<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/NCT04432194</url>
  </required_header>
  <id_info>
    <org_study_id>C68-18</org_study_id>
    <nct_id>NCT04432194</nct_id>
  </id_info>
  <brief_title>Effect of Nutritional Supplementation and Pulmonary Rehabilitation on the Clinical Status of HF and COPD</brief_title>
  <official_title>Evaluation of the Effect of Nutritional Supplementation and Pulmonary Rehabilitation on the Clinical Status of Patients With Heart Failure and Chronic Obstructive Pulmonary Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto Nacional de Enfermedades Respiratorias</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Instituto Nacional de Enfermedades Respiratorias</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>
      Cardiovascular diseases (CVD) are the leading cause of death in the world and our country.&#xD;
      The prevalence of Heart Failure (HF) is 1-2% in the adult population in developed countries,&#xD;
      up to 10% among people 70 years of age. Concerning COPD, it is estimated that by 2030 will be&#xD;
      the third leading cause of death in the world; the prevalence in Mexico is 18.4%. Also,&#xD;
      according to INEGI data, it is the 5th cause of death in people over 65.&#xD;
&#xD;
      50% of patients with COPD die of cardiovascular causes, and they are at higher risk of&#xD;
      developing HF, hospital readmissions, and death.&#xD;
&#xD;
      Subjects with HF and COPD concomitant have alterations such as; systemic inflammation, loss&#xD;
      of muscle mass and strength of both skeletal and respiratory muscles, reduced tolerance to&#xD;
      exercise, and lung function, which has an important impact on clinical status, quality of&#xD;
      life and prognosis.&#xD;
&#xD;
      The objective of nutritional treatment in HF is to reduce heart overload and reduce&#xD;
      cardiovascular risk. On the other hand, in COPD, it is to improve lung function. However,&#xD;
      this is not enough to maintain the protein reserves of patients due to previously affected&#xD;
      factors. Therefore, it is vitally essential to contemplate the supplementation with amino&#xD;
      acids that prevent and delay the loss of protein reserves, as well as the delay in clinical&#xD;
      status.&#xD;
&#xD;
      The β-hydroxy-β-methyl butyrate (HMB) is a metabolite of leucine, with an anticatabolic and&#xD;
      anabolic effect. HMB improves the synthesis of proteins, muscle mass, strength, and muscle&#xD;
      functionality. Citrulline has been associated with increased muscle mass, VO2, and exercise&#xD;
      tolerance.&#xD;
&#xD;
      On the other hand, pulmonary rehabilitation (RP) has improved exercise tolerance, mass, and&#xD;
      strength of skeletal and respiratory muscles, quality of life, reduction of hospitalizations,&#xD;
      and mortality. However, in concomitant HF and COPD, there are no guidelines that specify the&#xD;
      type of RP or if there is a synergistic effect with nutritional supplementation and its&#xD;
      impact on clinical status.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Heart Failure&#xD;
&#xD;
      Heart Failure (HF) is a complex syndrome consequence of any structural or functional&#xD;
      abnormality that impairs the capacity of filling or ejected of the heart. (1, 2).&#xD;
&#xD;
      Chronic obstructive pulmonary disease&#xD;
&#xD;
      Chronic obstructive pulmonary disease (COPD) is a progressive, systemic, and multi-organic&#xD;
      disease with structural and functional changes, mostly in the lungs. It is characterized by a&#xD;
      progressive limitation of airflow as a response to external factors such as airflow&#xD;
      contamination, smoking, biomass, which are associated with chronic inflammation. (3).&#xD;
&#xD;
      Epidemiology&#xD;
&#xD;
      The cardiovascular disease is the leading cause of death worldwide (4); The HF prevalence&#xD;
      goes from 1-2% in developed countries and increases to 10% in older &gt;70 years old.&#xD;
&#xD;
      COPD is an important global load affecting more than 600 million people corresponding to the&#xD;
      5 % off all cause of death worldwide (5).&#xD;
&#xD;
      Chronic Obstructive Pulmonary Disease and Heart Failure&#xD;
&#xD;
      COPD and HF are related between them, sharing the same risk factors and pathogenic&#xD;
      mechanisms. They are growing in time and are epidemic diseases because of multiple factors.&#xD;
      The cardiovascular disease takes an essential role in COPD, 30 to 50% of deaths are because&#xD;
      of them; one of the most important is HF. COPD patients have three times the risk to&#xD;
      developed HF (6), and between them, the risk of hospital readmission and death is higher than&#xD;
      those without HF (7).&#xD;
&#xD;
      Nutritional Supplementation&#xD;
&#xD;
      β-Hydroxy-β-Methylbutyrate (HMB) HMB is a leucine metabolite, are a branch chain amino acid,&#xD;
      and a regular potent in the muscular protein replacement and endogen sub-production that&#xD;
      occurs in the muscles and liver. The first stage of change is through the transamination of&#xD;
      the leucine to KIC, occurring in the mitochondrial and cytosol of the muscular cell. In the&#xD;
      mitochondria, the KIC oxidates into isovaril-CoA, subsequently by other metabolism processes,&#xD;
      it produces 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA). Approximately 90% of KIC oxidize&#xD;
      into isovaril CoA in the hepatic mitochondrial, lastly, acetoacetate and Acetyl-CoA. While&#xD;
      the last 10% oxides into HMB in the cellular cytosol (8-10).&#xD;
&#xD;
      Supplementation with HMB&#xD;
&#xD;
      HMB develops a nutritional role; the daily supplementation has an anti-catabolic effect in&#xD;
      the protein synthesis, increasing the muscular mass and diminished the muscular damage in&#xD;
      adulthood.&#xD;
&#xD;
      Several studies evaluate the effects of supplementation with HMB, isolated, or combined in&#xD;
      muscle functionality, strength, mortality, and indifferent pathologies(11). Recently, in a&#xD;
      meth analysis and systemic review of randomized clinical trials made by Wu et al. to evaluate&#xD;
      the effect of the administration with HMB over the corporal composition and muscular strength&#xD;
      in adulthood in 65 years with pathologies. The study includes supplementation of HMB at 3mg&#xD;
      doses at least eight weeks to increase the muscular strength and functionality (12).&#xD;
      Supplementation with Ca-HMB with or without resistance exercise in older than 75 years' old&#xD;
      was evaluated by Stout et al., in a pilot study, they made 2 phases: the first one (without&#xD;
      exercise) supplementation with 3g of CaHMB vs. placebo and the second (with resistance&#xD;
      exercise) with and without supplementation. They observed that the supplementation in the&#xD;
      long term has better benefits, and increase lean mass, strength, quality, and functional&#xD;
      muscle without exercise. In this study, they showed that there is no synergic effect with the&#xD;
      exercise combined with supplementation (10).&#xD;
&#xD;
      Citrulline-arginine The principal precursor of citrulline is glutamine, representing 60% of&#xD;
      the total synthesis of arginine de novo (13). Citrulline is released into the portal&#xD;
      circulation because the enterocytes do not have the succinate arginine synthase. The liver&#xD;
      absorbs one quantity in a normal hepatic function and goes to the systemic circulation and&#xD;
      finally is transformed by the kidney into arginine (14). The supplementation is a potent&#xD;
      nutrient-drug that helps to restore the arginine metabolism in different populations (14,&#xD;
      15).&#xD;
&#xD;
      Citrulline is considered a safe supplementation (16)with a maximum consumption of 15g/day and&#xD;
      13 g/day for arginine (17, 18). The blood levels in a healthy individual are 40 µmol/L (19).&#xD;
      L citrulline increases the concentration of L arginine more efficiently than the&#xD;
      supplementation of L-arginine; this is an amino acid, endogen precursor of the synthesis of&#xD;
      oxide nitric (ON) (20).&#xD;
&#xD;
      Different studies with supplementation show a reduction in adhesion cells and leucocyte&#xD;
      activation, as well as an improvement in endothelial function (21). Besides, in heathier&#xD;
      subjects, it has been associated with less muscular fatigue, better VO2, and exercise&#xD;
      tolerance. (22) In a randomized clinical trial (RCT) with healthy subjects, where they&#xD;
      receive oral supplementation with citrulline, they showed an increase of 57% of the nitrogen&#xD;
      balance 12 hrs. after (17)&#xD;
&#xD;
      Pulmonary rehabilitation&#xD;
&#xD;
      Pulmonary rehabilitation and physic therapy are essential components of the non-pharmacologic&#xD;
      treatment, for HF and COPD, the guidelines' treatment recommends the pulmonary rehabilitation&#xD;
      or physic therapy, to improve the exercise tolerance, skeletal and respiratory muscular&#xD;
      function, also the quality of life of the patients (23, 24). On the other side, it has been&#xD;
      demonstrated that pulmonary rehabilitation and physic therapy have benefits in the number of&#xD;
      hospitalization and mortality of patients.&#xD;
&#xD;
      Ancanfora et al., in a randomized clinical trial evaluate the effect of cardiovascular&#xD;
      training in patients with HF. The program consists of resistance activities and abdominal&#xD;
      exercises, depending on the clinical characteristics of each patient, they were followed by&#xD;
      four weeks, resulting in an improvement over-exercise tolerance, O2 maximum consumes and&#xD;
      ventilatory threshold (25). Similarly, Keteyian et al., evaluated the physiological&#xD;
      adaptation resulting by the physical training in patients with HF with Left ventricle&#xD;
      ejection fraction. Also reduced the effects and security in clinical results, had a followed&#xD;
      of 2-5 weeks, it consists by resistance exercises such as walking and the use of the static&#xD;
      bicycle by 20-30 minutes (23). They conclude that the exercise was secure and improves the&#xD;
      state of health, exercise capacity. O´connor et al., evaluated the effects of a regular&#xD;
      aerobic exercise (bicycle, treadmill) in patients with HF plus the habitual care, followed by&#xD;
      30 months, they observed that the mortality and hospitalization decreases (26).&#xD;
&#xD;
      Additionally, Benefits have also been seen in patients with COPD; Petersen et al., after&#xD;
      seven weeks, show that the resistance exercises twice a week improved exercise tolerance and&#xD;
      diminished the fast degradation of proteins (27). Nevertheless, patients with HF and COPD&#xD;
      have no guidelines that specified the type of exercise as well as the duration of it, or if&#xD;
      there is a synergic effect with nutritional supplementation and which is the impact over the&#xD;
      clinic stage.&#xD;
&#xD;
      General objective:&#xD;
&#xD;
      To assess the effect of nutritional supplementation and pulmonary rehabilitation on the&#xD;
      clinical status of patients with HF and COPD compared to those subjects who do not receive&#xD;
      nutritional supplementation or pulmonary rehabilitation.&#xD;
&#xD;
      Specific objectives&#xD;
&#xD;
      To evaluate the effect of pulmonary rehabilitation and supplementation over body composition&#xD;
      in COPD and HF patients compared to those subjects who receive non-pharmacology treatment&#xD;
      based on guidelines treatment.&#xD;
&#xD;
      To evaluate the effect of pulmonary rehabilitation and supplementation over the exercise&#xD;
      tolerance in COPD and HF patients compared to those subjects who receive non-pharmacology&#xD;
      treatment based on guidelines treatment.&#xD;
&#xD;
      To evaluate the effect of pulmonary rehabilitation and supplementation over pulmonary&#xD;
      function in COPD and HF patients compared to those subjects who receive non-pharmacology&#xD;
      treatment based on guidelines treatment.&#xD;
&#xD;
      To evaluate the effect of pulmonary rehabilitation and supplementation over endothelial&#xD;
      function in COPD and HF patients compared to those subjects who receive non-pharmacology&#xD;
      treatment based on guidelines treatment.&#xD;
&#xD;
      To evaluate the effect of pulmonary rehabilitation and supplementation over muscle function&#xD;
      in COPD and HF patients compared to those subjects who receive non-pharmacology treatment&#xD;
      based on guidelines treatment.&#xD;
&#xD;
      To evaluate the effect of pulmonary rehabilitation and supplementation over cognitive&#xD;
      function in COPD and HF patients compared to those subjects who receive non-pharmacology&#xD;
      treatment based on guidelines treatment.&#xD;
&#xD;
      Evaluated the effect of nutritional supplementation and pulmonary rehabilitation over&#xD;
      prognosis in COPD and HF patients compared to those subjects who receive non-pharmacology&#xD;
      treatment based on guidelines treatment.&#xD;
&#xD;
      Hypothesis Subjects with HF and COPD who receive nutritional supplementation and pulmonary&#xD;
      rehabilitation will have a better clinical status than those who do not receive nutritional&#xD;
      supplementation or pulmonary rehabilitation.&#xD;
&#xD;
      Methodology&#xD;
&#xD;
      Design Study:&#xD;
&#xD;
      Randomized clinical trial&#xD;
&#xD;
      Study Population:&#xD;
&#xD;
      Patients with Heart failure and Chronic Obstructive Pulmonary Disease diagnosisStatistical&#xD;
      Analysis&#xD;
&#xD;
      Descriptive analysis will be present as frequency and percentage if categorical variables and&#xD;
      mean &amp; standard deviation if the variable is continuous with normal distribution; if not, it&#xD;
      will report as median and percentiles (25-75). The normality distribution will be evaluated&#xD;
      through a Shapiro-Wilk test.&#xD;
&#xD;
      At the beginning of the study, we will compare both groups to determine statistical&#xD;
      significance differences. X2 will run in categorical variables and an independent t-study&#xD;
      test in continuous variables with normal distribution, if not, U de Mann Whitney will be run.&#xD;
&#xD;
      To identifying the differences between groups along with the study, repeated analysis of&#xD;
      variance measures will be done if the variable has a normal distribution. Otherwise, Friedman&#xD;
      tests will be made. McNemar will be made for categorical variables. Furthermore, changes&#xD;
      between groups along the time at student will be made with a normal distribution; otherwise,&#xD;
      Wilcoxon will be done.&#xD;
&#xD;
      Alpha type error: it considered as a statistical significance a p&lt;0.05&#xD;
&#xD;
      Sample size A simple size space of 100 patients, 25 subjects per group will be included if&#xD;
      prior consent is acquired, and they meet the inclusion criteria.&#xD;
&#xD;
      Procedures Invitation to participate All the patients who complete the inclusion criteria&#xD;
      will be invited to the protocol. They shall be informed about the study, the possible risks&#xD;
      and benefits of the treatment, and the possibility of leaving the study at any moment if the&#xD;
      patients want. Those who accept participated will be enrolled in a list and then randomized&#xD;
      into different groups of treatment.&#xD;
&#xD;
      Allocation to the treatment groups The allocation sequence will be generated in the site&#xD;
      http://www.randomization.com; therefore, the patients will be assigned into one of the next&#xD;
      groups: 1) control group 2)pulmonary rehabilitation 3) rehabilitation pulmonary group plus&#xD;
      beta-hydroxy beta-methyl butyric (HMB) (4g) 4) pulmonary rehabilitation group plus Citrulline&#xD;
      (4g). The cardiologist, nutritionist, the physic therapist, will be blinded to the&#xD;
      assignation group treatments.&#xD;
&#xD;
      Baseline evaluation During the first evaluation, the clinical stage will be assigned, and the&#xD;
      next valuations will be made: pulmonary function, endothelial function, exercise tolerance,&#xD;
      functional class, signs, and symptoms. anthropometric and body composition indicators by&#xD;
      electric bio-impedance, biochemical test, dietetics, handgrip strength Following visits All&#xD;
      the patients, no matter the group, will have a follow up for three months. In the beginning,&#xD;
      6week later and finally at three months.&#xD;
&#xD;
      Survival follow-up wil be after two years treatment initiation&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 30, 2019</start_date>
  <completion_date type="Anticipated">September 2023</completion_date>
  <primary_completion_date type="Anticipated">July 2023</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>Factorial Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Triple (Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluate the effect of nutritional supplementation and pulmonary rehabilitation on the clinical status</measure>
    <time_frame>Baseline, 6 weeks after treatment initiation, 12 weeks 6 weeks after treatment initiation</time_frame>
    <description>Change from baseline in functional class assessed by NYHA</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluated the effect of nutritional supplementation and pulmonary rehabilitation over the skeletal muscle mass</measure>
    <time_frame>Baseline, 6 weeks after treatment initiation, 12 weeks 6 weeks after treatment initiation</time_frame>
    <description>Change from baseline in the skeletal muscle mass assessed by bioelectrical impedance</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluated the effect of nutritional supplementation and pulmonary rehabilitation over pulmonary function</measure>
    <time_frame>Baseline, 6 weeks after treatment initiation, 12 weeks 6 weeks after treatment initiation</time_frame>
    <description>Change from baseline in pulmonary function assessed by spirometry test</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To evaluate the effect of pulmonary rehabilitation and supplementation over muscle function in COPD and HF patients</measure>
    <time_frame>Baseline, 6 weeks after treatment initiation, 12 weeks 6 weeks after treatment initiation</time_frame>
    <description>Change from baseline in pulmonary function assessed by dinamometry test</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluated the effect of nutritional supplementation and pulmonary rehabilitation over prognosis in COPD and HF patients</measure>
    <time_frame>Two years after treatment initiation</time_frame>
    <description>survival follow-up</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Heart Failure</condition>
  <condition>Copd</condition>
  <condition>Nutritional Supplementation</condition>
  <condition>Pulmonary Rehabilitation</condition>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The subjects in this group will receive the usual care, which includes the non-pharmacology recommendations by the European Society of Cardiologists 2006 (1) and COPD guides for treatment (6), both founded in the sodium and liquids restriction.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pulmonary Rehabilitation Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients in this group will receive pulmonary rehabilitation specified by rehabilitation doctors according to the needs and capacities of each individual, who will attend three times a week for three months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pulmonary Rehabilitation Group plus HMB (4g)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in this group will receive pulmonary rehabilitation specified by rehabilitation doctors according to the needs and capacities of each individual, who will attend three times a week for three months. Furthermore, they will receive 4g of citrulline supplementation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pulmonary Rehabilitation Group plus citrulline (3g)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in this group will receive pulmonary rehabilitation specified by the doctor specialized in rehabilitation according to the needs and capacities of each individual, who will attend three times a week for three months. Furthermore, they will receive 4g of citrulline supplementation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Nutritional supplementation and Pulmonary Rehabilitation</intervention_name>
    <description>Nutritional supplementation (HMB 4g) or Nutritional supplementation (citrulline 3g) with Pulmonary Rehabilitation</description>
    <arm_group_label>Pulmonary Rehabilitation Group</arm_group_label>
    <arm_group_label>Pulmonary Rehabilitation Group plus HMB (4g)</arm_group_label>
    <arm_group_label>Pulmonary Rehabilitation Group plus citrulline (3g)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients that accept and signed the study consent.&#xD;
&#xD;
          -  &gt; 40 years old&#xD;
&#xD;
          -  Patients with Heart failure diagnosis confirmed by echocardiographic criteria&#xD;
             according to the European Society of Cardiology guidelines (2).&#xD;
&#xD;
          -  Heart failure patients in functional class I to III according to NYHA&#xD;
&#xD;
          -  Patients with Chronic Obstructive Pulmonary Disease diagnosis according to GOLD&#xD;
             guidelines with a post-bronchodilator spirometry VEF1/FVC index &lt;0.70 (50)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with recent (&lt;3 months) exacerbations&#xD;
&#xD;
          -  Terminal Chronic Renal Kidney Disease with a creatinine clearance &lt;30 ml/min/1.73m2&#xD;
&#xD;
          -  Patients with a cancer diagnosis&#xD;
&#xD;
          -  Patients with limitation to exercise&#xD;
&#xD;
          -  Patients enrolled in another study protocol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Leslie Verdeja-Vendrell, M.Sc.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instituto Nacional de Enfermedades Respiratorias &quot;Ismael Cosío Villegas&quot;</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Dulce González-Islas, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Instituto Nacional de Enfermedades Respiratorias &quot;Ismael Cosío Villegas&quot;</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Arturo Orea-Tejeda, MD</last_name>
    <role>Study Director</role>
    <affiliation>Instituto Nacional de Enfermedades Respiratorias &quot;Ismael Cosío Villegas&quot;</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Martha E Quintero-Martínez, B.Sc</last_name>
    <role>Study Chair</role>
    <affiliation>Instituto Nacional de Enfermedades Respiratorias &quot;Ismael Cosío Villegas&quot;</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ilse C Pérez-García, B.Sc</last_name>
    <role>Study Chair</role>
    <affiliation>Instituto Nacional de Enfermedades Respiratorias &quot;Ismael Cosío Villegas&quot;</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dulce González-Islas, PhD</last_name>
    <phone>5514364002</phone>
    <email>gzz.dulce@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Dulce González-Islas</name>
      <address>
        <city>Mexico City</city>
        <state>Ciudad De México</state>
        <zip>14080</zip>
        <country>Mexico</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dulce González-Islas, PhD</last_name>
      <phone>5514364002</phone>
      <email>gzz.dulce@gmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <reference>
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  <reference>
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    <PMID>30496103</PMID>
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  <reference>
    <citation>Rodriguez LA, Wallander MA, Martin-Merino E, Johansson S. Heart failure, myocardial infarction, lung cancer and death in COPD patients: a UK primary care study. Respir Med. 2010 Nov;104(11):1691-9. doi: 10.1016/j.rmed.2010.04.018. Epub 2010 May 18.</citation>
    <PMID>20483577</PMID>
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    <citation>Boudestein LC, Rutten FH, Cramer MJ, Lammers JW, Hoes AW. The impact of concurrent heart failure on prognosis in patients with chronic obstructive pulmonary disease. Eur J Heart Fail. 2009 Dec;11(12):1182-8. doi: 10.1093/eurjhf/hfp148. Epub 2009 Nov 3.</citation>
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    <citation>Vukovich MD, Stubbs NB, Bohlken RM. Body composition in 70-year-old adults responds to dietary beta-hydroxy-beta-methylbutyrate similarly to that of young adults. J Nutr. 2001 Jul;131(7):2049-52. doi: 10.1093/jn/131.7.2049.</citation>
    <PMID>11435528</PMID>
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    <citation>Stout JR, Smith-Ryan AE, Fukuda DH, Kendall KL, Moon JR, Hoffman JR, Wilson JM, Oliver JS, Mustad VA. Effect of calcium beta-hydroxy-beta-methylbutyrate (CaHMB) with and without resistance training in men and women 65+yrs: a randomized, double-blind pilot trial. Exp Gerontol. 2013 Nov;48(11):1303-10. doi: 10.1016/j.exger.2013.08.007. Epub 2013 Aug 24.</citation>
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    <PMID>23022123</PMID>
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    <citation>Luiking YC, Poeze M, Ramsay G, Deutz NE. Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production. Am J Clin Nutr. 2009 Jan;89(1):142-52. doi: 10.3945/ajcn.2007.25765. Epub 2008 Dec 3.</citation>
    <PMID>19056593</PMID>
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    <citation>Cynober L. Citrulline: just a biomarker or a conditionally essential amino acid and a pharmaconutrient in critically ill patients? Crit Care. 2013 Mar 11;17(2):122. doi: 10.1186/cc12534.</citation>
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    <PMID>17901164</PMID>
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    <citation>Grimble GK. Adverse gastrointestinal effects of arginine and related amino acids. J Nutr. 2007 Jun;137(6 Suppl 2):1693S-1701S. doi: 10.1093/jn/137.6.1693S.</citation>
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    <citation>Moinard C, Nicolis I, Neveux N, Darquy S, Benazeth S, Cynober L. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study. Br J Nutr. 2008 Apr;99(4):855-62. doi: 10.1017/S0007114507841110. Epub 2007 Oct 22.</citation>
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    <PMID>26023227</PMID>
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    <citation>Keteyian SJ. Exercise training in congestive heart failure: risks and benefits. Prog Cardiovasc Dis. 2011 May-Jun;53(6):419-28. doi: 10.1016/j.pcad.2011.02.005.</citation>
    <PMID>21545928</PMID>
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    <citation>Acanfora D, Scicchitano P, Casucci G, Lanzillo B, Capuano N, Furgi G, Acanfora C, Longobardi M, Incalzi RA, Piscosquito G, Ciccone MM. Exercise training effects on elderly and middle-age patients with chronic heart failure after acute decompensation: A randomized, controlled trial. Int J Cardiol. 2016 Dec 15;225:313-323. doi: 10.1016/j.ijcard.2016.10.026. Epub 2016 Oct 11.</citation>
    <PMID>27750131</PMID>
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    <PMID>24724085</PMID>
  </reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>May 25, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>June 11, 2020</last_update_submitted>
  <last_update_submitted_qc>June 11, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Instituto Nacional de Enfermedades Respiratorias</investigator_affiliation>
    <investigator_full_name>Dulce González Islas, PhD</investigator_full_name>
    <investigator_title>Researcher in Medical Sciences</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</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/NCT04432194
org study id: C68-18
nct id: NCT04432194
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Cardiovascular diseases (CVD) are the leading cause of death in the world and our country.
      The prevalence of Heart Failure (HF) is 1-2% in the adult population in developed countries,
      up to 10% among people 70 years of age. Concerning COPD, it is estimated that by 2030 will be
      the third leading cause of death in the world; the prevalence in Mexico is 18.4%. Also,
      according to INEGI data, it is the 5th cause of death in people over 65.

      50% of patients with COPD die of cardiovascular causes, and they are at higher risk of
      developing HF, hospital readmissions, and death.

      Subjects with HF and COPD concomitant have alterations such as; systemic inflammation, loss
      of muscle mass and strength of both skeletal and respiratory muscles, reduced tolerance to
      exercise, and lung function, which has an important impact on clinical status, quality of
      life and prognosis.

      The objective of nutritional treatment in HF is to reduce heart overload and reduce
      cardiovascular risk. On the other hand, in COPD, it is to improve lung function. However,
      this is not enough to maintain the protein reserves of patients due to previously affected
      factors. Therefore, it is vitally essential to contemplate the supplementation with amino
      acids that prevent and delay the loss of protein reserves, as well as the delay in clinical
      status.

      The β-hydroxy-β-methyl butyrate (HMB) is a metabolite of leucine, with an anticatabolic and
      anabolic effect. HMB improves the synthesis of proteins, muscle mass, strength, and muscle
      functionality. Citrulline has been associated with increased muscle mass, VO2, and exercise
      tolerance.

      On the other hand, pulmonary rehabilitation (RP) has improved exercise tolerance, mass, and
      strength of skeletal and respiratory muscles, quality of life, reduction of hospitalizations,
      and mortality. However, in concomitant HF and COPD, there are no guidelines that specify the
      type of RP or if there is a synergistic effect with nutritional supplementation and its
      impact on clinical status.
Heart Failure

      Heart Failure (HF) is a complex syndrome consequence of any structural or functional
      abnormality that impairs the capacity of filling or ejected of the heart. (1, 2).

      Chronic obstructive pulmonary disease

      Chronic obstructive pulmonary disease (COPD) is a progressive, systemic, and multi-organic
      disease with structural and functional changes, mostly in the lungs. It is characterized by a
      progressive limitation of airflow as a response to external factors such as airflow
      contamination, smoking, biomass, which are associated with chronic inflammation. (3).

      Epidemiology

      The cardiovascular disease is the leading cause of death worldwide (4); The HF prevalence
      goes from 1-2% in developed countries and increases to 10% in older >70 years old.

      COPD is an important global load affecting more than 600 million people corresponding to the
      5 % off all cause of death worldwide (5).

      Chronic Obstructive Pulmonary Disease and Heart Failure

      COPD and HF are related between them, sharing the same risk factors and pathogenic
      mechanisms. They are growing in time and are epidemic diseases because of multiple factors.
      The cardiovascular disease takes an essential role in COPD, 30 to 50% of deaths are because
      of them; one of the most important is HF. COPD patients have three times the risk to
      developed HF (6), and between them, the risk of hospital readmission and death is higher than
      those without HF (7).

      Nutritional Supplementation

      β-Hydroxy-β-Methylbutyrate (HMB) HMB is a leucine metabolite, are a branch chain amino acid,
      and a regular potent in the muscular protein replacement and endogen sub-production that
      occurs in the muscles and liver. The first stage of change is through the transamination of
      the leucine to KIC, occurring in the mitochondrial and cytosol of the muscular cell. In the
      mitochondria, the KIC oxidates into isovaril-CoA, subsequently by other metabolism processes,
      it produces 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA). Approximately 90% of KIC oxidize
      into isovaril CoA in the hepatic mitochondrial, lastly, acetoacetate and Acetyl-CoA. While
      the last 10% oxides into HMB in the cellular cytosol (8-10).

      Supplementation with HMB

      HMB develops a nutritional role; the daily supplementation has an anti-catabolic effect in
      the protein synthesis, increasing the muscular mass and diminished the muscular damage in
      adulthood.

      Several studies evaluate the effects of supplementation with HMB, isolated, or combined in
      muscle functionality, strength, mortality, and indifferent pathologies(11). Recently, in a
      meth analysis and systemic review of randomized clinical trials made by Wu et al. to evaluate
      the effect of the administration with HMB over the corporal composition and muscular strength
      in adulthood in 65 years with pathologies. The study includes supplementation of HMB at 3mg
      doses at least eight weeks to increase the muscular strength and functionality (12).
      Supplementation with Ca-HMB with or without resistance exercise in older than 75 years' old
      was evaluated by Stout et al., in a pilot study, they made 2 phases: the first one (without
      exercise) supplementation with 3g of CaHMB vs. placebo and the second (with resistance
      exercise) with and without supplementation. They observed that the supplementation in the
      long term has better benefits, and increase lean mass, strength, quality, and functional
      muscle without exercise. In this study, they showed that there is no synergic effect with the
      exercise combined with supplementation (10).

      Citrulline-arginine The principal precursor of citrulline is glutamine, representing 60% of
      the total synthesis of arginine de novo (13). Citrulline is released into the portal
      circulation because the enterocytes do not have the succinate arginine synthase. The liver
      absorbs one quantity in a normal hepatic function and goes to the systemic circulation and
      finally is transformed by the kidney into arginine (14). The supplementation is a potent
      nutrient-drug that helps to restore the arginine metabolism in different populations (14,
      15).

      Citrulline is considered a safe supplementation (16)with a maximum consumption of 15g/day and
      13 g/day for arginine (17, 18). The blood levels in a healthy individual are 40 µmol/L (19).
      L citrulline increases the concentration of L arginine more efficiently than the
      supplementation of L-arginine; this is an amino acid, endogen precursor of the synthesis of
      oxide nitric (ON) (20).

      Different studies with supplementation show a reduction in adhesion cells and leucocyte
      activation, as well as an improvement in endothelial function (21). Besides, in heathier
      subjects, it has been associated with less muscular fatigue, better VO2, and exercise
      tolerance. (22) In a randomized clinical trial (RCT) with healthy subjects, where they
      receive oral supplementation with citrulline, they showed an increase of 57% of the nitrogen
      balance 12 hrs. after (17)

      Pulmonary rehabilitation

      Pulmonary rehabilitation and physic therapy are essential components of the non-pharmacologic
      treatment, for HF and COPD, the guidelines' treatment recommends the pulmonary rehabilitation
      or physic therapy, to improve the exercise tolerance, skeletal and respiratory muscular
      function, also the quality of life of the patients (23, 24). On the other side, it has been
      demonstrated that pulmonary rehabilitation and physic therapy have benefits in the number of
      hospitalization and mortality of patients.

      Ancanfora et al., in a randomized clinical trial evaluate the effect of cardiovascular
      training in patients with HF. The program consists of resistance activities and abdominal
      exercises, depending on the clinical characteristics of each patient, they were followed by
      four weeks, resulting in an improvement over-exercise tolerance, O2 maximum consumes and
      ventilatory threshold (25). Similarly, Keteyian et al., evaluated the physiological
      adaptation resulting by the physical training in patients with HF with Left ventricle
      ejection fraction. Also reduced the effects and security in clinical results, had a followed
      of 2-5 weeks, it consists by resistance exercises such as walking and the use of the static
      bicycle by 20-30 minutes (23). They conclude that the exercise was secure and improves the
      state of health, exercise capacity. O´connor et al., evaluated the effects of a regular
      aerobic exercise (bicycle, treadmill) in patients with HF plus the habitual care, followed by
      30 months, they observed that the mortality and hospitalization decreases (26).

      Additionally, Benefits have also been seen in patients with COPD; Petersen et al., after
      seven weeks, show that the resistance exercises twice a week improved exercise tolerance and
      diminished the fast degradation of proteins (27). Nevertheless, patients with HF and COPD
      have no guidelines that specified the type of exercise as well as the duration of it, or if
      there is a synergic effect with nutritional supplementation and which is the impact over the
      clinic stage.

      General objective:

      To assess the effect of nutritional supplementation and pulmonary rehabilitation on the
      clinical status of patients with HF and COPD compared to those subjects who do not receive
      nutritional supplementation or pulmonary rehabilitation.

      Specific objectives

      To evaluate the effect of pulmonary rehabilitation and supplementation over body composition
      in COPD and HF patients compared to those subjects who receive non-pharmacology treatment
      based on guidelines treatment.

      To evaluate the effect of pulmonary rehabilitation and supplementation over the exercise
      tolerance in COPD and HF patients compared to those subjects who receive non-pharmacology
      treatment based on guidelines treatment.

      To evaluate the effect of pulmonary rehabilitation and supplementation over pulmonary
      function in COPD and HF patients compared to those subjects who receive non-pharmacology
      treatment based on guidelines treatment.

      To evaluate the effect of pulmonary rehabilitation and supplementation over endothelial
      function in COPD and HF patients compared to those subjects who receive non-pharmacology
      treatment based on guidelines treatment.

      To evaluate the effect of pulmonary rehabilitation and supplementation over muscle function
      in COPD and HF patients compared to those subjects who receive non-pharmacology treatment
      based on guidelines treatment.

      To evaluate the effect of pulmonary rehabilitation and supplementation over cognitive
      function in COPD and HF patients compared to those subjects who receive non-pharmacology
      treatment based on guidelines treatment.

      Evaluated the effect of nutritional supplementation and pulmonary rehabilitation over
      prognosis in COPD and HF patients compared to those subjects who receive non-pharmacology
      treatment based on guidelines treatment.

      Hypothesis Subjects with HF and COPD who receive nutritional supplementation and pulmonary
      rehabilitation will have a better clinical status than those who do not receive nutritional
      supplementation or pulmonary rehabilitation.

      Methodology

      Design Study:

      Randomized clinical trial

      Study Population:

      Patients with Heart failure and Chronic Obstructive Pulmonary Disease diagnosisStatistical
      Analysis

      Descriptive analysis will be present as frequency and percentage if categorical variables and
      mean & standard deviation if the variable is continuous with normal distribution; if not, it
      will report as median and percentiles (25-75). The normality distribution will be evaluated
      through a Shapiro-Wilk test.

      At the beginning of the study, we will compare both groups to determine statistical
      significance differences. X2 will run in categorical variables and an independent t-study
      test in continuous variables with normal distribution, if not, U de Mann Whitney will be run.

      To identifying the differences between groups along with the study, repeated analysis of
      variance measures will be done if the variable has a normal distribution. Otherwise, Friedman
      tests will be made. McNemar will be made for categorical variables. Furthermore, changes
      between groups along the time at student will be made with a normal distribution; otherwise,
      Wilcoxon will be done.

      Alpha type error: it considered as a statistical significance a p<0.05

      Sample size A simple size space of 100 patients, 25 subjects per group will be included if
      prior consent is acquired, and they meet the inclusion criteria.

      Procedures Invitation to participate All the patients who complete the inclusion criteria
      will be invited to the protocol. They shall be informed about the study, the possible risks
      and benefits of the treatment, and the possibility of leaving the study at any moment if the
      patients want. Those who accept participated will be enrolled in a list and then randomized
      into different groups of treatment.

      Allocation to the treatment groups The allocation sequence will be generated in the site
      http://www.randomization.com; therefore, the patients will be assigned into one of the next
      groups: 1) control group 2)pulmonary rehabilitation 3) rehabilitation pulmonary group plus
      beta-hydroxy beta-methyl butyric (HMB) (4g) 4) pulmonary rehabilitation group plus Citrulline
      (4g). The cardiologist, nutritionist, the physic therapist, will be blinded to the
      assignation group treatments.

      Baseline evaluation During the first evaluation, the clinical stage will be assigned, and the
      next valuations will be made: pulmonary function, endothelial function, exercise tolerance,
      functional class, signs, and symptoms. anthropometric and body composition indicators by
      electric bio-impedance, biochemical test, dietetics, handgrip strength Following visits All
      the patients, no matter the group, will have a follow up for three months. In the beginning,
      6week later and finally at three months.

      Survival follow-up wil be after two years treatment initiation
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Supportive Care
masking: Triple (Care Provider, Investigator, Outcomes Assessor)
measure: Evaluate the effect of nutritional supplementation and pulmonary rehabilitation on the clinical status
time frame: Baseline, 6 weeks after treatment initiation, 12 weeks 6 weeks after treatment initiation
description: Change from baseline in functional class assessed by NYHA
measure: Evaluated the effect of nutritional supplementation and pulmonary rehabilitation over the skeletal muscle mass
time frame: Baseline, 6 weeks after treatment initiation, 12 weeks 6 weeks after treatment initiation
description: Change from baseline in the skeletal muscle mass assessed by bioelectrical impedance
measure: Evaluated the effect of nutritional supplementation and pulmonary rehabilitation over pulmonary function
time frame: Baseline, 6 weeks after treatment initiation, 12 weeks 6 weeks after treatment initiation
description: Change from baseline in pulmonary function assessed by spirometry test
measure: To evaluate the effect of pulmonary rehabilitation and supplementation over muscle function in COPD and HF patients
time frame: Baseline, 6 weeks after treatment initiation, 12 weeks 6 weeks after treatment initiation
description: Change from baseline in pulmonary function assessed by dinamometry test
measure: Evaluated the effect of nutritional supplementation and pulmonary rehabilitation over prognosis in COPD and HF patients
time frame: Two years after treatment initiation
description: survival follow-up
arm group label: Control group
arm group type: No Intervention
description: The subjects in this group will receive the usual care, which includes the non-pharmacology recommendations by the European Society of Cardiologists 2006 (1) and COPD guides for treatment (6), both founded in the sodium and liquids restriction.
arm group label: Pulmonary Rehabilitation Group
arm group type: Active Comparator
description: Patients in this group will receive pulmonary rehabilitation specified by rehabilitation doctors according to the needs and capacities of each individual, who will attend three times a week for three months.
arm group label: Pulmonary Rehabilitation Group plus HMB (4g)
arm group type: Experimental
description: Patients in this group will receive pulmonary rehabilitation specified by rehabilitation doctors according to the needs and capacities of each individual, who will attend three times a week for three months. Furthermore, they will receive 4g of citrulline supplementation.
arm group label: Pulmonary Rehabilitation Group plus citrulline (3g)
arm group type: Experimental
description: Patients in this group will receive pulmonary rehabilitation specified by the doctor specialized in rehabilitation according to the needs and capacities of each individual, who will attend three times a week for three months. Furthermore, they will receive 4g of citrulline supplementation.
intervention type: Dietary Supplement
intervention name: Nutritional supplementation and Pulmonary Rehabilitation
description: Nutritional supplementation (HMB 4g) or Nutritional supplementation (citrulline 3g) with Pulmonary Rehabilitation
arm group label: Pulmonary Rehabilitation Group
arm group label: Pulmonary Rehabilitation Group plus HMB (4g)
arm group label: Pulmonary Rehabilitation Group plus citrulline (3g)
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Leslie Verdeja-Vendrell, M.Sc.
role: Principal Investigator
affiliation: Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas"
last name: Dulce González-Islas, PhD
role: Study Director
affiliation: Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas"
last name: Arturo Orea-Tejeda, MD
role: Study Director
affiliation: Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas"
last name: Martha E Quintero-Martínez, B.Sc
role: Study Chair
affiliation: Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas"
last name: Ilse C Pérez-García, B.Sc
role: Study Chair
affiliation: Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas"
last name: Dulce González-Islas, PhD
phone: 5514364002
email: gzz.dulce@gmail.com
facility: 
status: Recruiting
contact: 
country: Mexico
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PMID: 19887495
citation: Nissen S, Sharp RL, Panton L, Vukovich M, Trappe S, Fuller JC Jr. beta-hydroxy-beta-methylbutyrate (HMB) supplementation in humans is safe and may decrease cardiovascular risk factors. J Nutr. 2000 Aug;130(8):1937-45. doi: 10.1093/jn/130.8.1937.
PMID: 10917905
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responsible party type: Principal Investigator
investigator affiliation: Instituto Nacional de Enfermedades Respiratorias
investigator full name: Dulce González Islas, PhD
investigator title: Researcher in Medical Sciences
mesh term: Heart Failure
sharing ipd: No