<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/NCT03234387</url>
  </required_header>
  <id_info>
    <org_study_id>ZS002</org_study_id>
    <nct_id>NCT03234387</nct_id>
  </id_info>
  <brief_title>A CFit Study - Baseline</brief_title>
  <official_title>A CFit Study: To What Extent Does Inflammation, Oxidative Stress, Nitric Oxide Bioavailability and Microvascular Endothelial Dysfunction Influence the Aerobic Exercise Function of Individuals With Cystic Fibrosis, With and Without Established Diabetes?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Portsmouth</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospital Southampton NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Loughborough University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Queen Alexandra Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Portsmouth</source>
  <oversight_info>
    <has_dmc>Yes</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>
      A great medical success is the increase in the median survival age associated with cystic&#xD;
      fibrosis (CF). However, this success has led to a new era of research with the aim to&#xD;
      maximise the quality of life (QoL) of the aging CF population. Recent research has&#xD;
      demonstrated that the traditional method of determining disease progression, i.e. pulmonary&#xD;
      function, no longer adequately predict survival rates. Therefore, various bodies have&#xD;
      promoted cardiopulmonary exercise testing (CPET), as outcomes from this test (e.g. one's&#xD;
      maximal O2 uptake [VO₂max]) are known predictors of the QoL, risk of hospitalisation and&#xD;
      prognosis of individuals with CF.&#xD;
&#xD;
      One of the most common non-pulmonary co-morbidities of CF is CF-related diabetes (CFRD).&#xD;
      Importantly, CFRD is associated with a poorer pulmonary function compared to CF patients&#xD;
      without CFRD, and ultimately a worsened prognosis. Despite this, the influence an impaired&#xD;
      glycaemic control has upon the VO₂max derived from a CPET is unknown in CF. Therefore, the&#xD;
      present study aims to assess whether VO₂max, an established determinant of QoL, differs&#xD;
      between patients with CF with and without established CFRD as well as a group of age- and&#xD;
      gender-matched healthy control subjects.&#xD;
&#xD;
      The additional measures within the present study, such as: biomarkers of inflammation, redox&#xD;
      balance and nitric oxide (NO2) bioavailability, as well as functional measures of&#xD;
      microvascular endothelial function will aid our knowledge of the physiological abnormalities&#xD;
      which are a cause or consequence of CFRD. Importantly, by identifying the factors which may&#xD;
      contribute to CFRD progression and those that are viable for early intervention, mean the&#xD;
      aims and objectives of this study are compatible with the top 10 research objectives set by&#xD;
      the CF Trust.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Participants and recruitment The present study will be a pilot, cross-sectional trial in&#xD;
      individuals with CFRD (n = 15), as well as age- and gender-matched CF controls without&#xD;
      diabetes (n = 15) and age- and gender-matched healthy control participants (n = 15).&#xD;
      Participants will be recruited from adult and paediatric CF outpatient clinics within the&#xD;
      Southampton CF network. The healthy control participants will be recruited from the&#xD;
      University of Portsmouth and local area. Individuals with CF will be tested at a laboratory&#xD;
      established within the CF unit at the Southampton General Hospital and/or the Department of&#xD;
      Sport and Exercise Sciences (University of Portsmouth), depending on participant convenience.&#xD;
      All healthy control participants will attend the Department of Sport and Exercise Sciences at&#xD;
      the University of Portsmouth.&#xD;
&#xD;
      Visit 1 During this visit, a valid informed consent and GCP trained member of the research&#xD;
      team will fully explain the information sheet and study protocol, as well as answer any&#xD;
      questions to ensure that all relevant parties are clear about the study requirements.&#xD;
      Following this, fully informed written consent will be obtained. Additionally, informed&#xD;
      written assent will be obtained from those &lt; 16 years of age.&#xD;
&#xD;
      Following the consent procedures the participants resting pulmonary function (forced vital&#xD;
      capacity, forced expiratory volume in 1 second, mid force expiratory flow and peak expiratory&#xD;
      flow) and anthropometric measures (weight, height and body fat percentage) will obtained. The&#xD;
      subsequent aim of this visit is then to habituate all participants with exercising on a cycle&#xD;
      ergometer in preparation for their CPET in visit 2, in particular maintaining a certain&#xD;
      cadence at a given power output. Appropriate adjustments will be made to the ergometer seat&#xD;
      and handlebar position, and noted for visit 2. Furthermore, the protocols of obtaining ones&#xD;
      ratings of perceived exertion and dyspnoea will be fully explained. Lastly, the participant&#xD;
      will be instructed to avoid consuming mouthwash for the entirety of the study period due to&#xD;
      evidence suggesting it may influence the uptake of dietary nitrate.&#xD;
&#xD;
      Visit 2 Participants will arrive to the laboratory at 1900 ± 2 hours. They will be instructed&#xD;
      to arrive 2 hours postprandial, having avoided caffeine for &gt; 12 hours, as well as nitrate&#xD;
      rich foods, alcohol and exhaustive exercise for &gt; 24 hours.&#xD;
&#xD;
      Upon arrival, CGM's will be fixed to the interior surface of the upper arm and worn for the&#xD;
      subsequent 14 days. In addition to this, hip worn accelerometers, as well as hourly specific&#xD;
      physical activity and food diaries will be distributed and completed for 14 days alongside&#xD;
      the CGM. The participants resting pulmonary function will be assessed using the spirometry&#xD;
      procedures described below, and a resting blood sample will be collected via venepuncture for&#xD;
      the analysis of plasma [NO-(₂)] and ET-1. Additionally, the cycle ergometer CPET with a&#xD;
      supramaximal (Smax) verification phase will be employed to determine ones aerobic exercise&#xD;
      function, and a second venous blood sample will be collected immediately following exercise&#xD;
      termination for the analysis of plasma [NO-(₂)] and ET-1. The total volume of blood collected&#xD;
      over this 2 hour visit will be approximately 20 mL.&#xD;
&#xD;
      Visit 3 Participants will be required to arrive to the laboratory ≥ 3 days post visit 1, at&#xD;
      0800 ± 2 hours, following an overnight fast (&gt; 10 hours). Furthermore, participants will be&#xD;
      instructed to avoid nitrate rich foods, caffeine, alcohol and exhaustive exercise for 24&#xD;
      hours prior to arrival.&#xD;
&#xD;
      Upon arrival participants will undergo the acetylcholine (ACh) and insulin iontophoresis&#xD;
      protocols described below, including 5 resting blood pressure measurements. Immediately&#xD;
      following this, the participant's pulmonary function will be assessed via spirometry.&#xD;
      Participants will be asked to rest, and entertainment will be provided, for the following 60&#xD;
      minutes. The iontophoresis procedures will then be repeated to assess the short-term&#xD;
      test-retest variability of the iontophoresis procedures. Following this, a cannula will be&#xD;
      inserted into a vein by a trained phlebotomist, prior to the 3 hour OGTT and a baseline blood&#xD;
      sample will be taken (measuring all the below biomarkers). Venous blood samples will be drawn&#xD;
      at 30, 60, 90, 120 and 180 minutes post glucose ingestion for the analysis of glucose,&#xD;
      insulin, active glucagon-like peptide-1 (GLP-1), TNF-α, soluble vascular cell adhesion&#xD;
      molecule-1 (sVCAM-1), IL-6, [NO-(₂)] and ET-1. NT, total glutathione (tGSH) and total&#xD;
      cysteine (tCys) will be analysed at 120 minutes post-glucose ingestion. The total volume of&#xD;
      blood collected over this 5 hour visit will be approximately 176 mL. Additionally, the&#xD;
      iontophoresis procedures will be repeated at 30, 90 and 150 minutes post-glucose ingestion&#xD;
      (i.e. hourly measurements of microvascular endothelial function).&#xD;
&#xD;
      Follow-up CGM's, accelerometers and physical activity/food diaries will be completed for 14&#xD;
      days following visit 1. A member of the research team will collect these from the preferred&#xD;
      location of the participant.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Poor recruitment&#xD;
  </why_stopped>
  <start_date type="Actual">November 17, 2017</start_date>
  <completion_date type="Actual">December 1, 2020</completion_date>
  <primary_completion_date type="Actual">December 1, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Maximal oxygen uptake (aerobic fitness)</measure>
    <time_frame>Visit 1 - Baseline</time_frame>
    <description>Maximal oxygen uptake (aerobic fitness) from a maximal cardiopulmonary exercise testing on a cycle ergometer</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>VO2 gain</measure>
    <time_frame>Visit 1 - Baseline</time_frame>
    <description>Oxygen cost of exercise (efficiency) - derived from maximal cardiopulmonary exercise test on a cycle ergometer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VO2 mean response time</measure>
    <time_frame>Visit 1 - Baseline</time_frame>
    <description>VO2 mean response time - derived from maximal cardiopulmonary exercise test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gas exchange threshold</measure>
    <time_frame>Visit 1 - Baseline</time_frame>
    <description>Gas exchange threshold - derived from maximal cardiopulmonary exercise test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Near-infrared spectroscopy derived deoxygenated [haemoglobin + myoglobin]</measure>
    <time_frame>Visit 1 - Baseline</time_frame>
    <description>Dynamics of near-infrared spectroscopy derived deoxygenated [haemoglobin + myoglobin]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulmonary function</measure>
    <time_frame>Visit 1 (baseline), Visit 2 (baseline)</time_frame>
    <description>Pulmonary function measured using flow-volume loop spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glycaemic control</measure>
    <time_frame>Glycaemic control will be measured continuously for 14 days following visit 1.</time_frame>
    <description>Glycaemic control measured using an arm-mounted continuous glucose monitor</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical activity</measure>
    <time_frame>Physical activity will be measured continuously for 14 days following visit 1.</time_frame>
    <description>Physical activity measured using a wrist-mounted physical activity monitor</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dietary intake</measure>
    <time_frame>Food diaries will be completed for 14 days following visit 1.</time_frame>
    <description>Dietary intake measured using MyFitness Pal application and food diaries</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumour necrosis factor alpha (TNF-alpha)</measure>
    <time_frame>Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Tumour necrosis factor alpha (TNF-alpha) measured from plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Soluble vascular cell adhesion molecule-1 (sVCAM)</measure>
    <time_frame>Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Soluble vascular cell adhesion molecule-1 (sVCAM) measured from plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endothelin-1 (ET-1)</measure>
    <time_frame>Visit 1 (baseline and following maximal cardiopulmonary exercise test on cycle ergometer), Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Endothelin-1 (ET-1) measured from plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interleukin-6 (IL-6)</measure>
    <time_frame>Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Interleukin-6 (IL-6) measured from plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>[Nitrite] (NO2)</measure>
    <time_frame>Visit 1 (baseline ), Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Nitrite concentration measured from plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nitrotyrosine (NT)</measure>
    <time_frame>Visit 2: (baseline) and 120 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Nitrotyrosine (NT) measured from plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total glutathione (tGSH)</measure>
    <time_frame>Visit 2: (baseline) and 120 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Total glutathione (tGSH) measured from plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total cysteine (tCys)</measure>
    <time_frame>Visit 2: (baseline) and 120 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Total cysteine (tCys) measured from plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acetylcholine (Ach) iontophoresis</measure>
    <time_frame>Visit 2: (baseline) and 1, 2 and 3 hours following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Acetylcholine (Ach) iontophoresis measure of microvascular function</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insulin iontophoresis</measure>
    <time_frame>Visit 2: (baseline) and 1, 2 and 3 hours following ingestion of 75 g glucose for an oral glucose tolerance</time_frame>
    <description>Insulin iontophoresis measure of microvascular function</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose concentration</measure>
    <time_frame>Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Glucose concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insulin concentration</measure>
    <time_frame>Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test</time_frame>
    <description>Insulin concentration</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">10</enrollment>
  <condition>Cystic Fibrosis (CF)</condition>
  <condition>Cystic Fibrosis-related Diabetes</condition>
  <arm_group>
    <arm_group_label>Cystic fibrosis (CF) with established CF-related diabetes</arm_group_label>
    <description>Cystic fibrosis (CF) with established CF-related diabetes&#xD;
Inclusion criteria:&#xD;
Males and females ≥ 12 years of age&#xD;
CF diagnosis based on clinical features, supported by an abnormal sweat test (sweat chloride &gt; 60 mmol·L-1 &gt; 100 mg sweat) and, where possible, diagnostic genotyping&#xD;
Established CFRD in accordance with the most recent American Diabetes Association positional statement]. This statement recommends CFRD is diagnosed using a 2 hour OGTT. However, the present study will also include those based on fasting plasma glucose and glycated hemoglobin levels, when symptoms of diabetes are also present:&#xD;
2 hour OGTT plasma glucose ≥ 200 mg.dL-1 (11.1 mmol.L-1)&#xD;
Fasting plasma glucose ≥ 126 mg.dL-1 (7.0 mmol.L-1)&#xD;
Glycated hemoglobin ≥ 48 mmol/mol&#xD;
No contraindications to performing exhaustive exercise&#xD;
Can understand and cooperate with the study protocol&#xD;
No increase in symptoms or weight loss in the preceding 2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cystic fibrosis (CF) without established CF-related diabetes</arm_group_label>
    <description>Cystic fibrosis (CF) without established CF-related diabetes&#xD;
Inclusion criteria:&#xD;
Males and females ≥ 12 years of age&#xD;
CF diagnosis based on clinical features, supported by an abnormal sweat test (sweat chloride &gt; 60 mmol·L-1 &gt; 100 mg sweat), where possible, diagnostic genotyping would also be desired&#xD;
No evidence of established, gestational or exacerbation induced CFRD in accordance with the American Diabetes Association criteria (stated above; [110]).&#xD;
No contraindications to performing exhaustive exercise&#xD;
Can understand and cooperate with the study protocol&#xD;
No increase in symptoms or weight loss in the preceding 2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy controls</arm_group_label>
    <description>Age- and gender-matched healthy control participants.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>No intervention - only assessments.</intervention_name>
    <description>No intervention only a number of assessments. Participants will be assessed during a maximal cardiopulmonary exercise testing on an exercise bike during 1 visit, and before and after an oral glucose tolerance test on a following visit.</description>
    <arm_group_label>Cystic fibrosis (CF) with established CF-related diabetes</arm_group_label>
    <arm_group_label>Cystic fibrosis (CF) without established CF-related diabetes</arm_group_label>
    <arm_group_label>Healthy controls</arm_group_label>
    <other_name>Exercise testing</other_name>
    <other_name>Insulin and acetylcholine iontophoresis measures of microvascular function</other_name>
    <other_name>Oral glucose tolerance test (75 g glucose)</other_name>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Acellular plasma will be stored at - 80 degrees&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        -  Individuals with cystic fibrosis (CF) and established CF-related diabetes (CFRD)&#xD;
&#xD;
          -  Individuals with CF and no established CFRD (age- and gender-matched to CFRD group)&#xD;
&#xD;
          -  Healthy age- and gender-matched control participants (matched to CFRD group)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        GROUP 1:&#xD;
&#xD;
        Cystic fibrosis (CF) with established CF-related diabetes:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females ≥ 12 years of age&#xD;
&#xD;
          -  CF diagnosis based on clinical features, supported by an abnormal sweat test (sweat&#xD;
             chloride &gt; 60 mmol·L-1 &gt; 100 mg sweat) and, where possible, diagnostic genotyping&#xD;
&#xD;
          -  Established CFRD in accordance with the most recent American Diabetes Association&#xD;
             positional statement. This statement recommends CFRD is diagnosed using a 2 hour OGTT.&#xD;
             However, the present study will also include those based on fasting plasma glucose and&#xD;
             glycated hemoglobin levels, when symptoms of diabetes are also present:&#xD;
&#xD;
               -  2 hour OGTT plasma glucose ≥ 200 mg.dL-1 (11.1 mmol.L-1)&#xD;
&#xD;
               -  Fasting plasma glucose ≥ 126 mg.dL-1 (7.0 mmol.L-1)&#xD;
&#xD;
               -  Glycated hemoglobin ≥ 48 mmol/mol&#xD;
&#xD;
          -  No contraindications to performing exhaustive exercise&#xD;
&#xD;
          -  Can understand and cooperate with the study protocol&#xD;
&#xD;
          -  No increase in symptoms or weight loss in the preceding 2 weeks&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any non-pulmonary conditions that may impair exercise ability, such as musculoskeletal&#xD;
             disorders (arthritis, joint or muscle disease) and cardiovascular disease (congenital&#xD;
             heart disease or cardiomyopathy).&#xD;
&#xD;
          -  Unstable co-morbid asthma (daily pulmonary function variability of &gt;20%)&#xD;
&#xD;
          -  Is pregnant during the initial screening process&#xD;
&#xD;
          -  Unable to understand or cooperate with the study protocol due to learning difficulties&#xD;
             or otherwise&#xD;
&#xD;
          -  Not of a suitable age for testing&#xD;
&#xD;
        GROUP 2:&#xD;
&#xD;
        Cystic fibrosis (CF) without established CF-related diabetes:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females ≥ 12 years of age&#xD;
&#xD;
          -  CF diagnosis based on clinical features, supported by an abnormal sweat test (sweat&#xD;
             chloride &gt; 60 mmol·L-1 &gt; 100 mg sweat), where possible, diagnostic genotyping would&#xD;
             also be desired&#xD;
&#xD;
          -  No evidence of established, gestational or exacerbation induced CFRD in accordance&#xD;
             with the American Diabetes Association criteria (stated above).&#xD;
&#xD;
          -  No contraindications to performing exhaustive exercise&#xD;
&#xD;
          -  Can understand and cooperate with the study protocol&#xD;
&#xD;
          -  No increase in symptoms or weight loss in the preceding 2 weeks&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any non-pulmonary conditions that may impair exercise ability, such as musculoskeletal&#xD;
             disorders (arthritis, joint or muscle disease) and cardiovascular disease (congenital&#xD;
             heart disease or cardiomyopathy).&#xD;
&#xD;
          -  Unstable co-morbid asthma (daily pulmonary function variability of &gt;20%)&#xD;
&#xD;
          -  Is pregnant during the initial screening process&#xD;
&#xD;
          -  Unable to understand or cooperate with the study protocol due to learning difficulties&#xD;
             or otherwise&#xD;
&#xD;
          -  Not of a suitable age for testing&#xD;
&#xD;
          -  Not a suitable age- and gender-match for those with CFRD&#xD;
&#xD;
        Exclusion during testing:&#xD;
&#xD;
          -  Onset of acute infection&#xD;
&#xD;
          -  Becomes and/or is tested to be pregnant following enrolment to the study&#xD;
&#xD;
          -  Unable to understand or cooperate with study protocol&#xD;
&#xD;
          -  The individual does not wish to participate further&#xD;
&#xD;
        GROUP 3:&#xD;
&#xD;
        Healthy age- and gender-matched control participants:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Age- and gender&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any non-pulmonary conditions that may impair exercise ability, such as musculoskeletal&#xD;
             disorders (arthritis, joint or muscle disease), respiratory and cardiovascular disease&#xD;
             (congenital heart disease or cardiomyopathy).&#xD;
&#xD;
          -  Is pregnant during the initial screening process&#xD;
&#xD;
          -  Unable to understand or cooperate with the study protocol due to learning difficulties&#xD;
             or otherwise&#xD;
&#xD;
          -  Not a suitable age- and gender-match for those with CFRD&#xD;
&#xD;
        Exclusion during testing:&#xD;
&#xD;
          -  Onset of acute illness or injury&#xD;
&#xD;
          -  Becomes and/or is tested to be pregnant following enrolment to the study&#xD;
&#xD;
          -  Unable to understand or cooperate with study protocol&#xD;
&#xD;
          -  The individual does not wish to participate further&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Department of Sport and Exercise Science</name>
      <address>
        <city>Portsmouth</city>
        <state>Hampshire</state>
        <zip>PO1 2ER</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>April 27, 2021</last_update_submitted>
  <last_update_submitted_qc>April 27, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 28, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Portsmouth</investigator_affiliation>
    <investigator_full_name>Dr Zoe Saynor</investigator_full_name>
    <investigator_title>Senior Lecturer in Physical Activity, Exercise and Health</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cystic Fibrosis</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetylcholine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Data will be shared with the study team only.</ipd_description>
  </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/NCT03234387
org study id: ZS002
nct id: NCT03234387
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
A great medical success is the increase in the median survival age associated with cystic
      fibrosis (CF). However, this success has led to a new era of research with the aim to
      maximise the quality of life (QoL) of the aging CF population. Recent research has
      demonstrated that the traditional method of determining disease progression, i.e. pulmonary
      function, no longer adequately predict survival rates. Therefore, various bodies have
      promoted cardiopulmonary exercise testing (CPET), as outcomes from this test (e.g. one's
      maximal O2 uptake [VO₂max]) are known predictors of the QoL, risk of hospitalisation and
      prognosis of individuals with CF.

      One of the most common non-pulmonary co-morbidities of CF is CF-related diabetes (CFRD).
      Importantly, CFRD is associated with a poorer pulmonary function compared to CF patients
      without CFRD, and ultimately a worsened prognosis. Despite this, the influence an impaired
      glycaemic control has upon the VO₂max derived from a CPET is unknown in CF. Therefore, the
      present study aims to assess whether VO₂max, an established determinant of QoL, differs
      between patients with CF with and without established CFRD as well as a group of age- and
      gender-matched healthy control subjects.

      The additional measures within the present study, such as: biomarkers of inflammation, redox
      balance and nitric oxide (NO2) bioavailability, as well as functional measures of
      microvascular endothelial function will aid our knowledge of the physiological abnormalities
      which are a cause or consequence of CFRD. Importantly, by identifying the factors which may
      contribute to CFRD progression and those that are viable for early intervention, mean the
      aims and objectives of this study are compatible with the top 10 research objectives set by
      the CF Trust.
Participants and recruitment The present study will be a pilot, cross-sectional trial in
      individuals with CFRD (n = 15), as well as age- and gender-matched CF controls without
      diabetes (n = 15) and age- and gender-matched healthy control participants (n = 15).
      Participants will be recruited from adult and paediatric CF outpatient clinics within the
      Southampton CF network. The healthy control participants will be recruited from the
      University of Portsmouth and local area. Individuals with CF will be tested at a laboratory
      established within the CF unit at the Southampton General Hospital and/or the Department of
      Sport and Exercise Sciences (University of Portsmouth), depending on participant convenience.
      All healthy control participants will attend the Department of Sport and Exercise Sciences at
      the University of Portsmouth.

      Visit 1 During this visit, a valid informed consent and GCP trained member of the research
      team will fully explain the information sheet and study protocol, as well as answer any
      questions to ensure that all relevant parties are clear about the study requirements.
      Following this, fully informed written consent will be obtained. Additionally, informed
      written assent will be obtained from those < 16 years of age.

      Following the consent procedures the participants resting pulmonary function (forced vital
      capacity, forced expiratory volume in 1 second, mid force expiratory flow and peak expiratory
      flow) and anthropometric measures (weight, height and body fat percentage) will obtained. The
      subsequent aim of this visit is then to habituate all participants with exercising on a cycle
      ergometer in preparation for their CPET in visit 2, in particular maintaining a certain
      cadence at a given power output. Appropriate adjustments will be made to the ergometer seat
      and handlebar position, and noted for visit 2. Furthermore, the protocols of obtaining ones
      ratings of perceived exertion and dyspnoea will be fully explained. Lastly, the participant
      will be instructed to avoid consuming mouthwash for the entirety of the study period due to
      evidence suggesting it may influence the uptake of dietary nitrate.

      Visit 2 Participants will arrive to the laboratory at 1900 ± 2 hours. They will be instructed
      to arrive 2 hours postprandial, having avoided caffeine for > 12 hours, as well as nitrate
      rich foods, alcohol and exhaustive exercise for > 24 hours.

      Upon arrival, CGM's will be fixed to the interior surface of the upper arm and worn for the
      subsequent 14 days. In addition to this, hip worn accelerometers, as well as hourly specific
      physical activity and food diaries will be distributed and completed for 14 days alongside
      the CGM. The participants resting pulmonary function will be assessed using the spirometry
      procedures described below, and a resting blood sample will be collected via venepuncture for
      the analysis of plasma [NO-(₂)] and ET-1. Additionally, the cycle ergometer CPET with a
      supramaximal (Smax) verification phase will be employed to determine ones aerobic exercise
      function, and a second venous blood sample will be collected immediately following exercise
      termination for the analysis of plasma [NO-(₂)] and ET-1. The total volume of blood collected
      over this 2 hour visit will be approximately 20 mL.

      Visit 3 Participants will be required to arrive to the laboratory ≥ 3 days post visit 1, at
      0800 ± 2 hours, following an overnight fast (> 10 hours). Furthermore, participants will be
      instructed to avoid nitrate rich foods, caffeine, alcohol and exhaustive exercise for 24
      hours prior to arrival.

      Upon arrival participants will undergo the acetylcholine (ACh) and insulin iontophoresis
      protocols described below, including 5 resting blood pressure measurements. Immediately
      following this, the participant's pulmonary function will be assessed via spirometry.
      Participants will be asked to rest, and entertainment will be provided, for the following 60
      minutes. The iontophoresis procedures will then be repeated to assess the short-term
      test-retest variability of the iontophoresis procedures. Following this, a cannula will be
      inserted into a vein by a trained phlebotomist, prior to the 3 hour OGTT and a baseline blood
      sample will be taken (measuring all the below biomarkers). Venous blood samples will be drawn
      at 30, 60, 90, 120 and 180 minutes post glucose ingestion for the analysis of glucose,
      insulin, active glucagon-like peptide-1 (GLP-1), TNF-α, soluble vascular cell adhesion
      molecule-1 (sVCAM-1), IL-6, [NO-(₂)] and ET-1. NT, total glutathione (tGSH) and total
      cysteine (tCys) will be analysed at 120 minutes post-glucose ingestion. The total volume of
      blood collected over this 5 hour visit will be approximately 176 mL. Additionally, the
      iontophoresis procedures will be repeated at 30, 90 and 150 minutes post-glucose ingestion
      (i.e. hourly measurements of microvascular endothelial function).

      Follow-up CGM's, accelerometers and physical activity/food diaries will be completed for 14
      days following visit 1. A member of the research team will collect these from the preferred
      location of the participant.
observational model: Cohort
time perspective: Cross-Sectional
measure: Maximal oxygen uptake (aerobic fitness)
time frame: Visit 1 - Baseline
description: Maximal oxygen uptake (aerobic fitness) from a maximal cardiopulmonary exercise testing on a cycle ergometer
measure: VO2 gain
time frame: Visit 1 - Baseline
description: Oxygen cost of exercise (efficiency) - derived from maximal cardiopulmonary exercise test on a cycle ergometer
measure: VO2 mean response time
time frame: Visit 1 - Baseline
description: VO2 mean response time - derived from maximal cardiopulmonary exercise test
measure: Gas exchange threshold
time frame: Visit 1 - Baseline
description: Gas exchange threshold - derived from maximal cardiopulmonary exercise test
measure: Near-infrared spectroscopy derived deoxygenated [haemoglobin + myoglobin]
time frame: Visit 1 - Baseline
description: Dynamics of near-infrared spectroscopy derived deoxygenated [haemoglobin + myoglobin]
measure: Pulmonary function
time frame: Visit 1 (baseline), Visit 2 (baseline)
description: Pulmonary function measured using flow-volume loop spirometry
measure: Glycaemic control
time frame: Glycaemic control will be measured continuously for 14 days following visit 1.
description: Glycaemic control measured using an arm-mounted continuous glucose monitor
measure: Physical activity
time frame: Physical activity will be measured continuously for 14 days following visit 1.
description: Physical activity measured using a wrist-mounted physical activity monitor
measure: Dietary intake
time frame: Food diaries will be completed for 14 days following visit 1.
description: Dietary intake measured using MyFitness Pal application and food diaries
measure: Tumour necrosis factor alpha (TNF-alpha)
time frame: Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Tumour necrosis factor alpha (TNF-alpha) measured from plasma
measure: Soluble vascular cell adhesion molecule-1 (sVCAM)
time frame: Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Soluble vascular cell adhesion molecule-1 (sVCAM) measured from plasma
measure: Endothelin-1 (ET-1)
time frame: Visit 1 (baseline and following maximal cardiopulmonary exercise test on cycle ergometer), Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Endothelin-1 (ET-1) measured from plasma
measure: Interleukin-6 (IL-6)
time frame: Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Interleukin-6 (IL-6) measured from plasma
measure: [Nitrite] (NO2)
time frame: Visit 1 (baseline ), Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Nitrite concentration measured from plasma
measure: Nitrotyrosine (NT)
time frame: Visit 2: (baseline) and 120 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Nitrotyrosine (NT) measured from plasma
measure: Total glutathione (tGSH)
time frame: Visit 2: (baseline) and 120 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Total glutathione (tGSH) measured from plasma
measure: Total cysteine (tCys)
time frame: Visit 2: (baseline) and 120 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Total cysteine (tCys) measured from plasma
measure: Acetylcholine (Ach) iontophoresis
time frame: Visit 2: (baseline) and 1, 2 and 3 hours following ingestion of 75 g glucose for an oral glucose tolerance test
description: Acetylcholine (Ach) iontophoresis measure of microvascular function
measure: Insulin iontophoresis
time frame: Visit 2: (baseline) and 1, 2 and 3 hours following ingestion of 75 g glucose for an oral glucose tolerance
description: Insulin iontophoresis measure of microvascular function
measure: Glucose concentration
time frame: Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Glucose concentration
measure: Insulin concentration
time frame: Visit 2: (baseline) and 30, 60, 90, 120 and 180 minutes following ingestion of 75 g glucose for an oral glucose tolerance test
description: Insulin concentration
arm group label: Cystic fibrosis (CF) with established CF-related diabetes
description: Cystic fibrosis (CF) with established CF-related diabetes
Inclusion criteria:
Males and females ≥ 12 years of age
CF diagnosis based on clinical features, supported by an abnormal sweat test (sweat chloride > 60 mmol·L-1 > 100 mg sweat) and, where possible, diagnostic genotyping
Established CFRD in accordance with the most recent American Diabetes Association positional statement]. This statement recommends CFRD is diagnosed using a 2 hour OGTT. However, the present study will also include those based on fasting plasma glucose and glycated hemoglobin levels, when symptoms of diabetes are also present:
2 hour OGTT plasma glucose ≥ 200 mg.dL-1 (11.1 mmol.L-1)
Fasting plasma glucose ≥ 126 mg.dL-1 (7.0 mmol.L-1)
Glycated hemoglobin ≥ 48 mmol/mol
No contraindications to performing exhaustive exercise
Can understand and cooperate with the study protocol
No increase in symptoms or weight loss in the preceding 2 weeks
arm group label: Cystic fibrosis (CF) without established CF-related diabetes
description: Cystic fibrosis (CF) without established CF-related diabetes
Inclusion criteria:
Males and females ≥ 12 years of age
CF diagnosis based on clinical features, supported by an abnormal sweat test (sweat chloride > 60 mmol·L-1 > 100 mg sweat), where possible, diagnostic genotyping would also be desired
No evidence of established, gestational or exacerbation induced CFRD in accordance with the American Diabetes Association criteria (stated above; [110]).
No contraindications to performing exhaustive exercise
Can understand and cooperate with the study protocol
No increase in symptoms or weight loss in the preceding 2 weeks
arm group label: Healthy controls
description: Age- and gender-matched healthy control participants.
intervention type: Other
intervention name: No intervention - only assessments.
description: No intervention only a number of assessments. Participants will be assessed during a maximal cardiopulmonary exercise testing on an exercise bike during 1 visit, and before and after an oral glucose tolerance test on a following visit.
arm group label: Cystic fibrosis (CF) with established CF-related diabetes
arm group label: Cystic fibrosis (CF) without established CF-related diabetes
arm group label: Healthy controls
other name: Exercise testing
other name: Insulin and acetylcholine iontophoresis measures of microvascular function
other name: Oral glucose tolerance test (75 g glucose)
Acellular plasma will be stored at - 80 degrees
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 12 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: University of Portsmouth
investigator full name: Dr Zoe Saynor
investigator title: Senior Lecturer in Physical Activity, Exercise and Health
mesh term: Cystic Fibrosis
mesh term: Fibrosis
mesh term: Acetylcholine
sharing ipd: No
ipd description: Data will be shared with the study team only.