<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/NCT03817294</url>
  </required_header>
  <id_info>
    <org_study_id>IRAS 243125</org_study_id>
    <nct_id>NCT03817294</nct_id>
  </id_info>
  <brief_title>Personalised Exercise Training in COPD</brief_title>
  <official_title>Personalised Exercise Training in COPD - Exploring the Interaction Between Exercise Physiology, Exercise Perception and Training Progression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Loughborough University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Loughborough 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>
      Exercise training as part of Pulmonary Rehabilitation (PR) has been shown conclusively to&#xD;
      improve breathlessness,quality of life and exercise capacity for people with COPD. However&#xD;
      generally PR is delivered in a 'one size fits all' approach without considering different&#xD;
      aspects of an individual's disease. It is hypothesised that a more personalised approach to&#xD;
      PR may yield even better results. However to design a personalised programme of PR we need a&#xD;
      better understanding of how different people with COPD respond to different possible exercise&#xD;
      training modalities. This study will therefore comprehensively characterise a group of&#xD;
      patients and then ask them to complete 3 weeks of exercise training in one of four&#xD;
      modalities; conventional cycling, eccentric cycling, one-legged cycling and resistance&#xD;
      training. The aim is not to prove which type of training is more effective but to develop an&#xD;
      idea of which groups of patients would benefit from which type of training.&#xD;
&#xD;
      Baseline measures would be designed to fully understand how an individual responds to&#xD;
      exercise and would therefore be comprised of a variety of endurance tests, strength tests,&#xD;
      questionnaires, and measurements of lung capacity and body composition. This is to give as&#xD;
      much information as possible to identify different responses to exercise.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition affecting an&#xD;
      estimated 1.2 million people in the UK and is the second most common lung disease after&#xD;
      asthma. COPD not only affect the lungs, but is a systemic disease with muscle dysfunction&#xD;
      being a significant feature. Exercise, as part of a programme of pulmonary rehabilitation&#xD;
      (PR), has been shown to improve exercise capacity and quality of life of patients with COPD.&#xD;
      However, despite the effectiveness of PR at a population level, there remains room for&#xD;
      improvement. The individual treatment response is heterogeneous with some patients failing to&#xD;
      achieve clinically significant improvements, whilst others struggle to adhere to the exercise&#xD;
      component or drop out altogether. Currently, whilst exercise intensities (the &quot;dose&quot;) are&#xD;
      individualised during PR, the character and content of PR is generally provided in a &quot;one&#xD;
      size fits all&quot; manner. There is therefore scope to modify the content of PR to meet&#xD;
      individual needs and underlying physiology thereby enhancing adherence and benefits.&#xD;
&#xD;
      Precision medicine, tailoring therapy to specific &quot;treatable traits&quot; of an individual's&#xD;
      condition, holds the potential to maximise treatment effect whilst minimising adverse&#xD;
      effects. The investigators propose the same principles of precision medicine can be used to&#xD;
      improve the delivery of PR by identifying an individual's exercise response at enrolment to&#xD;
      PR and using this information to personalise exercise training. There are a growing number of&#xD;
      diverse, novel training modalities that have been shown to be feasible and potentially&#xD;
      efficacious in COPD, offering opportunities for delivering a personalised training programme.&#xD;
      A key step in the development of this personalised/precision approach in exercise medicine is&#xD;
      the understanding and measurement of the individual exercise pathophysiology that predicts&#xD;
      preferential benefits to a particular exercise training modality. However, the relationship&#xD;
      between baseline exercise pathophysiology (and indeed other disease and demographic&#xD;
      variables) and such a response is currently unknown.&#xD;
&#xD;
      Eccentric exercise, contraction of a muscle as it lengthens, and one-legged cycling are two&#xD;
      options for diversifying PR. For a given muscle workload, eccentric exercise results in lower&#xD;
      energy demand and oxygen consumption and therefore puts less strain on the cardiopulmonary&#xD;
      system. Consequently, this type of exercise may be ideally suited for patients with lung&#xD;
      disease, particularly for those who stop exercise due to ventilatory limitations. It may be&#xD;
      more tolerable for patients as it causes less breathlessness, whilst allowing greater muscle&#xD;
      specific work. Eccentric cycling involves use of a bike with an attached motor which drives&#xD;
      the pedals in reverse. The subject must resist the rotation of the pedals to maintain a&#xD;
      constant pedal speed, thereby performing eccentric work with their legs. Using eccentric&#xD;
      exercise as a training modality had historically been avoided due to the fear of causing&#xD;
      muscle damage. High intensity eccentric resistance exercise leads to delayed onset muscle&#xD;
      soreness (DOMS) and has been used for many years as a model of inducing muscle damage.&#xD;
      However over the last 30 years there have been an increasing number of studies showing&#xD;
      comprehensively that if load is gradually increased, muscle damage and soreness is minimal&#xD;
      and acceptable. In patient populations, because loads achieved are particularly low, the&#xD;
      occurrence of significant muscle damage is even more infrequent and previous work, has&#xD;
      demonstrated that eccentric cycling is well tolerated in patients with COPD.&#xD;
&#xD;
      Whole body exercise, such as walking or cycling, requires recruitment of a large muscle mass&#xD;
      generating a high oxygen demand. However, there is a disparity between whole body maximal&#xD;
      oxygen uptake and muscle maximum aerobic capacity, even in a healthy population, and&#xD;
      consequently significant variation in the muscle training stimuli achieved. This is&#xD;
      emphasised in patients with COPD with a ventilatory limit to exercise. By exercising a&#xD;
      smaller muscle mass, this ventilatory limitation can be bypassed and the individual muscle&#xD;
      can be worked at significantly higher intensity. One method to reduce the exercising muscle&#xD;
      mass is one-legged cycling. Two randomised controlled trials have demonstrated a greater&#xD;
      improvement in V̇O2peak following one-legged cycling compared with two legged cycling in&#xD;
      patients with COPD. One-legged cycling has been demonstrated to be a feasible addition to a&#xD;
      PR programme and well received by patients and physiotherapists.&#xD;
&#xD;
      This study aims to determine how disease, demographic and exercise physiological variables&#xD;
      recorded at baseline relate to subsequent perception and progression of novel training&#xD;
      modalities compared to conventional training. The investigators will perform a comprehensive&#xD;
      assessment of physiological response to exercise at baseline in terms of exercise capacity,&#xD;
      exercise limitation, muscle volume and strength, physical activity, frailty and muscle&#xD;
      composition. Participants will then be randomly allocated to one of 4 training modalities;&#xD;
      eccentric cycling, one-legged cycling, concentric (traditional 2-legged cycling), or lower&#xD;
      limb resistance training.&#xD;
&#xD;
      This is a pilot/feasibility study with the broad aim of identifying potential subphenotypes&#xD;
      of patients with COPD that might respond preferentially to particular modalities of training.&#xD;
      This knowledge is crucial to the development of definitive clinical trials of such exercise&#xD;
      medicine interventions that could be delivered in routine clinical practice. The specific&#xD;
      aims are:&#xD;
&#xD;
        1. To characterise in detail the underlying pulmonary and systemic pathophysiological&#xD;
           characteristics of patients with COPD who are disabled by exercise limitation.&#xD;
&#xD;
        2. To measure progression of training loads during each training intervention relative to&#xD;
           baseline values.&#xD;
&#xD;
        3. To determine how baseline characteristics and pathophysiology relate to training&#xD;
           progression and exercise experience.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 3, 2018</start_date>
  <completion_date type="Actual">August 2, 2019</completion_date>
  <primary_completion_date type="Actual">August 2, 2019</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>This a pilot/feasibility study, aiming to characterise exercise limitation at baseline and then conducting an abridged RCT with 4 training arms. The main outcomes are related to training progression and perception</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Training Progression (Total work during training relative to baseline)</measure>
    <time_frame>3 weeks</time_frame>
    <description>(Total load during training in kJ or kg depending on exercise modality)/(load performed at baseline). This will therefore be presented as a standardised proportion (%) with no unit of measurement. Load refers to the total force production during exercise. For 2 leg and 1 leg concentric cycling and eccentric cycling this refers power output of the ergometer - total energy produced. For resistance exercise this refers to total weight lifted during training (in kg), i.e. weight lifted multiplied by number of repetitions.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Training adherence</measure>
    <time_frame>3 weeks</time_frame>
    <description>(percentage of training sessions attended)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Subjective exercise experience scale during each exercise modality</measure>
    <time_frame>Week 2</time_frame>
    <description>Validated 12 point questionnaire with each question scoring from 1 (not at all) to 7(very much so). 3 domains - fatigue (high score=high fatigue), positive well-being (high score=high positive well being) and psychological distress (high score=high distress). Each domain represents 4 questions and the score for each domain (from 4-28) will be presented. Completed during all 4 exercise modalities (eccentric cycling, resistance training, single leg cycling and concentric cycling) for each participant</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Experience of different exercise modalities - Qualitative questionnaire</measure>
    <time_frame>3 weeks</time_frame>
    <description>Structured questionnaire tailored to this study requiring short answers. Exploring preference and experience of each training modality. Note: This is not a scale questionnaire, but a short answer questionnaire with results presented as 'themes'</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exercise capacity - peak V̇O2 during a maximal incremental 2 leg cycle test</measure>
    <time_frame>Baseline</time_frame>
    <description>ml.min-1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exercise capacity - peak V̇O2 during a maximal incremental 1 leg cycle test</measure>
    <time_frame>Baseline</time_frame>
    <description>ml.min-1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inspiratory capacity during maximal 2 leg cycling</measure>
    <time_frame>Baseline</time_frame>
    <description>change from baseline (ml)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional capacity - constant work rate cycling test</measure>
    <time_frame>Baseline</time_frame>
    <description>Performed at 75% of maximum achieved power during two legged maximal incremental cycle test. Participants will be asked to cycle at a constant power output until volitional exhaustion. Outcome will be time (mins)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional capacity - measured by Timed up-and-go test</measure>
    <time_frame>Baseline</time_frame>
    <description>Time (secs) taken to get up from a chair, walk 3m, return to the chair and sit down.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscle strength - maximal concentric quadriceps strength</measure>
    <time_frame>Baseline</time_frame>
    <description>Isokinetic knee flexion/extension using dynamometry. Peak torque (Nm) and angle of peak torque recorded</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscle strength - maximal eccentric quadriceps strength</measure>
    <time_frame>Baseline</time_frame>
    <description>Isokinetic knee flexion/extension using dynamometry. Peak torque (Nm) and angle of peak torque recorded</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscle strength - 10 rep max Leg extension</measure>
    <time_frame>Baseline</time_frame>
    <description>Maximum load that participants can lift with two legs for 10 repetitions (kg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health related quality of life - St George's respiratory questionnaire</measure>
    <time_frame>Baseline</time_frame>
    <description>50 item questionnaire to measure health status (quality of life) in patients with diseases of airways obstruction. Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score (from 0-100). The minimum change score of 4 units is established as clinically relevant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frailty - Groningen Frailty Index</measure>
    <time_frame>Baseline</time_frame>
    <description>total score out of 15. A score of 4 of more indicates moderate to severe frailty</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Balance - Activities specific balance scale (ABC scale)</measure>
    <time_frame>Baseline</time_frame>
    <description>16 item score (each point answered from 0-10 with 0 representing no confidence and 100 representing complete confidence with performing specified activity without loosing balance). Total score given as an average of all questions (presented as a percentage from 0-100%). Lower scores represent worse balance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical activity - 7-day activity monitor</measure>
    <time_frame>Baseline</time_frame>
    <description>Percentage of time in light and moderate-to-vigorous physical activity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscle architectural measures seen on muscle biopsy</measure>
    <time_frame>Baseline</time_frame>
    <description>Fibre type composition - percentage of type 1 and type 2 muscle fibres</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscle architectural measures seen on muscle biopsy</measure>
    <time_frame>Baseline</time_frame>
    <description>Fibre size - mean fibre cross sectional area (micrometer2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Capillary density on muscle biopsy</measure>
    <time_frame>Baseline</time_frame>
    <description>Number of capillaries per mm2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body composition - bioelectrical impedance</measure>
    <time_frame>Baseline</time_frame>
    <description>fat free mass index (kg/m2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Breathlessness during exercise - Multidimensional dyspnoea profile</measure>
    <time_frame>Baseline</time_frame>
    <description>Validated questionnaire exploring multiple aspects of dyspnoea. Recorded at baseline and during each of 4 exercise modalities (eccentric cycling, concentric cycling, single leg cycling and lower limb resistance training). Pooled results of each question will be presented. This is not a traditional 'scale' with a 'total score' but produces a multidimensional picture of breathlessness and has been well described in breathlessness research. It is being used as a way to categorise breathlessness response or phenotype.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>COPD</condition>
  <arm_group>
    <arm_group_label>Eccentric cycling</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Concentric cycling</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Single leg cycling</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Lower limb resistance training</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Comparison of exercise training modalities</intervention_name>
    <description>As above</description>
    <arm_group_label>Concentric cycling</arm_group_label>
    <arm_group_label>Eccentric cycling</arm_group_label>
    <arm_group_label>Lower limb resistance training</arm_group_label>
    <arm_group_label>Single leg cycling</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or Female, aged 40 years or above&#xD;
&#xD;
          -  Diagnosis of COPD&#xD;
&#xD;
          -  FEV1/FVC &lt;0.7 and FEV1 &lt; 80% predicted&#xD;
&#xD;
          -  Medical Research Council (MRC) dyspnoea scale ≥3&#xD;
&#xD;
          -  Participant is willing and able to give informed consent for participation in the&#xD;
             study.&#xD;
&#xD;
          -  Stable dose of current regular medication for at least 4 weeks prior to study entry.&#xD;
&#xD;
          -  Participant has clinically acceptable ECG at enrolment.&#xD;
&#xD;
          -  Able (in the Investigators opinion) and willing to comply with all study requirements.&#xD;
&#xD;
          -  English speaking&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any other significant disease or disorder which, in the opinion of the Investigator,&#xD;
             may either put the participants at risk because of participation in the study, or may&#xD;
             influence the result of the study, or the participant's ability to participate in the&#xD;
             study.&#xD;
&#xD;
          -  Any major or uncontrolled comorbidity that would impair the participant's ability to&#xD;
             exercise or would mean exercise was unsafe.&#xD;
&#xD;
          -  Participants who have participated in another research study involving an&#xD;
             investigational product in the past 12 weeks&#xD;
&#xD;
          -  Participation in pulmonary rehabilitation in the preceding 6 months&#xD;
&#xD;
          -  Participation in another research study involving exercise training in the preceding 6&#xD;
             months&#xD;
&#xD;
          -  Acute exacerbation in the preceding 4 weeks (would become eligible 4 weeks following&#xD;
             recovery)&#xD;
&#xD;
          -  Scheduled elective surgery or other procedures requiring general anaesthesia during&#xD;
             the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Loughborough University</name>
      <address>
        <city>Loughborough</city>
        <zip>LE11 3TU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigare R, Dekhuijzen PN, Franssen F, Gayan-Ramirez G, Gea J, Gosker HR, Gosselink R, Hayot M, Hussain SN, Janssens W, Polkey MI, Roca J, Saey D, Schols AM, Spruit MA, Steiner M, Taivassalo T, Troosters T, Vogiatzis I, Wagner PD; ATS/ERS Ad Hoc Committee on Limb Muscle Dysfunction in COPD. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014 May 1;189(9):e15-62. doi: 10.1164/rccm.201402-0373ST.</citation>
    <PMID>24787074</PMID>
  </reference>
  <reference>
    <citation>Troosters T, Gosselink R, Decramer M. Exercise training in COPD: how to distinguish responders from nonresponders. J Cardiopulm Rehabil. 2001 Jan-Feb;21(1):10-7. doi: 10.1097/00008483-200101000-00004.</citation>
    <PMID>11271652</PMID>
  </reference>
  <reference>
    <citation>Camillo CA, Osadnik CR, van Remoortel H, Burtin C, Janssens W, Troosters T. Effect of &quot;add-on&quot; interventions on exercise training in individuals with COPD: a systematic review. ERJ Open Res. 2016 Mar 29;2(1):00078-2015. doi: 10.1183/23120541.00078-2015. eCollection 2016 Jan.</citation>
    <PMID>27730178</PMID>
  </reference>
  <reference>
    <citation>Rocha Vieira DS, Baril J, Richard R, Perrault H, Bourbeau J, Taivassalo T. Eccentric cycle exercise in severe COPD: feasibility of application. COPD. 2011 Aug;8(4):270-4. doi: 10.3109/15412555.2011.579926. Epub 2011 Jul 5.</citation>
    <PMID>21728805</PMID>
  </reference>
  <reference>
    <citation>Bjorgen S, Helgerud J, Husby V, Steinshamn S, Richadson RR, Hoff J. Aerobic high intensity one-legged interval cycling improves peak oxygen uptake in chronic obstructive pulmonary disease patients; no additional effect from hyperoxia. Int J Sports Med. 2009 Dec;30(12):872-8. doi: 10.1055/s-0029-1238292.</citation>
    <PMID>19821224</PMID>
  </reference>
  <reference>
    <citation>Evans RA, Dolmage TE, Mangovski-Alzamora S, Romano J, O'Brien L, Brooks D, Goldstein RS. One-Legged Cycle Training for Chronic Obstructive Pulmonary Disease. A Pragmatic Study of Implementation to Pulmonary Rehabilitation. Ann Am Thorac Soc. 2015 Oct;12(10):1490-7. doi: 10.1513/AnnalsATS.201504-231OC.</citation>
    <PMID>26291542</PMID>
  </reference>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>October 2, 2018</study_first_submitted>
  <study_first_submitted_qc>January 24, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>September 7, 2020</last_update_submitted>
  <last_update_submitted_qc>September 7, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Loughborough University</investigator_affiliation>
    <investigator_full_name>Dr Tom Ward</investigator_full_name>
    <investigator_title>Clinical PhD student</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>July 13, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT03817294/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03817294
org study id: IRAS 243125
nct id: NCT03817294
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Exercise training as part of Pulmonary Rehabilitation (PR) has been shown conclusively to
      improve breathlessness,quality of life and exercise capacity for people with COPD. However
      generally PR is delivered in a 'one size fits all' approach without considering different
      aspects of an individual's disease. It is hypothesised that a more personalised approach to
      PR may yield even better results. However to design a personalised programme of PR we need a
      better understanding of how different people with COPD respond to different possible exercise
      training modalities. This study will therefore comprehensively characterise a group of
      patients and then ask them to complete 3 weeks of exercise training in one of four
      modalities; conventional cycling, eccentric cycling, one-legged cycling and resistance
      training. The aim is not to prove which type of training is more effective but to develop an
      idea of which groups of patients would benefit from which type of training.

      Baseline measures would be designed to fully understand how an individual responds to
      exercise and would therefore be comprised of a variety of endurance tests, strength tests,
      questionnaires, and measurements of lung capacity and body composition. This is to give as
      much information as possible to identify different responses to exercise.
Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition affecting an
      estimated 1.2 million people in the UK and is the second most common lung disease after
      asthma. COPD not only affect the lungs, but is a systemic disease with muscle dysfunction
      being a significant feature. Exercise, as part of a programme of pulmonary rehabilitation
      (PR), has been shown to improve exercise capacity and quality of life of patients with COPD.
      However, despite the effectiveness of PR at a population level, there remains room for
      improvement. The individual treatment response is heterogeneous with some patients failing to
      achieve clinically significant improvements, whilst others struggle to adhere to the exercise
      component or drop out altogether. Currently, whilst exercise intensities (the "dose") are
      individualised during PR, the character and content of PR is generally provided in a "one
      size fits all" manner. There is therefore scope to modify the content of PR to meet
      individual needs and underlying physiology thereby enhancing adherence and benefits.

      Precision medicine, tailoring therapy to specific "treatable traits" of an individual's
      condition, holds the potential to maximise treatment effect whilst minimising adverse
      effects. The investigators propose the same principles of precision medicine can be used to
      improve the delivery of PR by identifying an individual's exercise response at enrolment to
      PR and using this information to personalise exercise training. There are a growing number of
      diverse, novel training modalities that have been shown to be feasible and potentially
      efficacious in COPD, offering opportunities for delivering a personalised training programme.
      A key step in the development of this personalised/precision approach in exercise medicine is
      the understanding and measurement of the individual exercise pathophysiology that predicts
      preferential benefits to a particular exercise training modality. However, the relationship
      between baseline exercise pathophysiology (and indeed other disease and demographic
      variables) and such a response is currently unknown.

      Eccentric exercise, contraction of a muscle as it lengthens, and one-legged cycling are two
      options for diversifying PR. For a given muscle workload, eccentric exercise results in lower
      energy demand and oxygen consumption and therefore puts less strain on the cardiopulmonary
      system. Consequently, this type of exercise may be ideally suited for patients with lung
      disease, particularly for those who stop exercise due to ventilatory limitations. It may be
      more tolerable for patients as it causes less breathlessness, whilst allowing greater muscle
      specific work. Eccentric cycling involves use of a bike with an attached motor which drives
      the pedals in reverse. The subject must resist the rotation of the pedals to maintain a
      constant pedal speed, thereby performing eccentric work with their legs. Using eccentric
      exercise as a training modality had historically been avoided due to the fear of causing
      muscle damage. High intensity eccentric resistance exercise leads to delayed onset muscle
      soreness (DOMS) and has been used for many years as a model of inducing muscle damage.
      However over the last 30 years there have been an increasing number of studies showing
      comprehensively that if load is gradually increased, muscle damage and soreness is minimal
      and acceptable. In patient populations, because loads achieved are particularly low, the
      occurrence of significant muscle damage is even more infrequent and previous work, has
      demonstrated that eccentric cycling is well tolerated in patients with COPD.

      Whole body exercise, such as walking or cycling, requires recruitment of a large muscle mass
      generating a high oxygen demand. However, there is a disparity between whole body maximal
      oxygen uptake and muscle maximum aerobic capacity, even in a healthy population, and
      consequently significant variation in the muscle training stimuli achieved. This is
      emphasised in patients with COPD with a ventilatory limit to exercise. By exercising a
      smaller muscle mass, this ventilatory limitation can be bypassed and the individual muscle
      can be worked at significantly higher intensity. One method to reduce the exercising muscle
      mass is one-legged cycling. Two randomised controlled trials have demonstrated a greater
      improvement in V̇O2peak following one-legged cycling compared with two legged cycling in
      patients with COPD. One-legged cycling has been demonstrated to be a feasible addition to a
      PR programme and well received by patients and physiotherapists.

      This study aims to determine how disease, demographic and exercise physiological variables
      recorded at baseline relate to subsequent perception and progression of novel training
      modalities compared to conventional training. The investigators will perform a comprehensive
      assessment of physiological response to exercise at baseline in terms of exercise capacity,
      exercise limitation, muscle volume and strength, physical activity, frailty and muscle
      composition. Participants will then be randomly allocated to one of 4 training modalities;
      eccentric cycling, one-legged cycling, concentric (traditional 2-legged cycling), or lower
      limb resistance training.

      This is a pilot/feasibility study with the broad aim of identifying potential subphenotypes
      of patients with COPD that might respond preferentially to particular modalities of training.
      This knowledge is crucial to the development of definitive clinical trials of such exercise
      medicine interventions that could be delivered in routine clinical practice. The specific
      aims are:

        1. To characterise in detail the underlying pulmonary and systemic pathophysiological
           characteristics of patients with COPD who are disabled by exercise limitation.

        2. To measure progression of training loads during each training intervention relative to
           baseline values.

        3. To determine how baseline characteristics and pathophysiology relate to training
           progression and exercise experience.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This a pilot/feasibility study, aiming to characterise exercise limitation at baseline and then conducting an abridged RCT with 4 training arms. The main outcomes are related to training progression and perception
primary purpose: Treatment
masking: None (Open Label)
measure: Training Progression (Total work during training relative to baseline)
time frame: 3 weeks
description: (Total load during training in kJ or kg depending on exercise modality)/(load performed at baseline). This will therefore be presented as a standardised proportion (%) with no unit of measurement. Load refers to the total force production during exercise. For 2 leg and 1 leg concentric cycling and eccentric cycling this refers power output of the ergometer - total energy produced. For resistance exercise this refers to total weight lifted during training (in kg), i.e. weight lifted multiplied by number of repetitions.
measure: Training adherence
time frame: 3 weeks
description: (percentage of training sessions attended)
measure: Subjective exercise experience scale during each exercise modality
time frame: Week 2
description: Validated 12 point questionnaire with each question scoring from 1 (not at all) to 7(very much so). 3 domains - fatigue (high score=high fatigue), positive well-being (high score=high positive well being) and psychological distress (high score=high distress). Each domain represents 4 questions and the score for each domain (from 4-28) will be presented. Completed during all 4 exercise modalities (eccentric cycling, resistance training, single leg cycling and concentric cycling) for each participant
measure: Experience of different exercise modalities - Qualitative questionnaire
time frame: 3 weeks
description: Structured questionnaire tailored to this study requiring short answers. Exploring preference and experience of each training modality. Note: This is not a scale questionnaire, but a short answer questionnaire with results presented as 'themes'
measure: Exercise capacity - peak V̇O2 during a maximal incremental 2 leg cycle test
time frame: Baseline
description: ml.min-1
measure: Exercise capacity - peak V̇O2 during a maximal incremental 1 leg cycle test
time frame: Baseline
description: ml.min-1
measure: Inspiratory capacity during maximal 2 leg cycling
time frame: Baseline
description: change from baseline (ml)
measure: Functional capacity - constant work rate cycling test
time frame: Baseline
description: Performed at 75% of maximum achieved power during two legged maximal incremental cycle test. Participants will be asked to cycle at a constant power output until volitional exhaustion. Outcome will be time (mins)
measure: Functional capacity - measured by Timed up-and-go test
time frame: Baseline
description: Time (secs) taken to get up from a chair, walk 3m, return to the chair and sit down.
measure: Muscle strength - maximal concentric quadriceps strength
time frame: Baseline
description: Isokinetic knee flexion/extension using dynamometry. Peak torque (Nm) and angle of peak torque recorded
measure: Muscle strength - maximal eccentric quadriceps strength
time frame: Baseline
description: Isokinetic knee flexion/extension using dynamometry. Peak torque (Nm) and angle of peak torque recorded
measure: Muscle strength - 10 rep max Leg extension
time frame: Baseline
description: Maximum load that participants can lift with two legs for 10 repetitions (kg)
measure: Health related quality of life - St George's respiratory questionnaire
time frame: Baseline
description: 50 item questionnaire to measure health status (quality of life) in patients with diseases of airways obstruction. Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score (from 0-100). The minimum change score of 4 units is established as clinically relevant.
measure: Frailty - Groningen Frailty Index
time frame: Baseline
description: total score out of 15. A score of 4 of more indicates moderate to severe frailty
measure: Balance - Activities specific balance scale (ABC scale)
time frame: Baseline
description: 16 item score (each point answered from 0-10 with 0 representing no confidence and 100 representing complete confidence with performing specified activity without loosing balance). Total score given as an average of all questions (presented as a percentage from 0-100%). Lower scores represent worse balance
measure: Physical activity - 7-day activity monitor
time frame: Baseline
description: Percentage of time in light and moderate-to-vigorous physical activity
measure: Muscle architectural measures seen on muscle biopsy
time frame: Baseline
description: Fibre type composition - percentage of type 1 and type 2 muscle fibres
measure: Muscle architectural measures seen on muscle biopsy
time frame: Baseline
description: Fibre size - mean fibre cross sectional area (micrometer2)
measure: Capillary density on muscle biopsy
time frame: Baseline
description: Number of capillaries per mm2
measure: Body composition - bioelectrical impedance
time frame: Baseline
description: fat free mass index (kg/m2)
measure: Breathlessness during exercise - Multidimensional dyspnoea profile
time frame: Baseline
description: Validated questionnaire exploring multiple aspects of dyspnoea. Recorded at baseline and during each of 4 exercise modalities (eccentric cycling, concentric cycling, single leg cycling and lower limb resistance training). Pooled results of each question will be presented. This is not a traditional 'scale' with a 'total score' but produces a multidimensional picture of breathlessness and has been well described in breathlessness research. It is being used as a way to categorise breathlessness response or phenotype.
arm group label: Eccentric cycling
arm group type: Active Comparator
arm group label: Concentric cycling
arm group type: Active Comparator
arm group label: Single leg cycling
arm group type: Active Comparator
arm group label: Lower limb resistance training
arm group type: Active Comparator
intervention type: Other
intervention name: Comparison of exercise training modalities
description: As above
arm group label: Concentric cycling
arm group label: Eccentric cycling
arm group label: Lower limb resistance training
arm group label: Single leg cycling
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United Kingdom
citation: Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigare R, Dekhuijzen PN, Franssen F, Gayan-Ramirez G, Gea J, Gosker HR, Gosselink R, Hayot M, Hussain SN, Janssens W, Polkey MI, Roca J, Saey D, Schols AM, Spruit MA, Steiner M, Taivassalo T, Troosters T, Vogiatzis I, Wagner PD; ATS/ERS Ad Hoc Committee on Limb Muscle Dysfunction in COPD. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014 May 1;189(9):e15-62. doi: 10.1164/rccm.201402-0373ST.
PMID: 24787074
citation: Troosters T, Gosselink R, Decramer M. Exercise training in COPD: how to distinguish responders from nonresponders. J Cardiopulm Rehabil. 2001 Jan-Feb;21(1):10-7. doi: 10.1097/00008483-200101000-00004.
PMID: 11271652
citation: Camillo CA, Osadnik CR, van Remoortel H, Burtin C, Janssens W, Troosters T. Effect of "add-on" interventions on exercise training in individuals with COPD: a systematic review. ERJ Open Res. 2016 Mar 29;2(1):00078-2015. doi: 10.1183/23120541.00078-2015. eCollection 2016 Jan.
PMID: 27730178
citation: Rocha Vieira DS, Baril J, Richard R, Perrault H, Bourbeau J, Taivassalo T. Eccentric cycle exercise in severe COPD: feasibility of application. COPD. 2011 Aug;8(4):270-4. doi: 10.3109/15412555.2011.579926. Epub 2011 Jul 5.
PMID: 21728805
citation: Bjorgen S, Helgerud J, Husby V, Steinshamn S, Richadson RR, Hoff J. Aerobic high intensity one-legged interval cycling improves peak oxygen uptake in chronic obstructive pulmonary disease patients; no additional effect from hyperoxia. Int J Sports Med. 2009 Dec;30(12):872-8. doi: 10.1055/s-0029-1238292.
PMID: 19821224
citation: Evans RA, Dolmage TE, Mangovski-Alzamora S, Romano J, O'Brien L, Brooks D, Goldstein RS. One-Legged Cycle Training for Chronic Obstructive Pulmonary Disease. A Pragmatic Study of Implementation to Pulmonary Rehabilitation. Ann Am Thorac Soc. 2015 Oct;12(10):1490-7. doi: 10.1513/AnnalsATS.201504-231OC.
PMID: 26291542
responsible party type: Principal Investigator
investigator affiliation: Loughborough University
investigator full name: Dr Tom Ward
investigator title: Clinical PhD student
sharing ipd: Undecided
provided document: 