<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/NCT03807310</url>
  </required_header>
  <id_info>
    <org_study_id>METC18-011</org_study_id>
    <secondary_id>10.2.16.119</secondary_id>
    <nct_id>NCT03807310</nct_id>
  </id_info>
  <brief_title>Targeted Nutrient Supplement in COPD (NUTRECOVER-trial)</brief_title>
  <acronym>NUTRECOVER</acronym>
  <official_title>The Effect of Targeted Nutrient Supplementation on Physical Activity and Healthy Related Quality of Life in COPD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Maastricht University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Nutricia Research</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Maastricht University Medical Center</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>
      The overall objective is to investigate the efficacy of targeted nutrient supplementation on&#xD;
      daily physical activity level as well as generic health status in patients with COPD.&#xD;
      Additionally the investigators aim to investigate the relative effect of targeted nutrient&#xD;
      supplementation on the recovery after hospitalization for a COPD exacerbation. The secondary&#xD;
      objective is to investigate the effect of targeted nutrient supplementation on mental health,&#xD;
      physical performance, blood markers, patient related outcomes and gut health. Additionally, a&#xD;
      secondary objective is to compare the gut microbiome composition of patients with COPD&#xD;
      compared to healthy controls.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale: Impaired physical and mental health are common features in COPD adversely&#xD;
      affecting disease course and quality of life. Furthermore, nutritional status is often&#xD;
      impaired due to dietary and plasma nutrient deficiencies, decreased muscle oxidative&#xD;
      metabolism and impaired intestinal permeability. The investigators hypothesize that targeted&#xD;
      nutrient supplementation can lead to gut-muscle-brain axis-mediated amelioration of physical,&#xD;
      cognitive and mental health domains, resulting in a healthier lifestyle, in patients with&#xD;
      COPD.&#xD;
&#xD;
      Study design: Randomized, placebo-controlled, double-blind trial.&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness: The nutrient supplement is hypothesized to have beneficial effects on general&#xD;
      health because it applies physical and mental health domains. The healthy lifestyle&#xD;
      counselling aims to improve medical adherence, to address a healthier lifestyle and to manage&#xD;
      weight loss which would contribute to improved general health. Risks and inconveniences are&#xD;
      limited to the time investment associated with taking the supplements and measuring days.&#xD;
      During the test-days various non-invasive measurements as well as minor invasive blood&#xD;
      sampling will be performed. The investigators expect no risk of the nutrient supplementation.&#xD;
      Healthy controls will only attend a subgroup of baseline measurements which are limited to&#xD;
      non-invasive measurements and one minor invasive blood sampling. Healthy controls will not&#xD;
      receive the nutritional supplement.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 19, 2020</start_date>
  <completion_date type="Anticipated">May 2025</completion_date>
  <primary_completion_date type="Anticipated">May 2025</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>Next to the 166 COPD patients that receive the nutritional supplement, a subgroup of 30 healthy controls will be included for baseline comparison of the microbiome composition. These healthy controls will not be included in the intervention arm.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in physical activity level assessed by measuring step count with accelerometry</measure>
    <time_frame>0, 3, and 12-14 months and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later</time_frame>
    <description>Subjects will wear an activPAL accelerometer for 1 week to assess physical activity.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in generic health status measured by EuroQol-5 dimensions (EQ-5D)</measure>
    <time_frame>0, 3, and 12-14 months and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later</time_frame>
    <description>The EQ-5D is a generic classification system used to characterize current health states of patients. It consists of 5 domains (mobility; self-care; usual activity; pain/discomfort; anxiety/depression) and a visual analogue scale (EQ-VAS). The domains have a scale from 1-3 and the VAS-scale from 0-100 in which higher values represent a better outcome.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in cognitive function measured by the Neuropsychological test automated battery (CANTAB)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The investigators will use the Motor Screening Task, Reaction Time Task, Paired Associates Learning, Delayed Matching-to-Sample, Spatial Working Memory and Stop Signal Task. The higher the score on these tasks, the better the cognitive function.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Depression Anxiety Stress Scale 21 (DASS-21)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The DASS-21 measures 3 related states of depression, anxiety and stress. The DASS-21 consists of 21 negative emotional symptoms and subjects will be asked to extent to which have experienced each symptom over the past week, on a 4-point severity/frequency scale. The total score will range from 0-66 in which a higher score means more susceptibility to depression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Hospital and Anxiety Scale (HADS)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The HADS will allow the investigators to measure domain-specific quality of life. This is a 14-item instrument designed to detect the presence and severity of mild degrees of mood disorder, anxiety and depression in hospital and community setting and outside. Per scale (anxiety and depression) a maximum of 21 points can be scored, in which a higher score means worse outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Cohen's Perceived Stress Scale (PSS)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The PSS is a measure of the degree to which situations in one's life are appraised as stressful. Individual scores on the PSS can range from 0 to 40 with higher scores indicating higher perceived stress.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in blood pressure after the socially evaluated cold pressure test</measure>
    <time_frame>0-12 months.</time_frame>
    <description>The SECPT asks the participant to immerse their right hand up to and including the writs into ice water for a maximum of 3 minutes. Blood pressure will be measured before and after the test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in cortisol in the saliva after the socially evaluated cold pressure test</measure>
    <time_frame>0-12 months.</time_frame>
    <description>The SECPT asks the participant to immerse their right hand up to and including the writs into ice water for a maximum of 3 minutes. Cortisol in the saliva will be measured before and after the test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in hair cortisol</measure>
    <time_frame>0 and 12-14 months and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Cortisol level in hair is a biomarker of chronic stress.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in lower extremity performance by the short physical performance battery (SPPB)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Three manoeuvres will be performed: the balance test, the gait speed test and the chair stand test. Each individual can score 0-12 points in which a higher score means a better physical performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in muscle strength by measuring handgrip strength</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Handgrip strength is measured in the dominant hand using a hydraulic grip strength dynamometer.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in respiratory muscle strength by measuring the inspiratory and expiratory mouth pressure</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The mouth pressure will be measured using the MicroRPM monitor.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in exercise performance by measuring the 6 minute walking distance</measure>
    <time_frame>0-12 months.</time_frame>
    <description>Subjects will be instructed to walk as fast as possible for 6 minutes. The distance walked during these 6 minutes will be measured.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in body composition by performing Dual energy X-ray absorptiometry (DEXA-scan)</measure>
    <time_frame>0-12 months.</time_frame>
    <description>Using the DEXA-scan three compartments of the body composition (lean mass, fat mass, bone mass) will be measured.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in weight</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Weight will be measured in kg.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in height</measure>
    <time_frame>0-12 months</time_frame>
    <description>Height will be measured in cm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in blood markers of systemic inflammation</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Markers include high-sensitive C-reactive protein, procalcitonin, interleukin-6, interleukin-8 and leucocyte levels.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in blood markers of nutritional status</measure>
    <time_frame>0-3 months; 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Markers include vitamin E, vitamin D, poly unsaturated fatty acids, amino acids (tryptophan), and homocysteine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in blood markers of gut-muscle-brain cross-talk</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Markers include tryptophan, kynurenine and kynurenic acid.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in fatigue by using the checklist individual strength (CIS)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The CIS is a 20-item self-report questionnaire that measures several aspects of fatigue: fatigue severity, concentration, motivation and physical activity. Individual scores can range from 20-140 in which higher scores mean fatigue problems.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in pain using the Visual Analogue Scale (VAS)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Pain will be assessed by the VAS range from 0-100, in which a higher score means more pain experience.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in sleep quality by the Pittsburgh Sleep Quality Index (PSQI)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The PSQI is a self-report questionnaire to assess sleep quality. It consists of 19 individual items, creating 7 components that produce one global score (0-21, in which higher scores indicate worse sleep quality).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in intestinal fatty acid binding protein (blood) in rest</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>IFABP is a marker for intestinal integrity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in intestinal fatty acid binding protein (blood) after the 6MWT</measure>
    <time_frame>0-12 months.</time_frame>
    <description>IFABP is a marker for intestinal integrity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in gut microbiome composition (optional)</measure>
    <time_frame>0, 3 and 12 months.</time_frame>
    <description>Several analysis will be performed after completion of the study. The exact markers of the microbiome will be determined.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in forced expiratory volume in 1 second</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Measured by spirometry within 3 previous months.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in forced vital capacity</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Measured by spirometry within 3 previous months.</description>
  </other_outcome>
  <other_outcome>
    <measure>Total lung capacity</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Measured by body plethysmography within 3 previous months</description>
  </other_outcome>
  <other_outcome>
    <measure>Functional residual capacity</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Measured by body plethysmography within 3 previous months</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in diffusion capacity</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>measured within 3 previous months</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in the global impacts of COPD on health status using the COPD assessment test (CAT)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The CAT score ranges from 0-40, in which a higher score means worse outcome.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in health status using the Clinical COPD questionnaire (CCQ)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The CCQ is a 10-item questionnaire and individual scores range from 0-6 in which a higher score means worse health status</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in breathlessness using the medical research council (MRC-scale)</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>The MRC-scale ranges from 0-5 in which a higher score means more breathlessness.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in medication use by self-report</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>All medications used by participants will be reported to determine difference in medication use between groups.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in medical history will be assessed from medical records</measure>
    <time_frame>0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.</time_frame>
    <description>Comorbidities will be extracted from the medical history</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in food intake</measure>
    <time_frame>0, 3 and 12-14 months</time_frame>
    <description>3-day 24h food diary</description>
  </other_outcome>
  <other_outcome>
    <measure>Blood gases</measure>
    <time_frame>in case of hospitalization for COPD exacerbation within one week after discharge</time_frame>
    <description>retrieved from medical records</description>
  </other_outcome>
  <other_outcome>
    <measure>Type of infection</measure>
    <time_frame>in case of hospitalization for COPD exacerbation within one week after discharge</time_frame>
    <description>Viral or bacterial infection based on medical records</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of patients died</measure>
    <time_frame>from beginning of the study till 1 year after study completion</time_frame>
    <description>from the medical records</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of patients readmitted for a COPD exacerbation</measure>
    <time_frame>from beginning of the study till 1 year after study completion</time_frame>
    <description>from the medical records</description>
  </other_outcome>
  <other_outcome>
    <measure>Difference in gut microbiome composition between healthy controls and COPD patients</measure>
    <time_frame>Baseline asssment</time_frame>
    <description>To determine difference between COPD patients and healthy controls in gut microbiome composition, 30 healthy controls will sample stool at baseline which will be compared to a subgroup of 30 COPD patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Difference in lung function between healthy controls and COPD patients</measure>
    <time_frame>Baseline asssment</time_frame>
    <description>To ascertain that healthy controls have no obstructive lung disease, a baseline lung function measurement will be performed in the 30 healthy controls and compared to a subgroup of 30 COPD patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Difference in blood systemic inflammation between healthy controls and COPD patients</measure>
    <time_frame>Baseline asssment</time_frame>
    <description>To determine difference between COPD patients and healthy controls in systemic inflammation, blood samples will be obtained at baseline from 30 healthy controls and compared to a subgroup of 30 COPD patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Difference in food intake between healthy controls and COPD patients</measure>
    <time_frame>Baseline asssment</time_frame>
    <description>To determine difference between COPD patients and healthy controls in food intake, a 3-day 24h food diary will be obtained at baseline from 30 healthy controls and compared to a subgroup of 30 COPD patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Difference in medication use between healthy controls and COPD patients</measure>
    <time_frame>Baseline asssment</time_frame>
    <description>To determine difference between COPD patients and healthy controls in medication use, all medications used by the 30 healthy controls will be reported at baseline and compared to a subgroup of 30 COPD patients.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">166</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <arm_group>
    <arm_group_label>Group Long-drink</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>83 COPD patients will receive:&#xD;
Targeted nutrient supplementation (Long-drink) once daily&#xD;
Counselling once monthly</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>83 COPD patients will receive:&#xD;
Isocaloric placebo supplement once daily&#xD;
Counselling once monthly</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>30 healthy controls will be included for baseline comparison of the microbiome composition. These healthy controls will only perform a subset of baseline measurements and will not be included in the intervention.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Targeted nutrient supplementation (Long-drink)</intervention_name>
    <description>Once daily for at least 12 months</description>
    <arm_group_label>Group Long-drink</arm_group_label>
    <other_name>Nutritional supplementation</other_name>
    <other_name>Dietary supplement</other_name>
    <other_name>Nutritional supplement</other_name>
    <other_name>Food supplement</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo supplement</intervention_name>
    <description>Once daily for at least 12 months</description>
    <arm_group_label>Group Placebo</arm_group_label>
    <other_name>Non-active supplement</other_name>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Counselling</intervention_name>
    <description>Counselling on healthy lifestyle (in particular physical activity, smoking cessation) and weight management by motivational interviewing</description>
    <arm_group_label>Group Long-drink</arm_group_label>
    <arm_group_label>Group Placebo</arm_group_label>
    <other_name>Motivational interviewing</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria COPD Patients:&#xD;
&#xD;
          -  COPD patients with moderate to very severe disease stage according to GOLD criteria&#xD;
             (i.e. GOLD stage II-IV);&#xD;
&#xD;
          -  Medically stable.&#xD;
&#xD;
        Exclusion Criteria COPD Patients:&#xD;
&#xD;
          -  Age &lt;18 years;&#xD;
&#xD;
          -  Allergy or intolerance to components of the study product;&#xD;
&#xD;
          -  Not willing or not able to quit vitamin D or fatty acid supplement intake;&#xD;
&#xD;
          -  Investigator's uncertainty about the willingness or ability of the patient to comply&#xD;
             with the protocol requirements (e.g. leg amputation) or patients suffering from other&#xD;
             acute or unstable chronic diseases that will compromise the study outcome (e.g. active&#xD;
             cancer requiring treatment);&#xD;
&#xD;
          -  Participation in any other study involving investigational or marketed products&#xD;
             concomitantly or within four weeks prior to entry into the study;&#xD;
&#xD;
          -  Patients with terminal illness;&#xD;
&#xD;
          -  Recent hospital admission (&lt;4 weeks prior to the start of the study);&#xD;
&#xD;
          -  Temporary oral steroid or antibiotics use due to a COPD exacerbation in the last 4&#xD;
             weeks;&#xD;
&#xD;
          -  Lung malignancy in the previous 5 years;&#xD;
&#xD;
          -  Diagnosis of dementia or neurodegenerative disease (e.g., Alzheimer's disease,&#xD;
             Parkinson's disease, Huntington's chorea, frontotemporal dementia) in the medical&#xD;
             records;&#xD;
&#xD;
          -  Recent diagnosis of cerebral conditions (&lt;1 year e.g. cerebral infarction, hemorrhage,&#xD;
             brain tumors, transient ischemic attack) in the medical records;&#xD;
&#xD;
          -  Any medical condition that significantly interferes with digestion and/or&#xD;
             gastrointestinal function (e.g. short bowel syndrome, inflammatory bowel disease,&#xD;
             gastric ulcers, gastritis, (gastro)-enteritis, GI-cancer) as judged by the&#xD;
             investigator.&#xD;
&#xD;
        Inclusion Criteria Healthy Controls&#xD;
&#xD;
          -  Forced expiratory volume in 1 second/Forced vital capacity &gt; 0.7;&#xD;
&#xD;
          -  Medically stable.&#xD;
&#xD;
        Exclusion Criteria Healthy Controls&#xD;
&#xD;
          -  Age &lt;18 years;&#xD;
&#xD;
          -  Investigator's uncertainty about the willingness or ability of the patient to comply&#xD;
             with the protocol requirements (e.g. leg amputation) or patients suffering from other&#xD;
             acute or unstable chronic diseases that will compromise the study outcome (e.g. active&#xD;
             cancer requiring treatment);&#xD;
&#xD;
          -  Participation in any other study involving investigational or marketed products&#xD;
             concomitantly or within four weeks prior to entry into the study;&#xD;
&#xD;
          -  Patients with terminal illness;&#xD;
&#xD;
          -  Recent hospital admission (&lt;4 weeks prior to the start of the study);&#xD;
&#xD;
          -  Temporary antibiotics use in the last 4 weeks;&#xD;
&#xD;
          -  Lung malignancy in the previous 5 years;&#xD;
&#xD;
          -  Diagnosis of dementia or neurodegenerative disease (e.g., Alzheimer's disease,&#xD;
             Parkinson's disease, Huntington's chorea, frontotemporal dementia) in the medical&#xD;
             records;&#xD;
&#xD;
          -  Recent diagnosis of cerebral conditions (&lt;1 year e.g. cerebral infarction, hemorrhage,&#xD;
             brain tumors, transient ischemic attack) in the medical records;&#xD;
&#xD;
          -  Any medical condition that significantly interferes with digestion and/or&#xD;
             gastrointestinal function (e.g. short bowel syndrome, inflammatory bowel disease,&#xD;
             gastric ulcers, gastritis, (gastro)-enteritis, GI-cancer) as judged by the&#xD;
             investigator.&#xD;
&#xD;
          -  Diagnosis of any chronic lung disease.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Annemie Schols, Prof. dr.</last_name>
    <role>Study Director</role>
    <affiliation>Maastricht UMC+ / NUTRIM, Department of Respiratory Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Rosanne Beijers, Dr</last_name>
    <phone>+31433882990</phone>
    <email>r.beijers@maastrichtuniversity.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Harry Gosker, Dr</last_name>
    <phone>+31433884298</phone>
    <email>h.gosker@maastrichtuniversity.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Maastricht University Medical Centre+ (MUMC+)</name>
      <address>
        <city>Maastricht</city>
        <state>Limburg</state>
        <zip>6202 AZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rosanne Beijers, PhD</last_name>
      <email>r.beijers@maastrichtuniversity.nl</email>
    </contact>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 9, 2019</study_first_submitted>
  <study_first_submitted_qc>January 15, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 16, 2019</study_first_posted>
  <last_update_submitted>March 14, 2023</last_update_submitted>
  <last_update_submitted_qc>March 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Maastricht University Medical Center</investigator_affiliation>
    <investigator_full_name>Rosanne Beijers</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <keyword>COPD</keyword>
  <keyword>nutrient supplementation</keyword>
  <keyword>Physical activity</keyword>
  <keyword>Health related quality of life</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Deidentified data will only be shared based on a reasonable request.</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/NCT03807310
org study id: METC18-011
secondary id: 10.2.16.119
nct id: NCT03807310
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The overall objective is to investigate the efficacy of targeted nutrient supplementation on
      daily physical activity level as well as generic health status in patients with COPD.
      Additionally the investigators aim to investigate the relative effect of targeted nutrient
      supplementation on the recovery after hospitalization for a COPD exacerbation. The secondary
      objective is to investigate the effect of targeted nutrient supplementation on mental health,
      physical performance, blood markers, patient related outcomes and gut health. Additionally, a
      secondary objective is to compare the gut microbiome composition of patients with COPD
      compared to healthy controls.
Rationale: Impaired physical and mental health are common features in COPD adversely
      affecting disease course and quality of life. Furthermore, nutritional status is often
      impaired due to dietary and plasma nutrient deficiencies, decreased muscle oxidative
      metabolism and impaired intestinal permeability. The investigators hypothesize that targeted
      nutrient supplementation can lead to gut-muscle-brain axis-mediated amelioration of physical,
      cognitive and mental health domains, resulting in a healthier lifestyle, in patients with
      COPD.

      Study design: Randomized, placebo-controlled, double-blind trial.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: The nutrient supplement is hypothesized to have beneficial effects on general
      health because it applies physical and mental health domains. The healthy lifestyle
      counselling aims to improve medical adherence, to address a healthier lifestyle and to manage
      weight loss which would contribute to improved general health. Risks and inconveniences are
      limited to the time investment associated with taking the supplements and measuring days.
      During the test-days various non-invasive measurements as well as minor invasive blood
      sampling will be performed. The investigators expect no risk of the nutrient supplementation.
      Healthy controls will only attend a subgroup of baseline measurements which are limited to
      non-invasive measurements and one minor invasive blood sampling. Healthy controls will not
      receive the nutritional supplement.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Next to the 166 COPD patients that receive the nutritional supplement, a subgroup of 30 healthy controls will be included for baseline comparison of the microbiome composition. These healthy controls will not be included in the intervention arm.
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Change in physical activity level assessed by measuring step count with accelerometry
time frame: 0, 3, and 12-14 months and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later
description: Subjects will wear an activPAL accelerometer for 1 week to assess physical activity.
measure: Change in generic health status measured by EuroQol-5 dimensions (EQ-5D)
time frame: 0, 3, and 12-14 months and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later
description: The EQ-5D is a generic classification system used to characterize current health states of patients. It consists of 5 domains (mobility; self-care; usual activity; pain/discomfort; anxiety/depression) and a visual analogue scale (EQ-VAS). The domains have a scale from 1-3 and the VAS-scale from 0-100 in which higher values represent a better outcome.
measure: Change in cognitive function measured by the Neuropsychological test automated battery (CANTAB)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The investigators will use the Motor Screening Task, Reaction Time Task, Paired Associates Learning, Delayed Matching-to-Sample, Spatial Working Memory and Stop Signal Task. The higher the score on these tasks, the better the cognitive function.
measure: Change in Depression Anxiety Stress Scale 21 (DASS-21)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The DASS-21 measures 3 related states of depression, anxiety and stress. The DASS-21 consists of 21 negative emotional symptoms and subjects will be asked to extent to which have experienced each symptom over the past week, on a 4-point severity/frequency scale. The total score will range from 0-66 in which a higher score means more susceptibility to depression.
measure: Change in Hospital and Anxiety Scale (HADS)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The HADS will allow the investigators to measure domain-specific quality of life. This is a 14-item instrument designed to detect the presence and severity of mild degrees of mood disorder, anxiety and depression in hospital and community setting and outside. Per scale (anxiety and depression) a maximum of 21 points can be scored, in which a higher score means worse outcome.
measure: Change in Cohen's Perceived Stress Scale (PSS)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The PSS is a measure of the degree to which situations in one's life are appraised as stressful. Individual scores on the PSS can range from 0 to 40 with higher scores indicating higher perceived stress.
measure: Change in blood pressure after the socially evaluated cold pressure test
time frame: 0-12 months.
description: The SECPT asks the participant to immerse their right hand up to and including the writs into ice water for a maximum of 3 minutes. Blood pressure will be measured before and after the test.
measure: Change in cortisol in the saliva after the socially evaluated cold pressure test
time frame: 0-12 months.
description: The SECPT asks the participant to immerse their right hand up to and including the writs into ice water for a maximum of 3 minutes. Cortisol in the saliva will be measured before and after the test.
measure: Change in hair cortisol
time frame: 0 and 12-14 months and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Cortisol level in hair is a biomarker of chronic stress.
measure: Change in lower extremity performance by the short physical performance battery (SPPB)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Three manoeuvres will be performed: the balance test, the gait speed test and the chair stand test. Each individual can score 0-12 points in which a higher score means a better physical performance.
measure: Change in muscle strength by measuring handgrip strength
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Handgrip strength is measured in the dominant hand using a hydraulic grip strength dynamometer.
measure: Change in respiratory muscle strength by measuring the inspiratory and expiratory mouth pressure
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The mouth pressure will be measured using the MicroRPM monitor.
measure: Change in exercise performance by measuring the 6 minute walking distance
time frame: 0-12 months.
description: Subjects will be instructed to walk as fast as possible for 6 minutes. The distance walked during these 6 minutes will be measured.
measure: Change in body composition by performing Dual energy X-ray absorptiometry (DEXA-scan)
time frame: 0-12 months.
description: Using the DEXA-scan three compartments of the body composition (lean mass, fat mass, bone mass) will be measured.
measure: Change in weight
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Weight will be measured in kg.
measure: Change in height
time frame: 0-12 months
description: Height will be measured in cm.
measure: Change in blood markers of systemic inflammation
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Markers include high-sensitive C-reactive protein, procalcitonin, interleukin-6, interleukin-8 and leucocyte levels.
measure: Change in blood markers of nutritional status
time frame: 0-3 months; 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Markers include vitamin E, vitamin D, poly unsaturated fatty acids, amino acids (tryptophan), and homocysteine.
measure: Change in blood markers of gut-muscle-brain cross-talk
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Markers include tryptophan, kynurenine and kynurenic acid.
measure: Change in fatigue by using the checklist individual strength (CIS)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The CIS is a 20-item self-report questionnaire that measures several aspects of fatigue: fatigue severity, concentration, motivation and physical activity. Individual scores can range from 20-140 in which higher scores mean fatigue problems.
measure: Change in pain using the Visual Analogue Scale (VAS)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Pain will be assessed by the VAS range from 0-100, in which a higher score means more pain experience.
measure: Change in sleep quality by the Pittsburgh Sleep Quality Index (PSQI)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The PSQI is a self-report questionnaire to assess sleep quality. It consists of 19 individual items, creating 7 components that produce one global score (0-21, in which higher scores indicate worse sleep quality).
measure: Change in intestinal fatty acid binding protein (blood) in rest
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: IFABP is a marker for intestinal integrity.
measure: Change in intestinal fatty acid binding protein (blood) after the 6MWT
time frame: 0-12 months.
description: IFABP is a marker for intestinal integrity.
measure: Change in gut microbiome composition (optional)
time frame: 0, 3 and 12 months.
description: Several analysis will be performed after completion of the study. The exact markers of the microbiome will be determined.
measure: Change in forced expiratory volume in 1 second
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Measured by spirometry within 3 previous months.
measure: Change in forced vital capacity
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Measured by spirometry within 3 previous months.
measure: Total lung capacity
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Measured by body plethysmography within 3 previous months
measure: Functional residual capacity
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Measured by body plethysmography within 3 previous months
measure: Change in diffusion capacity
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: measured within 3 previous months
measure: Change in the global impacts of COPD on health status using the COPD assessment test (CAT)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The CAT score ranges from 0-40, in which a higher score means worse outcome.
measure: Change in health status using the Clinical COPD questionnaire (CCQ)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The CCQ is a 10-item questionnaire and individual scores range from 0-6 in which a higher score means worse health status
measure: Change in breathlessness using the medical research council (MRC-scale)
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: The MRC-scale ranges from 0-5 in which a higher score means more breathlessness.
measure: Change in medication use by self-report
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: All medications used by participants will be reported to determine difference in medication use between groups.
measure: Change in medical history will be assessed from medical records
time frame: 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later.
description: Comorbidities will be extracted from the medical history
measure: Change in food intake
time frame: 0, 3 and 12-14 months
description: 3-day 24h food diary
measure: Blood gases
time frame: in case of hospitalization for COPD exacerbation within one week after discharge
description: retrieved from medical records
measure: Type of infection
time frame: in case of hospitalization for COPD exacerbation within one week after discharge
description: Viral or bacterial infection based on medical records
measure: Number of patients died
time frame: from beginning of the study till 1 year after study completion
description: from the medical records
measure: Number of patients readmitted for a COPD exacerbation
time frame: from beginning of the study till 1 year after study completion
description: from the medical records
measure: Difference in gut microbiome composition between healthy controls and COPD patients
time frame: Baseline asssment
description: To determine difference between COPD patients and healthy controls in gut microbiome composition, 30 healthy controls will sample stool at baseline which will be compared to a subgroup of 30 COPD patients.
measure: Difference in lung function between healthy controls and COPD patients
time frame: Baseline asssment
description: To ascertain that healthy controls have no obstructive lung disease, a baseline lung function measurement will be performed in the 30 healthy controls and compared to a subgroup of 30 COPD patients.
measure: Difference in blood systemic inflammation between healthy controls and COPD patients
time frame: Baseline asssment
description: To determine difference between COPD patients and healthy controls in systemic inflammation, blood samples will be obtained at baseline from 30 healthy controls and compared to a subgroup of 30 COPD patients.
measure: Difference in food intake between healthy controls and COPD patients
time frame: Baseline asssment
description: To determine difference between COPD patients and healthy controls in food intake, a 3-day 24h food diary will be obtained at baseline from 30 healthy controls and compared to a subgroup of 30 COPD patients.
measure: Difference in medication use between healthy controls and COPD patients
time frame: Baseline asssment
description: To determine difference between COPD patients and healthy controls in medication use, all medications used by the 30 healthy controls will be reported at baseline and compared to a subgroup of 30 COPD patients.
arm group label: Group Long-drink
arm group type: Experimental
description: 83 COPD patients will receive:
Targeted nutrient supplementation (Long-drink) once daily
Counselling once monthly
arm group label: Group Placebo
arm group type: Placebo Comparator
description: 83 COPD patients will receive:
Isocaloric placebo supplement once daily
Counselling once monthly
arm group label: Healthy control group
arm group type: No Intervention
description: 30 healthy controls will be included for baseline comparison of the microbiome composition. These healthy controls will only perform a subset of baseline measurements and will not be included in the intervention.
intervention type: Dietary Supplement
intervention name: Targeted nutrient supplementation (Long-drink)
description: Once daily for at least 12 months
arm group label: Group Long-drink
other name: Nutritional supplementation
other name: Dietary supplement
other name: Nutritional supplement
other name: Food supplement
intervention type: Dietary Supplement
intervention name: Placebo supplement
description: Once daily for at least 12 months
arm group label: Group Placebo
other name: Non-active supplement
intervention type: Behavioral
intervention name: Counselling
description: Counselling on healthy lifestyle (in particular physical activity, smoking cessation) and weight management by motivational interviewing
arm group label: Group Long-drink
arm group label: Group Placebo
other name: Motivational interviewing
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Annemie Schols, Prof. dr.
role: Study Director
affiliation: Maastricht UMC+ / NUTRIM, Department of Respiratory Medicine
last name: Rosanne Beijers, Dr
phone: +31433882990
email: r.beijers@maastrichtuniversity.nl
last name: Harry Gosker, Dr
phone: +31433884298
email: h.gosker@maastrichtuniversity.nl
facility: 
status: Recruiting
contact: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Maastricht University Medical Center
investigator full name: Rosanne Beijers
investigator title: Principal investigator
mesh term: Pulmonary Disease, Chronic Obstructive
sharing ipd: No
ipd description: Deidentified data will only be shared based on a reasonable request.