<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/NCT03796455</url>
  </required_header>
  <id_info>
    <org_study_id>2017-0870</org_study_id>
    <nct_id>NCT03796455</nct_id>
  </id_info>
  <brief_title>Fish Oil and HMB Supplementation in COPD</brief_title>
  <acronym>COPD fish oil</acronym>
  <official_title>Effects of Low Dose of Fish Oil (EPA+DHA) vs. Combined EPA+DHA and HMB Supplementation on Protein Metabolism, Muscle Mass and Functional Capacity in Moderate to Severe COPD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Texas A&amp;M University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Texas A&amp;M University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      In the present study, the role of chronic (10 weeks) intake of low dose (2g/day) of EPA+DHA&#xD;
      in whole body protein metabolism, and functional performance and systemic inflammation will&#xD;
      be examined, and whether adding either HMB at 3.0 g/d to the low dose of EPA+DHA (2.0 g/d)&#xD;
      will enhance these effects even more.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Weight loss commonly occurs in patients with Chronic Obstructive Pulmonary Disease (COPD),&#xD;
      negatively influencing their quality of life, treatment response and survival. Furthermore,&#xD;
      limb muscle dysfunction (weakness and/or enhanced fatigue) is a major systemic comorbidity in&#xD;
      patients with Chronic Obstructive Pulmonary Disease (COPD), negatively affecting their&#xD;
      exercise performance, physical activity, quality of life, and mortality. As nutritional&#xD;
      abnormalities are main contributors to muscle loss and dysfunction in COPD, nutritional&#xD;
      support is viewed as an essential component of integrated care in these patients.&#xD;
&#xD;
      Although nutritional support is effective in the treatment of weight loss in COPD, attempts&#xD;
      to increase muscle mass and function in COPD by supplying large amounts of protein or&#xD;
      calories to these patients have been small. This suggests that gains in muscle mass and&#xD;
      function are difficult to achieve in COPD unless specific metabolic abnormalities are&#xD;
      targeted. The investigators and other researchers found that low muscle mass in COPD was&#xD;
      strongly associated with elevated whole body protein turnover and increased myofibrillar&#xD;
      protein breakdown rates indicative of muscle contractile protein loss. The investigators have&#xD;
      extended this finding recently to normal weight COPD patients characterized by muscle&#xD;
      weakness using a more precise and accurate pulse method of tau-methylhistidine tracer.&#xD;
&#xD;
      A substantial number of COPD patients, underweight as well as normal weight to obese, are&#xD;
      characterized by an increased inflammatory response as evidenced by elevated levels of the&#xD;
      pro-inflammatory cytokines (Tumor Necrosis Factor (TNF)-α, Interleukin (IL) 6 and 8, and the&#xD;
      soluble TNF-α receptors (55 and 75). Furthermore, CRP levels are elevated in COPD and&#xD;
      associated with reduced quadriceps strength, lower maximal and submaximal exercise capacity&#xD;
      and increased morbidity.&#xD;
&#xD;
      One of the few agents capable to suppress the generation of pro-inflammatory cytokines are&#xD;
      eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), primary ω-3 fatty acids found in&#xD;
      fish oils.&#xD;
&#xD;
      Previous experimental research and clinical studies in cachectic conditions (mostly&#xD;
      malignancy) indicate that polyunsaturated fatty acids (PUFA) are able to attenuate protein&#xD;
      degradation by improving the anabolic response to feeding and by decreasing the acute phase&#xD;
      response. Eicosapentaenoic acid (EPA), in combination with docosahexaenoic acid (DHA), has&#xD;
      been shown to effectively inhibit weight loss in several disease states, however weight&#xD;
      weight and muscle mass and function increase was not present or minimal. Also in healthy&#xD;
      older adults, fish oil can slow the decline in muscle mass and function. A randomized&#xD;
      clinical trial in COPD patients showed that extra nutritional supplementation with PUFAs&#xD;
      daily of 1000 mg EPA+DHA as adjunct to exercise training during 8 weeks enhanced exercise&#xD;
      capacity but did not lead to muscle mass gain. The patients who did not respond adequately (&lt;&#xD;
      2% gain in weight), had a higher TNF-α level than those who did gain sufficient weight, which&#xD;
      is in line with previous data in COPD showing an association between an increased systemic&#xD;
      inflammation with non-response to nutritional therapy.&#xD;
&#xD;
      Although previous studies support the concept of EPA+DHA supplementation to ameliorate the&#xD;
      systemic inflammatory response and decrease protein breakdown, there is no information&#xD;
      present on the effects of EPA+DHA supplementation on whole body and muscle protein metabolism&#xD;
      in COPD. The investigators have recently examined the dose-response effects of 0, 2 and 3.5 g&#xD;
      of EPA+DHA intervention ( EPA / DHA) for 4 weeks in stable moderate to severe COPD patients&#xD;
      (8pts /group) (unpublished data) but were not able to find a positive effect of muscle mass&#xD;
      and strength, even with the highest dose, likely related to the relatively short (4 week)&#xD;
      supplementation period. The effect of EPA+DHA intervention on whole body and muscle protein&#xD;
      synthesis and breakdown rates is currently being analysed.&#xD;
&#xD;
      Although numerous animal studies have shown the benefit of HMB in downregulating muscle&#xD;
      protein breakdown under catabolic conditions, there is very little data in COPD patients.&#xD;
      Others have tested HMB (3g/d) in COPD patients in the ICU and reported anti-inflammatory&#xD;
      benefits and improvement in pulmonary function. In patients with bronchiectasis, 24 week&#xD;
      supplementation with an ONS containing HMB (1.5g/d) versus standard of care during pulmonary&#xD;
      rehabilitation program, resulted in benefits on body composition, muscle strength and QoL. A&#xD;
      combination of HMB and EPA/DHA in a mouse model of cancer cachexia showed a synergy between&#xD;
      the two ingredients on preventing muscle loss and downregulation of muscle protein&#xD;
      degradation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 25, 2018</start_date>
  <completion_date type="Actual">April 1, 2020</completion_date>
  <primary_completion_date type="Actual">April 1, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes to net whole body protein metabolism</measure>
    <time_frame>baseline and after 10-week supplementation</time_frame>
    <description>whole body protein synthesis and myofibrillar protein breakdown measured by labeled amino acids on each study day via blood drawn at time 4, 10, 15, 20, 30, 40, 60, 120, 180, 240 minutes of infusion</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>muscle mass</measure>
    <time_frame>15 minutes on baseline visit, visit at week 5 of supplement intake, and after 10-week supplementation</time_frame>
    <description>Body composition as measured by Dual-Energy X-ray Absorptiometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>limb muscle strength</measure>
    <time_frame>15 minutes on baseline visit, visit at week 5 of supplement intake, and after 10-week supplementation</time_frame>
    <description>kin-com 1-leg test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>respiratory muscle strength</measure>
    <time_frame>15 minutes on baseline visit, visit at week 5 of supplement intake, and after 10-week supplementation</time_frame>
    <description>Micro-respiratory pressure meter to measure maximum inspiratory and expiratory pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>functional performance via six minute walk test</measure>
    <time_frame>baseline visit, visit at week 5 of supplement intake, and after 10-week supplementation</time_frame>
    <description>walk a predetermined loop of 69.77 meters (228.89 feet) at self-selected pace for six minutes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>systemic inflammatory markers</measure>
    <time_frame>baseline visit and after 10-week supplementation</time_frame>
    <description>blood sample will be taken to measure c-reactive protein levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>resting energy expenditure</measure>
    <time_frame>baseline visit and after 10-week supplementation</time_frame>
    <description>Oxygen consumption and carbon dioxide production will be calculated from the airflow in a transparent plastic (Plexiglas) hood to determine concentration differences between inhaled and exhaled air</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">54</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <arm_group>
    <arm_group_label>Fish Oil</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2.0 g EPA + DHA / day + placebo powder</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fish Oil and HMB</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2.0 g EPA + DHA + 3.0 g HMB / day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>3 g/d soy oil: corn oil (50:50 ratio) + placebo powder</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Capsule + Powder supplementation</intervention_name>
    <description>For Fish oil and Placebo oil, treatment will be provided in capsules.Each group will receive dose distributed to 3 capsules per day. Participants will be instructed to take all capsules with morning meal. . For HMB and a placebo powder, product will be delivered as powder taken with water or non-carbonated beverage (like juice). Product will be provided in 2 sachets/day. One sachet should be consumed with breakfast and the other prior to bedtime (approx. 10pm).</description>
    <arm_group_label>Fish Oil</arm_group_label>
    <arm_group_label>Fish Oil and HMB</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>stable tracer infusion</intervention_name>
    <description>labeled amino acids L-Phenylalanine (ring-13C6), L-Tyrosine (ring-D4), and tau-Methylhistidine will be infused as a single injection. Subsequently, the catheter will be used for arterialized venous blood samples (3 ml) drawn multiple through the day</description>
    <arm_group_label>Fish Oil</arm_group_label>
    <arm_group_label>Fish Oil and HMB</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria&#xD;
&#xD;
          -  Ability to walk, sit down and stand up independently&#xD;
&#xD;
          -  Ability to lie in supine or slightly elevated position for 8.5 hours&#xD;
&#xD;
          -  Age 45 - 100&#xD;
&#xD;
          -  Clinical diagnosis of COPD, including moderate to very severe chronic airflow&#xD;
             limitation, and an FEV1 &lt; 70% of reference FEV1 (GOLD II-III). If subjects are on β2&#xD;
             agonists, only those subjects with &lt;10% improvement in FEV1 will be included.&#xD;
&#xD;
          -  Clinically stable condition and not suffering from a respiratory tract infection or&#xD;
             exacerbation of their disease (defined as a combination of increased cough, sputum&#xD;
             purulence, shortness of breath, systemic symptoms such as fever, and a decrease in&#xD;
             FEV1 &gt; 10% compared with values when clinically stable in the preceding year) at least&#xD;
             4 weeks prior to the first test day&#xD;
&#xD;
          -  Shortness of breath on exertion&#xD;
&#xD;
          -  Willingness and ability to comply with the protocol, including:&#xD;
&#xD;
               -  Refraining from intense physical activities (72h) prior to each study visit&#xD;
&#xD;
               -  Adhering to fasting state and no smoking from 10 pm ± 2h onwards the day prior to&#xD;
                  each study visit&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Participants 86 and older that fail to get physician approval&#xD;
&#xD;
          -  Established diagnosis of malignancy&#xD;
&#xD;
          -  Established diagnosis of Insulin Dependent Diabetes Mellitus&#xD;
&#xD;
          -  History of untreated metabolic diseases including hepatic or renal disorder&#xD;
&#xD;
          -  Presence of acute illness or metabolically unstable chronic illness&#xD;
&#xD;
          -  Recent myocardial infarction (less than 1 year)&#xD;
&#xD;
          -  Any other condition according to the PI or nurse that was found during the screening&#xD;
             visit, that would interfere with the study or safety of the patient&#xD;
&#xD;
          -  BMI ≥ 45 kg/m2&#xD;
&#xD;
          -  Dietary or lifestyle characteristics:&#xD;
&#xD;
               -  Daily use of supplements containing EPA+DHA or HMB prior to the first test day&#xD;
&#xD;
               -  Use of protein or amino acid containing nutritional supplements within 5 days of&#xD;
                  first test day&#xD;
&#xD;
               -  Indications related to interaction with study products. Known hypersensitivity to&#xD;
                  fish and/or shellfish and/or soy&#xD;
&#xD;
               -  Use of long-term oral corticosteroids or short course of oral corticosteroids 4&#xD;
                  weeks preceding first test day&#xD;
&#xD;
          -  Failure to give informed consent or Investigator's uncertainty about the willingness&#xD;
             or ability of the subject to comply with the protocol requirements&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Texas A&amp;M University-CTRAL</name>
      <address>
        <city>College Station</city>
        <state>Texas</state>
        <zip>77843</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>September 28, 2018</study_first_submitted>
  <study_first_submitted_qc>January 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>February 3, 2022</last_update_submitted>
  <last_update_submitted_qc>February 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Texas A&amp;M University</investigator_affiliation>
    <investigator_full_name>Marielle PKJ Engelen, PhD</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Fish Oil supplement</keyword>
  <keyword>HMB supplement</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03796455
org study id: 2017-0870
nct id: NCT03796455
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In the present study, the role of chronic (10 weeks) intake of low dose (2g/day) of EPA+DHA
      in whole body protein metabolism, and functional performance and systemic inflammation will
      be examined, and whether adding either HMB at 3.0 g/d to the low dose of EPA+DHA (2.0 g/d)
      will enhance these effects even more.
Weight loss commonly occurs in patients with Chronic Obstructive Pulmonary Disease (COPD),
      negatively influencing their quality of life, treatment response and survival. Furthermore,
      limb muscle dysfunction (weakness and/or enhanced fatigue) is a major systemic comorbidity in
      patients with Chronic Obstructive Pulmonary Disease (COPD), negatively affecting their
      exercise performance, physical activity, quality of life, and mortality. As nutritional
      abnormalities are main contributors to muscle loss and dysfunction in COPD, nutritional
      support is viewed as an essential component of integrated care in these patients.

      Although nutritional support is effective in the treatment of weight loss in COPD, attempts
      to increase muscle mass and function in COPD by supplying large amounts of protein or
      calories to these patients have been small. This suggests that gains in muscle mass and
      function are difficult to achieve in COPD unless specific metabolic abnormalities are
      targeted. The investigators and other researchers found that low muscle mass in COPD was
      strongly associated with elevated whole body protein turnover and increased myofibrillar
      protein breakdown rates indicative of muscle contractile protein loss. The investigators have
      extended this finding recently to normal weight COPD patients characterized by muscle
      weakness using a more precise and accurate pulse method of tau-methylhistidine tracer.

      A substantial number of COPD patients, underweight as well as normal weight to obese, are
      characterized by an increased inflammatory response as evidenced by elevated levels of the
      pro-inflammatory cytokines (Tumor Necrosis Factor (TNF)-α, Interleukin (IL) 6 and 8, and the
      soluble TNF-α receptors (55 and 75). Furthermore, CRP levels are elevated in COPD and
      associated with reduced quadriceps strength, lower maximal and submaximal exercise capacity
      and increased morbidity.

      One of the few agents capable to suppress the generation of pro-inflammatory cytokines are
      eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), primary ω-3 fatty acids found in
      fish oils.

      Previous experimental research and clinical studies in cachectic conditions (mostly
      malignancy) indicate that polyunsaturated fatty acids (PUFA) are able to attenuate protein
      degradation by improving the anabolic response to feeding and by decreasing the acute phase
      response. Eicosapentaenoic acid (EPA), in combination with docosahexaenoic acid (DHA), has
      been shown to effectively inhibit weight loss in several disease states, however weight
      weight and muscle mass and function increase was not present or minimal. Also in healthy
      older adults, fish oil can slow the decline in muscle mass and function. A randomized
      clinical trial in COPD patients showed that extra nutritional supplementation with PUFAs
      daily of 1000 mg EPA+DHA as adjunct to exercise training during 8 weeks enhanced exercise
      capacity but did not lead to muscle mass gain. The patients who did not respond adequately (<
      2% gain in weight), had a higher TNF-α level than those who did gain sufficient weight, which
      is in line with previous data in COPD showing an association between an increased systemic
      inflammation with non-response to nutritional therapy.

      Although previous studies support the concept of EPA+DHA supplementation to ameliorate the
      systemic inflammatory response and decrease protein breakdown, there is no information
      present on the effects of EPA+DHA supplementation on whole body and muscle protein metabolism
      in COPD. The investigators have recently examined the dose-response effects of 0, 2 and 3.5 g
      of EPA+DHA intervention ( EPA / DHA) for 4 weeks in stable moderate to severe COPD patients
      (8pts /group) (unpublished data) but were not able to find a positive effect of muscle mass
      and strength, even with the highest dose, likely related to the relatively short (4 week)
      supplementation period. The effect of EPA+DHA intervention on whole body and muscle protein
      synthesis and breakdown rates is currently being analysed.

      Although numerous animal studies have shown the benefit of HMB in downregulating muscle
      protein breakdown under catabolic conditions, there is very little data in COPD patients.
      Others have tested HMB (3g/d) in COPD patients in the ICU and reported anti-inflammatory
      benefits and improvement in pulmonary function. In patients with bronchiectasis, 24 week
      supplementation with an ONS containing HMB (1.5g/d) versus standard of care during pulmonary
      rehabilitation program, resulted in benefits on body composition, muscle strength and QoL. A
      combination of HMB and EPA/DHA in a mouse model of cancer cachexia showed a synergy between
      the two ingredients on preventing muscle loss and downregulation of muscle protein
      degradation.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: Double (Participant, Investigator)
measure: Changes to net whole body protein metabolism
time frame: baseline and after 10-week supplementation
description: whole body protein synthesis and myofibrillar protein breakdown measured by labeled amino acids on each study day via blood drawn at time 4, 10, 15, 20, 30, 40, 60, 120, 180, 240 minutes of infusion
measure: muscle mass
time frame: 15 minutes on baseline visit, visit at week 5 of supplement intake, and after 10-week supplementation
description: Body composition as measured by Dual-Energy X-ray Absorptiometry
measure: limb muscle strength
time frame: 15 minutes on baseline visit, visit at week 5 of supplement intake, and after 10-week supplementation
description: kin-com 1-leg test
measure: respiratory muscle strength
time frame: 15 minutes on baseline visit, visit at week 5 of supplement intake, and after 10-week supplementation
description: Micro-respiratory pressure meter to measure maximum inspiratory and expiratory pressure
measure: functional performance via six minute walk test
time frame: baseline visit, visit at week 5 of supplement intake, and after 10-week supplementation
description: walk a predetermined loop of 69.77 meters (228.89 feet) at self-selected pace for six minutes
measure: systemic inflammatory markers
time frame: baseline visit and after 10-week supplementation
description: blood sample will be taken to measure c-reactive protein levels
measure: resting energy expenditure
time frame: baseline visit and after 10-week supplementation
description: Oxygen consumption and carbon dioxide production will be calculated from the airflow in a transparent plastic (Plexiglas) hood to determine concentration differences between inhaled and exhaled air
arm group label: Fish Oil
arm group type: Experimental
description: 2.0 g EPA + DHA / day + placebo powder
arm group label: Fish Oil and HMB
arm group type: Experimental
description: 2.0 g EPA + DHA + 3.0 g HMB / day
arm group label: Placebo
arm group type: Placebo Comparator
description: 3 g/d soy oil: corn oil (50:50 ratio) + placebo powder
intervention type: Dietary Supplement
intervention name: Capsule + Powder supplementation
description: For Fish oil and Placebo oil, treatment will be provided in capsules.Each group will receive dose distributed to 3 capsules per day. Participants will be instructed to take all capsules with morning meal. . For HMB and a placebo powder, product will be delivered as powder taken with water or non-carbonated beverage (like juice). Product will be provided in 2 sachets/day. One sachet should be consumed with breakfast and the other prior to bedtime (approx. 10pm).
arm group label: Fish Oil
arm group label: Fish Oil and HMB
arm group label: Placebo
intervention type: Other
intervention name: stable tracer infusion
description: labeled amino acids L-Phenylalanine (ring-13C6), L-Tyrosine (ring-D4), and tau-Methylhistidine will be infused as a single injection. Subsequently, the catheter will be used for arterialized venous blood samples (3 ml) drawn multiple through the day
arm group label: Fish Oil
arm group label: Fish Oil and HMB
arm group label: Placebo
criteria: 
gender: All
minimum age: 45 Years
maximum age: 100 Years
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Texas A&M University
investigator full name: Marielle PKJ Engelen, PhD
investigator title: Associate Professor
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
sharing ipd: No