, inconclusive and&#xD;
      show significant heterogeneity between studies. Small intakes may have beneficial effects in&#xD;
      comparison to null intake whereas higher intakes may have other effects and non-linear&#xD;
      relationships are rarely examined. Frequently, different milk products are considered as one&#xD;
      entity in cohort studies. The investigators recently showed that different milk products&#xD;
      might have differential effects on disease. A high long-term milk intake was associated with&#xD;
      an increased risk of mortality (total, cardiovascular, and cancer mortality) and hip&#xD;
      fracture, especially among women, whereas a high long-term intake of fermented milk (soured&#xD;
      milk and yogurt or cheese) was associated with a lower risk of mortality and fracture among&#xD;
      women. Similar results have been presented for total mortality (Northern Sweden) and humeral&#xD;
      fractures (South-Eastern Australia).&#xD;
&#xD;
      Intake of milk and fermented milk is of tradition high in Sweden. The prevalence of lactase&#xD;
      persistence is high (around 95%). The range in milk intake from non- and low-consumers to&#xD;
      high consumers makes Sweden an appropriate setting for epidemiological and interventional&#xD;
      studies.&#xD;
&#xD;
      A common potential mechanism for intake of fruits, vegetables, and different dairy products&#xD;
      on risk of disease is their influence on inflammation and oxidative stress. Chronic low-grade&#xD;
      inflammation and age-related increase of oxidative stress are suggested pathogenic mechanisms&#xD;
      of premature ageing and many diseases including cardiovascular disease, cancer, accelerated&#xD;
      bone loss (leading to osteoporosis), and age-related reduction of muscle strength and mass&#xD;
      (sarcopenia) with potential impacts on risk of falling and fracture. The lower risk of&#xD;
      fractures with a high intake of fermented milk products observed may be due to potential&#xD;
      probiotic, antioxidative, and anti-inflammatory effects and effects on gut microbiota. A high&#xD;
      intake of milk was not only associated with risk of mortality and fractures but also with&#xD;
      increased concentrations of inflammation and oxidative stress markers. An inverse association&#xD;
      was seen for intake of soured milk and yogurt [Michaëlsson, 2014]. Fermented milk products&#xD;
      with probiotics have been shown to reduce the levels of inflammation markers, other studies&#xD;
      have been small to show conclusive effects and results may also be dependent on the probiotic&#xD;
      strain. A head-to-head comparison of the effect of regular milk and soured milk (or yogurt)&#xD;
      on markers of inflammation and oxidative stress in a randomized intervention study is&#xD;
      warranted. The randomized crossover intervention study will be performed among both men and&#xD;
      women.&#xD;
&#xD;
      The aim of the study is to examine the potentially different short-term effects of milk and&#xD;
      sour milk on markers of oxidative stress and inflammation in a randomized cross-over trial.&#xD;
      The research questions are:&#xD;
&#xD;
        1. In a randomized cross-over trial, what is the effect of a daily intake of at least 500&#xD;
           ml of Swedish milk compared with an intake of at least 500 ml Swedish soured milk&#xD;
           (filmjölk) during 3 weeks on markers of oxidative stress and inflammation?&#xD;
&#xD;
        2. What are the effects of these milk products on a large number of proteins related with&#xD;
           inflammation and ageing diseases, assessed with large-scale proteomic analysis?&#xD;
&#xD;
        3. What are the effects of these milk products on metabolites involved in inflammation and&#xD;
           ageing diseases using large-scale metabolomics analysis?&#xD;
&#xD;
        4. What are the effects of these milk products on the gut microflora (microbiome)?&#xD;
&#xD;
      Changes in proteomics, metabolomics and the gut microbiome are other pre-specified outcome&#xD;
      measures but since they are exploratory in nature, we do not specify them under outcomes&#xD;
      since it is not possible to exactly specify these outcome measures. Exploratory analyses will&#xD;
      include whether effects are different between men and women, dependent on body composition&#xD;
      (assessed with whole body dual X-ray absorptiometry, DXA) or long-term dietary intake&#xD;
      (assessed by fatty acid composition in subcutaneous fat). Participants will be allowed to&#xD;
      consume more than 500 ml of milk/filmjölk during the intervention periods and, if possible, a&#xD;
      potential dose-response effect will be evaluated.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 7, 2019</start_date>
  <completion_date type="Actual">June 9, 2020</completion_date>
  <primary_completion_date type="Actual">June 9, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in oxidative stress marker</measure>
    <time_frame>baseline and 3 weeks</time_frame>
    <description>urinary 8-iso-prostaglandin F2 alpha (8-iso-PGF2alpha)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in oxidative stress marker</measure>
    <time_frame>6 weeks and 9 weeks</time_frame>
    <description>urinary 8-iso-prostaglandin F2 alpha (8-iso-PGF2alpha)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in interleukin-6 (IL-6)</measure>
    <time_frame>baseline and 3 weeks</time_frame>
    <description>Inflammation marker, measured in serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in interleukin-6 (IL-6)</measure>
    <time_frame>6 weeks and 9 weeks</time_frame>
    <description>Inflammation marker, measured in serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change high sensitive C-reactive protein (hs-CRP)</measure>
    <time_frame>baseline and 3 weeks</time_frame>
    <description>Inflammation marker, measured in serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change high sensitive C-reactive protein (hs-CRP)</measure>
    <time_frame>6 weeks and 9 weeks</time_frame>
    <description>Inflammation marker, measured in serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in 15-keto-dihydro-prostaglandin F2 alpha (15-keto-dihydro-PGF2alpha)</measure>
    <time_frame>baseline and 3 weeks</time_frame>
    <description>Inflammation marker, a major metabolite of prostaglandin F2alpha, measured in urine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in 15-keto-dihydro-prostaglandin F2 alpha (15-keto-dihydro-PGF2alpha)</measure>
    <time_frame>6 weeks and 9 weeks</time_frame>
    <description>Inflammation marker, a major metabolite of prostaglandin F2alpha, measured in urine</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">84</enrollment>
  <condition>Oxidative Stress</condition>
  <condition>Inflammation</condition>
  <arm_group>
    <arm_group_label>Milk</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>At least 500 ml of Swedish milk daily for three weeks (crossover). Intervention and crossover preceded by 3 weeks with max 50 ml of milk or soured milk (filmjölk) daily. Fat content of milk and soured milk should be the same: 0.5%, 1.5% or 3%.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Soured milk (filmjölk)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>At least 500 ml of Swedish soured milk (filmjölk) daily for three weeks (crossover). Intervention and crossover preceded by 3 weeks with max 50 ml of milk or soured milk (filmjölk) daily. Fat content of milk and soured milk should be the same: 0.5%, 1.5% or 3%.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Milk</intervention_name>
    <description>Swedish milk from cow.</description>
    <arm_group_label>Milk</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Soured milk (filmjölk)</intervention_name>
    <description>Swedish soured milk (from cow milk).</description>
    <arm_group_label>Soured milk (filmjölk)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Tolerates both a low and a high intake of milk and soured milk&#xD;
&#xD;
          -  Agrees to comply with study protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inflammatory bowel disease&#xD;
&#xD;
          -  Major gastric tract operation&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Eating disorder&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Liisa Byberg, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Surgical Sciences, Uppsala University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Forskningsmottagning bentäthet, Kirurgiska vetenskaper, Uppsala Universitet</name>
      <address>
        <city>Uppsala</city>
        <zip>75185</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <reference>
    <citation>Larsson SC, Crippa A, Orsini N, Wolk A, Michaelsson K. Milk Consumption and Mortality from All Causes, Cardiovascular Disease, and Cancer: A Systematic Review and Meta-Analysis. Nutrients. 2015 Sep 11;7(9):7749-63. doi: 10.3390/nu7095363.</citation>
    <PMID>26378576</PMID>
  </reference>
  <reference>
    <citation>Michaelsson K, Wolk A, Langenskiold S, Basu S, Warensjo Lemming E, Melhus H, Byberg L. Milk intake and risk of mortality and fractures in women and men: cohort studies. BMJ. 2014 Oct 28;349:g6015. doi: 10.1136/bmj.g6015.</citation>
    <PMID>25352269</PMID>
  </reference>
  <reference>
    <citation>Tognon G, Nilsson LM, Shungin D, Lissner L, Jansson JH, Renstrom F, Wennberg M, Winkvist A, Johansson I. Nonfermented milk and other dairy products: associations with all-cause mortality. Am J Clin Nutr. 2017 Jun;105(6):1502-1511. doi: 10.3945/ajcn.116.140798. Epub 2017 May 10.</citation>
    <PMID>28490510</PMID>
  </reference>
  <reference>
    <citation>Holloway KL, Bucki-Smith G, Morse AG, Brennan-Olsen SL, Kotowicz MA, Moloney DJ, Sanders KM, Korn S, Timney EN, Dobbins AG, Pasco JA. Humeral Fractures in South-Eastern Australia: Epidemiology and Risk Factors. Calcif Tissue Int. 2015 Nov;97(5):453-65. doi: 10.1007/s00223-015-0039-9. Epub 2015 Jul 14.</citation>
    <PMID>26169198</PMID>
  </reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>January 16, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 29, 2019</study_first_posted>
  <last_update_submitted>November 3, 2020</last_update_submitted>
  <last_update_submitted_qc>November 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03821116
org study id: MILK: EPN-Uppsala dnr 2018-328
nct id: NCT03821116
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study evaluates a high intake of milk compared with a high intake of soured milk
      (Swedish filmjölk) on markers of oxidative stress and inflammation in a randomized crossover
      intervention study.
A diet rich in antioxidants reduces oxidative stress and inflammation and could potentially
      improve health and lower the rate of hip fracture. Milk and dairy are also promoted as part
      of a healthy diet since they contain 18 of 22 essential nutrients including calcium,
      phosphorous, and vitamin D and have been suggested to be associated with lower risk of
      cardiovascular disease, especially stroke, type 2 diabetes, and cancer. Meta-analyses of milk
      and dairy on fracture and mortality risk in cohort studies are, however, inconclusive and
      show significant heterogeneity between studies. Small intakes may have beneficial effects in
      comparison to null intake whereas higher intakes may have other effects and non-linear
      relationships are rarely examined. Frequently, different milk products are considered as one
      entity in cohort studies. The investigators recently showed that different milk products
      might have differential effects on disease. A high long-term milk intake was associated with
      an increased risk of mortality (total, cardiovascular, and cancer mortality) and hip
      fracture, especially among women, whereas a high long-term intake of fermented milk (soured
      milk and yogurt or cheese) was associated with a lower risk of mortality and fracture among
      women. Similar results have been presented for total mortality (Northern Sweden) and humeral
      fractures (South-Eastern Australia).

      Intake of milk and fermented milk is of tradition high in Sweden. The prevalence of lactase
      persistence is high (around 95%). The range in milk intake from non- and low-consumers to
      high consumers makes Sweden an appropriate setting for epidemiological and interventional
      studies.

      A common potential mechanism for intake of fruits, vegetables, and different dairy products
      on risk of disease is their influence on inflammation and oxidative stress. Chronic low-grade
      inflammation and age-related increase of oxidative stress are suggested pathogenic mechanisms
      of premature ageing and many diseases including cardiovascular disease, cancer, accelerated
      bone loss (leading to osteoporosis), and age-related reduction of muscle strength and mass
      (sarcopenia) with potential impacts on risk of falling and fracture. The lower risk of
      fractures with a high intake of fermented milk products observed may be due to potential
      probiotic, antioxidative, and anti-inflammatory effects and effects on gut microbiota. A high
      intake of milk was not only associated with risk of mortality and fractures but also with
      increased concentrations of inflammation and oxidative stress markers. An inverse association
      was seen for intake of soured milk and yogurt [Michaëlsson, 2014]. Fermented milk products
      with probiotics have been shown to reduce the levels of inflammation markers, other studies
      have been small to show conclusive effects and results may also be dependent on the probiotic
      strain. A head-to-head comparison of the effect of regular milk and soured milk (or yogurt)
      on markers of inflammation and oxidative stress in a randomized intervention study is
      warranted. The randomized crossover intervention study will be performed among both men and
      women.

      The aim of the study is to examine the potentially different short-term effects of milk and
      sour milk on markers of oxidative stress and inflammation in a randomized cross-over trial.
      The research questions are:

        1. In a randomized cross-over trial, what is the effect of a daily intake of at least 500
           ml of Swedish milk compared with an intake of at least 500 ml Swedish soured milk
           (filmjölk) during 3 weeks on markers of oxidative stress and inflammation?

        2. What are the effects of these milk products on a large number of proteins related with
           inflammation and ageing diseases, assessed with large-scale proteomic analysis?

        3. What are the effects of these milk products on metabolites involved in inflammation and
           ageing diseases using large-scale metabolomics analysis?

        4. What are the effects of these milk products on the gut microflora (microbiome)?

      Changes in proteomics, metabolomics and the gut microbiome are other pre-specified outcome
      measures but since they are exploratory in nature, we do not specify them under outcomes
      since it is not possible to exactly specify these outcome measures. Exploratory analyses will
      include whether effects are different between men and women, dependent on body composition
      (assessed with whole body dual X-ray absorptiometry, DXA) or long-term dietary intake
      (assessed by fatty acid composition in subcutaneous fat). Participants will be allowed to
      consume more than 500 ml of milk/filmjölk during the intervention periods and, if possible, a
      potential dose-response effect will be evaluated.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in oxidative stress marker
time frame: baseline and 3 weeks
description: urinary 8-iso-prostaglandin F2 alpha (8-iso-PGF2alpha)
measure: Change in oxidative stress marker
time frame: 6 weeks and 9 weeks
description: urinary 8-iso-prostaglandin F2 alpha (8-iso-PGF2alpha)
measure: Change in interleukin-6 (IL-6)
time frame: baseline and 3 weeks
description: Inflammation marker, measured in serum
measure: Change in interleukin-6 (IL-6)
time frame: 6 weeks and 9 weeks
description: Inflammation marker, measured in serum
measure: Change high sensitive C-reactive protein (hs-CRP)
time frame: baseline and 3 weeks
description: Inflammation marker, measured in serum
measure: Change high sensitive C-reactive protein (hs-CRP)
time frame: 6 weeks and 9 weeks
description: Inflammation marker, measured in serum
measure: Change in 15-keto-dihydro-prostaglandin F2 alpha (15-keto-dihydro-PGF2alpha)
time frame: baseline and 3 weeks
description: Inflammation marker, a major metabolite of prostaglandin F2alpha, measured in urine
measure: Change in 15-keto-dihydro-prostaglandin F2 alpha (15-keto-dihydro-PGF2alpha)
time frame: 6 weeks and 9 weeks
description: Inflammation marker, a major metabolite of prostaglandin F2alpha, measured in urine
arm group label: Milk
arm group type: Experimental
description: At least 500 ml of Swedish milk daily for three weeks (crossover). Intervention and crossover preceded by 3 weeks with max 50 ml of milk or soured milk (filmjölk) daily. Fat content of milk and soured milk should be the same: 0.5%, 1.5% or 3%.
arm group label: Soured milk (filmjölk)
arm group type: Experimental
description: At least 500 ml of Swedish soured milk (filmjölk) daily for three weeks (crossover). Intervention and crossover preceded by 3 weeks with max 50 ml of milk or soured milk (filmjölk) daily. Fat content of milk and soured milk should be the same: 0.5%, 1.5% or 3%.
intervention type: Other
intervention name: Milk
description: Swedish milk from cow.
arm group label: Milk
intervention type: Other
intervention name: Soured milk (filmjölk)
description: Swedish soured milk (from cow milk).
arm group label: Soured milk (filmjölk)
criteria: 
gender: All
minimum age: 40 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Liisa Byberg, PhD
role: Principal Investigator
affiliation: Department of Surgical Sciences, Uppsala University
facility: 
country: Sweden
citation: Larsson SC, Crippa A, Orsini N, Wolk A, Michaelsson K. Milk Consumption and Mortality from All Causes, Cardiovascular Disease, and Cancer: A Systematic Review and Meta-Analysis. Nutrients. 2015 Sep 11;7(9):7749-63. doi: 10.3390/nu7095363.
PMID: 26378576
citation: Michaelsson K, Wolk A, Langenskiold S, Basu S, Warensjo Lemming E, Melhus H, Byberg L. Milk intake and risk of mortality and fractures in women and men: cohort studies. BMJ. 2014 Oct 28;349:g6015. doi: 10.1136/bmj.g6015.
PMID: 25352269
citation: Tognon G, Nilsson LM, Shungin D, Lissner L, Jansson JH, Renstrom F, Wennberg M, Winkvist A, Johansson I. Nonfermented milk and other dairy products: associations with all-cause mortality. Am J Clin Nutr. 2017 Jun;105(6):1502-1511. doi: 10.3945/ajcn.116.140798. Epub 2017 May 10.
PMID: 28490510
citation: Holloway KL, Bucki-Smith G, Morse AG, Brennan-Olsen SL, Kotowicz MA, Moloney DJ, Sanders KM, Korn S, Timney EN, Dobbins AG, Pasco JA. Humeral Fractures in South-Eastern Australia: Epidemiology and Risk Factors. Calcif Tissue Int. 2015 Nov;97(5):453-65. doi: 10.1007/s00223-015-0039-9. Epub 2015 Jul 14.
PMID: 26169198
responsible party type: Sponsor
mesh term: Inflammation
sharing ipd: No