xml: <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/NCT06030388</url>
    </required_header>
    <id_info>
      <org_study_id>START2022-05030-1</org_study_id>
      <nct_id>NCT06030388</nct_id>
    </id_info>
    <brief_title>Strength and Aerobic Training Against Hot Flushes in Postmenopausal Women</brief_title>
    <acronym>START</acronym>
    <official_title>STrength and AeRobic Training Against Vasomotor Symptoms (START) in Postmenopausal Women</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Linkoeping University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Region Östergötland</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Länssjukhuset i Kalmar län</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Linkoeping 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>
        The goal of this randomised controlled trial is to investigate the effects of and compare two&#xD;
        modes of physical exercise (strength training and high-intensity aerobic exercise) to&#xD;
        unchanged physical activity on vasomotor symptoms (hot flushes) in postmenopausal women. The&#xD;
        main question it aims to answer is the effect of 15 weeks of strength training vs high&#xD;
        intensity aerobic training vs unchanged physical activity on frequency and severity of hot&#xD;
        flushes. Participants will be randomised to:&#xD;
  &#xD;
          1. strength training&#xD;
  &#xD;
          2. high-intensity aerobic training&#xD;
  &#xD;
          3. untreated control group.&#xD;
  &#xD;
        Researchers will compare strength training, high-intensity aerobic training and untreated&#xD;
        control group to see if training can reduce hot flushes.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The overall aim is to investigate the efficacy of and compare two modes of physical exercise&#xD;
        (strength training and high-intensity aerobic exercise) to unchanged physical activity on&#xD;
        vasomotor symptoms (VMS), as well as secondary outcomes such as health-related quality of&#xD;
        life, sleep quality, physical activity levels, clinical outcomes, biomarkers, perceptions of&#xD;
        and adherence to the interventions. In a longer perspective, the goal is to find&#xD;
        evidence-based treatment options for VMS in postmenopausal women that are safe and effective,&#xD;
        and have positive effects on health and quality of life after menopause.&#xD;
  &#xD;
        Our hypothesis is that strength training and high-intensity aerobic exercise will reduce VMS&#xD;
        in postmenopausal women and improve quality of life as well as clinical outcomes more than in&#xD;
        a control group with unchanged physical activity. We also hypothesize that strength training&#xD;
        and high-intensity aerobic training will have the same effect on the primary outcome (change&#xD;
        in VMS) and that most of the changes in secondary outcomes will be superior in the&#xD;
        high-intensity aerobic training group compared to the strength training group.&#xD;
  &#xD;
        This is an open, two-centre, parallel, randomized controlled study performed according to the&#xD;
        SPIRIT and CONSORT statements&#xD;
  &#xD;
        Recruitment will take place by advertising on social media, in local newspapers and in the&#xD;
        Women's clinics and primary care centers in Linköping and Kalmar. Women who respond to the&#xD;
        advertisements will be contacted by a member of the research group or research nurse to&#xD;
        receive information about the study and screen for inclusion and exclusion criteria. Women&#xD;
        who are possibly eligible will be invited to a screening visit for further information and&#xD;
        informed consent. At the visit, inclusion and exclusion criteria will be checked by a&#xD;
        physician, and a clinical examination will be performed. Eligible participants will receive a&#xD;
        VMS screening diary and invited to a second visit 2-3 weeks later where inclusion and&#xD;
        randomization will be performed if the VMS inclusion criteria are fulfilled.&#xD;
  &#xD;
        Randomization An allocation sequence using a computerized random number generator will be&#xD;
        prepared by a statistician not involved in recruitment. Opaque sealed and sequentially&#xD;
        numbered envelopes with group allocation will be prepared and opened in the presence of the&#xD;
        participant upon inclusion and randomization.&#xD;
  &#xD;
        Power analysis: A sample size calculation was made based on the results of our previous study&#xD;
        on strength training for VMS (Berin et al 2019) and showed that to detect a 50% difference in&#xD;
        moderate and severe hot flushes with 80% power and expected dropout rate of 20% 40&#xD;
        participants in total would be needed. For this three-armed set-up we estimate that 20&#xD;
        participants in each group will be needed, i.e. 60 in total. To also achieve sufficient power&#xD;
        for some of the secondary outcomes the intended sample size is increased to 30 per group, 90&#xD;
        in total.&#xD;
  &#xD;
        Data analysis: The primary analysis will be performed according to the intention-to-treat&#xD;
        principle, including all participants who provided more than baseline data for the primary&#xD;
        outcome. For quantitative interval data mixed design ANOVAs will be used to analyze the&#xD;
        effect over time between and within groups. For the between-group comparisons effect sizes&#xD;
        will be calculated. For ordinal data, such as the questionnaires, Kruskal-Wallis and Friedman&#xD;
        test will be used for statistical analysis of the effect. Participants who complete two or&#xD;
        more training sessions per week will be considered adherent with their assigned intervention&#xD;
        and included in a per-protocol analysis. Detailed description of adherence, such as the&#xD;
        fidelity with the training interventions, will be presented descriptively.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 2023</start_date>
    <completion_date type="Anticipated">December 2032</completion_date>
    <primary_completion_date type="Anticipated">June 2027</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>Parallel Assignment</intervention_model>
      <intervention_model_description>Three-armed randomised trial where participants are randomised to 1) strength training, 2) high-intensity aerobic training or 3) untreated control group.</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Frequency of moderate and severe hot flushes</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>Frequency of hot flushes per 24 h daily recorded in hot flush diary from baseline throughout 15 weeks of intervention.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Frequency of moderate and severe hot flushes</measure>
      <time_frame>baseline to 6 months, 1, 2 and 5 years</time_frame>
      <description>Frequency of hot flushes per 24 h daily recorded in hot flush diary 2 weeks at baseline and 2 weeks at each of the time points.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Severity of hot flushes</measure>
      <time_frame>baseline to 15 weeks, 6 months, 1, 2 and 5 years</time_frame>
      <description>Severity of hot flushes per 24 hours recorded in hot flush diary from baseline throughout 15 weeks of intervention and two weeks during follow-up.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Generic health-related quality of life</measure>
      <time_frame>baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention</time_frame>
      <description>Short-form 36, 36 questions in 8 scales. Scores for each domain range from 0-100, and a high score represents a higher health-related quality of life.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Women specific health-related quality of life</measure>
      <time_frame>baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention</time_frame>
      <description>Women's health questionnaire nine sub-scales with four-point scales (yes definitely, yes sometimes, not not much, no not at all) that are reduced to binary options (0/1). The subscale items are summated and divided by the number of items in each subscale.A higher score represents worse outcome.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Physical activity levels</measure>
      <time_frame>baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention</time_frame>
      <description>International Physical Activity Questionnaire short form, the participant describes the amount of time (minutes and hours) that is spent on different physical activities each week, the more time, the better, except for the question about the amount of time spent in sitting.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Sleep quality</measure>
      <time_frame>baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention</time_frame>
      <description>Pittsburgh sleep quality index, 7 domains. For the total instrument, the lower score, the better, from 0 (best) to 21 (worst).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Diet</measure>
      <time_frame>baseline to 15 weeks, 6 months, 1, 2 and 5 years</time_frame>
      <description>Bespoke questionnaire, primarily to control for changes during the intervention period. Registration of amounts or portions. Results are presented question by question descriptively.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Accomplished physical activity</measure>
      <time_frame>baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention</time_frame>
      <description>Bespoke training diary</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Bioimpedance</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>Fat mass (%) and fat-free (muscle) mass (%)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Weight</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>kilogram (kg)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Lenght</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>meters (m)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Body mass index</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>kilograms/meters2 (kg/m2)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Waist circumference</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>millimeters (mm)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Systolic and diastolic blood pressure</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>Unit millimetre of mercury (mmHg)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Hematologic and ironstatus changes</measure>
      <time_frame>baseline to 15 weeks, and 1 year</time_frame>
      <description>Hemoglobin full body count, Transferrin(gram/Litre), and Ferritin (microgram/Litre)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in blood-lipids</measure>
      <time_frame>baseline to 15 weeks, and 1 year</time_frame>
      <description>apolipoprotein A1, apolipoprotein B (gram/Litre) and total cholesterol, low-density lipoprotein, high-density lipoprotein (mmol/L) and leptin (ng/mL)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in sex hormones and gonadotrophins</measure>
      <time_frame>baseline to 15 weeks, and 1 year</time_frame>
      <description>Estradiol (pmol/Litre), Sex hormone bindning globulin, Testosterone (nmol/Litre), follicle-stimulating hormone, luteinizing hormone (IE/Litre)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in glucose profile</measure>
      <time_frame>baseline to 15 weeks, and 1 year</time_frame>
      <description>HbA1c (mmol/Litre) and fasting blood glucose (mmol/L)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in inflammatory biomarkers</measure>
      <time_frame>baseline to 15 weeks, and 1 year</time_frame>
      <description>high-sensitive C-reactive Protein (microgram/Litre), Brain-derived neutrophic factor, Matrix metalloproteinase-2 and -9 (ng/mL), Interleukin -4, -6, -7, -8, 10, -15, tumour necrosis factor, monocyte chemoattractant protein-1 (pg/mL)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in the lenght of telomeres in white blood cells</measure>
      <time_frame>baseline to 15 weeks, and 1 year</time_frame>
      <description>Telomeres (kilobase) pair</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in exercise capacity</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>Change in exercise capacity is primarily used as a measure of adherence and obtained through cardiopulmonary exercise testing assessing maximum oxygen uptake milliliter/kilogram/minute (ml/kg/minute) and analysed according to local clinical routines.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Experiences of the interventions, facilitators and barriers</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>Bespoke questionnaire, only for intervention groups. Results will be presented descriptively question by question.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Adherence to the interventions</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>Assessed through bespoke training diary where each training session is registered and the total number of training sessions as well as training sessions/week will be calculated.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Muscle strength</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>For strength training group only, measured using 8 repetition-maximum tests.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Adverse events</measure>
      <time_frame>baseline to 15 weeks</time_frame>
      <description>Adverse events of taking part in the study</description>
    </secondary_outcome>
    <number_of_arms>3</number_of_arms>
    <enrollment type="Anticipated">90</enrollment>
    <condition>Postmenopausal Symptoms</condition>
    <condition>Hot Flashes</condition>
    <arm_group>
      <arm_group_label>Strength training</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Standardised programme with the following exercises: chest press, leg press, row, leg curl, latissimus dorsi pull down and leg extension in seated resistance machines. Training will be preceded by 7-10 minutes of warm-up and followed by two body-weight exercises for the abdominal and back muscles for two sets as many repetitions as possible, and thereafter cool down and stretches. The set-up of each machine will be recorded in the training diary.&#xD;
  Weeks 1-3 will include two sets of training with 15-20 repetition-maximum (RM) and weeks 4-15 two sets with 8-12 RM. Throughout the intervention, loads will be adjusted to achieve muscle fatigue and approach training to failure during each set with the intent to maximize beta-endorphin release.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>High-intensity aerobic training</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Participants will be recommended to attend spinning classes three times per week. During their first visit to the training venue, they will meet a sports physiotherapist or personal trainer to be introduced to the spinning bike intervention. The intended intensity is ≥ 14 on the Borg rating of perceived exertion scale, equivalent to high intensity training (&gt;70% of VO2max) with the aim of attaining sufficient stimulus for beta-endorphin release. During weeks 1-3 participants will attend spinning classes for beginners with lower intensity and predominantly seated cycling. They will progress to higher intensity classes with greater variation between seated and standing cycling during week 4-15.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control group</arm_group_label>
      <arm_group_type>No Intervention</arm_group_type>
      <description>The control group will be recommended to carry on physical activity as usual and not to change their training or dietary habits during the 15-week study period. The control group will be contacted every fourth weeks by a research nurse to follow up on their general well-being and any questions they might have about menopause. After the study period they will be offered individual advise about training from a physiotherapist or personal trainer.</description>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Strength training</intervention_name>
      <description>Both interventions (strength training and high intensity aerobic training) will be introduced with a 3-week adaptation period with lower loads (strength training) or intensity (aerobic training) followed by a 12-week period on the intended load/intensity. All participants in the intervention groups will be recommended to exercise three times per week (one hour per session) and in addition be active with everyday low-intensity physical activity. A structured and detailed training diary will be used in both groups to register frequency of each training session, as well as everyday physical activity. For the strength training, load and dose will also be registered for each training session.</description>
      <arm_group_label>Strength training</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>High-intensity aerobic training</intervention_name>
      <description>Both interventions (strength training and high intensity aerobic training) will be introduced with a 3-week adaptation period with lower loads (strength training) or intensity (aerobic training) followed by a 12-week period on the intended load/intensity. All participants in the intervention groups will be recommended to exercise three times per week (one hour per session) and in addition be active with everyday low-intensity physical activity. A structured and detailed training diary will be used in both groups to register frequency of each training session, as well as everyday physical activity. For the strength training, load and dose will also be registered for each training session.</description>
      <arm_group_label>High-intensity aerobic training</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Postmenopausal women (one of: ≥ 12 months since last menstruation; amenorrhea due to&#xD;
               intrauterine device or hysterectomy and Follicle Stimulating Hormone (FSH) &gt;30 mIU/ml;&#xD;
               bilateral oophorectomy; induced menopause due to chemotherapy or radiation and ≥2&#xD;
               years amenorrhea);&#xD;
  &#xD;
            -  ≥ 28 moderate to severe hot flushes per week during a 2-week screening period,&#xD;
               registered through a daily VMS diary;&#xD;
  &#xD;
            -  Age ≥45 years;&#xD;
  &#xD;
            -  Physical ability to participate in strength training or high intensity aerobic&#xD;
               exercise for 60 minutes, 3 times/week during 15 weeks;&#xD;
  &#xD;
            -  Understand Swedish orally and in writing&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Regular physical activity &gt;30 minutes per week of vigorous intensity or ≥150 minutes&#xD;
               of moderate intensity or combined activities representing maximum 150 minutes of&#xD;
               moderate intensity;&#xD;
  &#xD;
            -  Use of systemic menopausal hormone therapy the last 2 months;&#xD;
  &#xD;
            -  Use of natural preparations such as herbal preparations for VMS, or other medications&#xD;
               for VMS the last 2 months;&#xD;
  &#xD;
            -  Capillary hemoglobin &lt;110 g/l;&#xD;
  &#xD;
            -  Blood pressure &gt;160 mmHg systolic or &gt;100 mmHg diastolic;&#xD;
  &#xD;
            -  Unstable medical condition with a potential to affect VMS (like unregulated thyroid&#xD;
               disease);&#xD;
  &#xD;
            -  Medical condition that by a physician is judged not appropriate (because of potential&#xD;
               to affect VMS or risk of injury with vigorous exercise)&#xD;
        </textblock>
      </criteria>
      <gender>Female</gender>
      <minimum_age>45 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Anna-Clara Spetz Holm, Ass prof, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Region Östergötland, Linköping university</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Anna-Clara Spetz Holm, Ass prof, MD</last_name>
      <phone>+46101033130</phone>
      <email>anna-clara.spetz.holm@liu.se</email>
    </overall_contact>
    <location>
      <facility>
        <name>Region Kalmar Län</name>
        <address>
          <city>Kalmar</city>
          <zip>S-39126</zip>
          <country>Sweden</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Region Östergötland</name>
        <address>
          <city>Linköping</city>
          <zip>S-58185</zip>
          <country>Sweden</country>
        </address>
      </facility>
      <contact>
        <last_name>Anna-Clara Spetz Holm, Ass prof, MD</last_name>
      </contact>
    </location>
    <location_countries>
      <country>Sweden</country>
    </location_countries>
    <results_reference>
      <citation>Berin E, Hammar M, Lindblom H, Lindh-Astrand L, Ruber M, Spetz Holm AC. Resistance training for hot flushes in postmenopausal women: A randomised controlled trial. Maturitas. 2019 Aug;126:55-60. doi: 10.1016/j.maturitas.2019.05.005. Epub 2019 May 14.</citation>
      <PMID>31239119</PMID>
    </results_reference>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>June 15, 2023</study_first_submitted>
    <study_first_submitted_qc>September 8, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 11, 2023</study_first_posted>
    <last_update_submitted>September 8, 2023</last_update_submitted>
    <last_update_submitted_qc>September 8, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 11, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Linkoeping University</investigator_affiliation>
      <investigator_full_name>Anna-Clara Spetz Holm</investigator_full_name>
      <investigator_title>Associate professor, Medical Doctor</investigator_title>
    </responsible_party>
    <keyword>aerobic training</keyword>
    <keyword>strength training</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Hot Flashes</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>Individual participant data that underlie results in publications may be available upon reasonable request to the principal investigator</ipd_description>
      <ipd_time_frame>1 year after publication.</ipd_time_frame>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06030388
  org study id: START2022-05030-1
  nct id: NCT06030388
  lead sponsor: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  The goal of this randomised controlled trial is to investigate the effects of and compare two
        modes of physical exercise (strength training and high-intensity aerobic exercise) to
        unchanged physical activity on vasomotor symptoms (hot flushes) in postmenopausal women. The
        main question it aims to answer is the effect of 15 weeks of strength training vs high
        intensity aerobic training vs unchanged physical activity on frequency and severity of hot
        flushes. Participants will be randomised to:
  
          1. strength training
  
          2. high-intensity aerobic training
  
          3. untreated control group.
  
        Researchers will compare strength training, high-intensity aerobic training and untreated
        control group to see if training can reduce hot flushes.
  The overall aim is to investigate the efficacy of and compare two modes of physical exercise
        (strength training and high-intensity aerobic exercise) to unchanged physical activity on
        vasomotor symptoms (VMS), as well as secondary outcomes such as health-related quality of
        life, sleep quality, physical activity levels, clinical outcomes, biomarkers, perceptions of
        and adherence to the interventions. In a longer perspective, the goal is to find
        evidence-based treatment options for VMS in postmenopausal women that are safe and effective,
        and have positive effects on health and quality of life after menopause.
  
        Our hypothesis is that strength training and high-intensity aerobic exercise will reduce VMS
        in postmenopausal women and improve quality of life as well as clinical outcomes more than in
        a control group with unchanged physical activity. We also hypothesize that strength training
        and high-intensity aerobic training will have the same effect on the primary outcome (change
        in VMS) and that most of the changes in secondary outcomes will be superior in the
        high-intensity aerobic training group compared to the strength training group.
  
        This is an open, two-centre, parallel, randomized controlled study performed according to the
        SPIRIT and CONSORT statements
  
        Recruitment will take place by advertising on social media, in local newspapers and in the
        Women's clinics and primary care centers in Linköping and Kalmar. Women who respond to the
        advertisements will be contacted by a member of the research group or research nurse to
        receive information about the study and screen for inclusion and exclusion criteria. Women
        who are possibly eligible will be invited to a screening visit for further information and
        informed consent. At the visit, inclusion and exclusion criteria will be checked by a
        physician, and a clinical examination will be performed. Eligible participants will receive a
        VMS screening diary and invited to a second visit 2-3 weeks later where inclusion and
        randomization will be performed if the VMS inclusion criteria are fulfilled.
  
        Randomization An allocation sequence using a computerized random number generator will be
        prepared by a statistician not involved in recruitment. Opaque sealed and sequentially
        numbered envelopes with group allocation will be prepared and opened in the presence of the
        participant upon inclusion and randomization.
  
        Power analysis: A sample size calculation was made based on the results of our previous study
        on strength training for VMS (Berin et al 2019) and showed that to detect a 50% difference in
        moderate and severe hot flushes with 80% power and expected dropout rate of 20% 40
        participants in total would be needed. For this three-armed set-up we estimate that 20
        participants in each group will be needed, i.e. 60 in total. To also achieve sufficient power
        for some of the secondary outcomes the intended sample size is increased to 30 per group, 90
        in total.
  
        Data analysis: The primary analysis will be performed according to the intention-to-treat
        principle, including all participants who provided more than baseline data for the primary
        outcome. For quantitative interval data mixed design ANOVAs will be used to analyze the
        effect over time between and within groups. For the between-group comparisons effect sizes
        will be calculated. For ordinal data, such as the questionnaires, Kruskal-Wallis and Friedman
        test will be used for statistical analysis of the effect. Participants who complete two or
        more training sessions per week will be considered adherent with their assigned intervention
        and included in a per-protocol analysis. Detailed description of adherence, such as the
        fidelity with the training interventions, will be presented descriptively.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Three-armed randomised trial where participants are randomised to 1) strength training, 2) high-intensity aerobic training or 3) untreated control group.
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Frequency of moderate and severe hot flushes
  time frame: baseline to 15 weeks
  description: Frequency of hot flushes per 24 h daily recorded in hot flush diary from baseline throughout 15 weeks of intervention.
  measure: Frequency of moderate and severe hot flushes
  time frame: baseline to 6 months, 1, 2 and 5 years
  description: Frequency of hot flushes per 24 h daily recorded in hot flush diary 2 weeks at baseline and 2 weeks at each of the time points.
  measure: Severity of hot flushes
  time frame: baseline to 15 weeks, 6 months, 1, 2 and 5 years
  description: Severity of hot flushes per 24 hours recorded in hot flush diary from baseline throughout 15 weeks of intervention and two weeks during follow-up.
  measure: Generic health-related quality of life
  time frame: baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention
  description: Short-form 36, 36 questions in 8 scales. Scores for each domain range from 0-100, and a high score represents a higher health-related quality of life.
  measure: Women specific health-related quality of life
  time frame: baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention
  description: Women's health questionnaire nine sub-scales with four-point scales (yes definitely, yes sometimes, not not much, no not at all) that are reduced to binary options (0/1). The subscale items are summated and divided by the number of items in each subscale.A higher score represents worse outcome.
  measure: Physical activity levels
  time frame: baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention
  description: International Physical Activity Questionnaire short form, the participant describes the amount of time (minutes and hours) that is spent on different physical activities each week, the more time, the better, except for the question about the amount of time spent in sitting.
  measure: Sleep quality
  time frame: baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention
  description: Pittsburgh sleep quality index, 7 domains. For the total instrument, the lower score, the better, from 0 (best) to 21 (worst).
  measure: Diet
  time frame: baseline to 15 weeks, 6 months, 1, 2 and 5 years
  description: Bespoke questionnaire, primarily to control for changes during the intervention period. Registration of amounts or portions. Results are presented question by question descriptively.
  measure: Accomplished physical activity
  time frame: baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention
  description: Bespoke training diary
  measure: Bioimpedance
  time frame: baseline to 15 weeks
  description: Fat mass (%) and fat-free (muscle) mass (%)
  measure: Weight
  time frame: baseline to 15 weeks
  description: kilogram (kg)
  measure: Lenght
  time frame: baseline to 15 weeks
  description: meters (m)
  measure: Body mass index
  time frame: baseline to 15 weeks
  description: kilograms/meters2 (kg/m2)
  measure: Waist circumference
  time frame: baseline to 15 weeks
  description: millimeters (mm)
  measure: Systolic and diastolic blood pressure
  time frame: baseline to 15 weeks
  description: Unit millimetre of mercury (mmHg)
  measure: Hematologic and ironstatus changes
  time frame: baseline to 15 weeks, and 1 year
  description: Hemoglobin full body count, Transferrin(gram/Litre), and Ferritin (microgram/Litre)
  measure: Changes in blood-lipids
  time frame: baseline to 15 weeks, and 1 year
  description: apolipoprotein A1, apolipoprotein B (gram/Litre) and total cholesterol, low-density lipoprotein, high-density lipoprotein (mmol/L) and leptin (ng/mL)
  measure: Changes in sex hormones and gonadotrophins
  time frame: baseline to 15 weeks, and 1 year
  description: Estradiol (pmol/Litre), Sex hormone bindning globulin, Testosterone (nmol/Litre), follicle-stimulating hormone, luteinizing hormone (IE/Litre)
  measure: Changes in glucose profile
  time frame: baseline to 15 weeks, and 1 year
  description: HbA1c (mmol/Litre) and fasting blood glucose (mmol/L)
  measure: Changes in inflammatory biomarkers
  time frame: baseline to 15 weeks, and 1 year
  description: high-sensitive C-reactive Protein (microgram/Litre), Brain-derived neutrophic factor, Matrix metalloproteinase-2 and -9 (ng/mL), Interleukin -4, -6, -7, -8, 10, -15, tumour necrosis factor, monocyte chemoattractant protein-1 (pg/mL)
  measure: Changes in the lenght of telomeres in white blood cells
  time frame: baseline to 15 weeks, and 1 year
  description: Telomeres (kilobase) pair
  measure: Change in exercise capacity
  time frame: baseline to 15 weeks
  description: Change in exercise capacity is primarily used as a measure of adherence and obtained through cardiopulmonary exercise testing assessing maximum oxygen uptake milliliter/kilogram/minute (ml/kg/minute) and analysed according to local clinical routines.
  measure: Experiences of the interventions, facilitators and barriers
  time frame: baseline to 15 weeks
  description: Bespoke questionnaire, only for intervention groups. Results will be presented descriptively question by question.
  measure: Adherence to the interventions
  time frame: baseline to 15 weeks
  description: Assessed through bespoke training diary where each training session is registered and the total number of training sessions as well as training sessions/week will be calculated.
  measure: Muscle strength
  time frame: baseline to 15 weeks
  description: For strength training group only, measured using 8 repetition-maximum tests.
  measure: Adverse events
  time frame: baseline to 15 weeks
  description: Adverse events of taking part in the study
  arm group label: Strength training
  arm group type: Active Comparator
  description: Standardised programme with the following exercises: chest press, leg press, row, leg curl, latissimus dorsi pull down and leg extension in seated resistance machines. Training will be preceded by 7-10 minutes of warm-up and followed by two body-weight exercises for the abdominal and back muscles for two sets as many repetitions as possible, and thereafter cool down and stretches. The set-up of each machine will be recorded in the training diary.
  Weeks 1-3 will include two sets of training with 15-20 repetition-maximum (RM) and weeks 4-15 two sets with 8-12 RM. Throughout the intervention, loads will be adjusted to achieve muscle fatigue and approach training to failure during each set with the intent to maximize beta-endorphin release.
  arm group label: High-intensity aerobic training
  arm group type: Active Comparator
  description: Participants will be recommended to attend spinning classes three times per week. During their first visit to the training venue, they will meet a sports physiotherapist or personal trainer to be introduced to the spinning bike intervention. The intended intensity is ≥ 14 on the Borg rating of perceived exertion scale, equivalent to high intensity training (>70% of VO2max) with the aim of attaining sufficient stimulus for beta-endorphin release. During weeks 1-3 participants will attend spinning classes for beginners with lower intensity and predominantly seated cycling. They will progress to higher intensity classes with greater variation between seated and standing cycling during week 4-15.
  arm group label: Control group
  arm group type: No Intervention
  description: The control group will be recommended to carry on physical activity as usual and not to change their training or dietary habits during the 15-week study period. The control group will be contacted every fourth weeks by a research nurse to follow up on their general well-being and any questions they might have about menopause. After the study period they will be offered individual advise about training from a physiotherapist or personal trainer.
  intervention type: Other
  intervention name: Strength training
  description: Both interventions (strength training and high intensity aerobic training) will be introduced with a 3-week adaptation period with lower loads (strength training) or intensity (aerobic training) followed by a 12-week period on the intended load/intensity. All participants in the intervention groups will be recommended to exercise three times per week (one hour per session) and in addition be active with everyday low-intensity physical activity. A structured and detailed training diary will be used in both groups to register frequency of each training session, as well as everyday physical activity. For the strength training, load and dose will also be registered for each training session.
  arm group label: Strength training
  intervention type: Other
  intervention name: High-intensity aerobic training
  description: Both interventions (strength training and high intensity aerobic training) will be introduced with a 3-week adaptation period with lower loads (strength training) or intensity (aerobic training) followed by a 12-week period on the intended load/intensity. All participants in the intervention groups will be recommended to exercise three times per week (one hour per session) and in addition be active with everyday low-intensity physical activity. A structured and detailed training diary will be used in both groups to register frequency of each training session, as well as everyday physical activity. For the strength training, load and dose will also be registered for each training session.
  arm group label: High-intensity aerobic training
  criteria: 
  gender: Female
  minimum age: 45 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Anna-Clara Spetz Holm, Ass prof, MD
  role: Principal Investigator
  affiliation: Region Östergötland, Linköping university
  last name: Anna-Clara Spetz Holm, Ass prof, MD
  phone: +46101033130
  email: anna-clara.spetz.holm@liu.se
  facility: 
  facility: 
  contact: 
  country: Sweden
  citation: Berin E, Hammar M, Lindblom H, Lindh-Astrand L, Ruber M, Spetz Holm AC. Resistance training for hot flushes in postmenopausal women: A randomised controlled trial. Maturitas. 2019 Aug;126:55-60. doi: 10.1016/j.maturitas.2019.05.005. Epub 2019 May 14.
  PMID: 31239119
  responsible party type: Principal Investigator
  investigator affiliation: Linkoeping University
  investigator full name: Anna-Clara Spetz Holm
  investigator title: Associate professor, Medical Doctor
  mesh term: Hot Flashes
  sharing ipd: Yes
  ipd description: Individual participant data that underlie results in publications may be available upon reasonable request to the principal investigator
  ipd time frame: 1 year after publication.